Asociality refers to the lack of motivation to engage in social interaction, or a preference for solitary activities. Asociality may be associated with avolition, but it can, moreover, be a manifestation of limited opportunities for social relationships. Developmental psychologists use the synonyms non-social, unsocial, and social uninterest. Asociality is distinct from, but not mutually exclusive to, anti-social behaviour. A degree of asociality is routinely observed in introverts, while extreme asociality is observed in people with a variety of clinical conditions.
Asociality is not necessarily perceived as a totally negative trait by society, since asociality has been used as a way to express dissent from prevailing ideas. It is seen as a desirable trait in several mystical and monastic traditions, notably in Hinduism, Jainism, Roman Catholicism, Eastern Orthodoxy, Buddhism and Sufism.
Introversion
Introversion is “the state of or tendency toward being wholly or predominantly concerned with and interested in one’s own mental life.” Introverted persons are considered the opposite of extraverts, who seem to thrive in social settings rather than being alone. An introvert may present as an individual preferring being alone or interacting with smaller groups over interaction with larger groups, writing over speaking, having fewer but more fulfilling friendships, and needing time for reflection. While not a measurable personality trait, some popular writers have characterised introverts as people whose energy tends to expand through reflection and dwindle during interaction.
In matters of the brain, researchers have found differences in anatomy between introverted and extraverted persons. Introverted people are found to experience a higher flow of blood to the frontal lobe than extraverts, which is the part of the brain that contributes to problem-solving, memory, and pre-emptive thought.
Social Anhedonia
Social anhedonia is found in both typical and extreme cases of asociality or personality disorders that feature social withdrawal. Social anhedonia is distinct from introversion and is frequently accompanied with alexithymia.
Many cases of social anhedonia are marked by extreme social withdrawal and the complete avoidance of social interaction. One research article studying the individual differences in social anhedonia discusses the negative aspects of this form of extreme or aberrant asociality. Some individuals with social anhedonia are at higher risk of developing schizophrenia and may have mental functioning that becomes poorer than the average
In Human Evolution and Anthropology
Scientific research suggests that asocial traits in human behaviour, personality, and cognition may have several useful evolutionary benefits. Traits of introversion and aloofness can protect an individual from impulsive and dangerous social situations because of reduced impulsivity and reward. Frequent voluntary seclusion stimulates creativity and can give the individual time to think, work, reflect, and see useful patterns more easily.
Research indicates the social and analytical functions of the brain function in a mutually exclusive way. With this in mind, researchers posit that people who devoted less time or interest to socialisation used the analytical part of the brain more frequently and thereby were often responsible for devising hunting strategies, creating tools, and spotting useful patterns in the environment in general for both their own safety and the safety of the group.
Imitation and social learning have been confirmed to be potentially limiting and maladaptive in animal and human populations. When social learning overrides personal experience (asocial learning), negative effects can be observed such as the inability to seek or pick the most efficient way to accomplish a task and a resulting inflexibility to changing environments. Individuals who are less receptible, motivated, and interested in sociability are likely less affected by or sensible to socially imitated information and faster to notice and react to changes in the environment, essentially holding onto their own observations in a rigid manner and, consequently, not imitating a maladaptive behaviour through social learning. These behaviours, including deficits in imitative behaviour, have been observed in individuals with autism spectrum disorders and introverts, and are correlated with the personality traits of neuroticism and disagreeableness.
The benefits of this behaviour for the individual and their kin caused it to be preserved in part of the human population. The usefulness for acute senses, novel discoveries, and critical analytical thought may have culminated in the preservation of the suspected genetic factors of autism and introversion itself due to their increased cognitive, sensorial, and analytical awareness.
In Psychopathology
Schizophrenia
In schizophrenia, asociality is one of the main five “negative symptoms”, with the others being avolition, anhedonia, reduced affect, and alogia. Due to a lack of desire to form relationships, social withdrawal is common in people with schizophrenia. People with schizophrenia may experience social deficits or dysfunction as a result of the disorder, leading to asocial behaviour. Frequent or ongoing delusions and hallucinations can deteriorate relationships and other social ties, isolating individuals with schizophrenia from reality and in some cases leading to homelessness. Even when treated with medication for the disorder, they may be unable to engage in social behaviours. These behaviours include things like maintaining conversations, accurately perceiving emotions in others, or functioning in crowded settings. There has been extensive research on the effective use of social skills training (SST) for the treatment of schizophrenia, in outpatient clinics as well as inpatient units. SST can be used to help patients with schizophrenia make better eye contact with other people, increase assertiveness, and improve their general conversational skills.
Personality Disorders
Avoidant Personality Disorder
Asociality is common amongst people with avoidant personality disorder (AvPD). They experience discomfort and feel inhibited in social situations, being overwhelmed by feelings of inadequacy. Such people remain consistently fearful of social rejection, choosing to avoid social engagements as they do not want to give people the opportunity to reject (or possibly, accept) them. Though they inherently crave a sense of belonging, their fear of criticism and rejection leads people with AvPD to actively avoid occasions that require social interaction, leading to extremely asocial tendencies; as a result, these individuals often have difficulty cultivating and preserving close relationships.
People with AvPD may also display social phobia, the difference being that social phobia is the fear of social circumstances whereas AvPD is better described as an aversion to intimacy in relationships.
Schizoid Personality Disorder
Schizoid personality disorder (SzPD) is characterised by a lack of interest in social relationships, a tendency towards a solitary lifestyle, secretiveness, emotional coldness, and apathy. Affected individuals may simultaneously demonstrate a rich and elaborate but exclusively internal fantasy world.
It is not the same as schizophrenia, although they share such similar characteristics as detachment and blunted affect. There is, moreover, increased prevalence of the disorder in families with schizophrenia.
Schizotypal Personality Disorder
Schizotypal personality disorder is characterized by a need for social isolation, anxiety in social situations, odd behaviour and thinking, and often unconventional beliefs. People with this disorder feel extreme discomfort with maintaining close relationships with people, and therefore they often do not. People who have this disorder may display peculiar manners of talking and dressing and often have difficulty in forming relationships. In some cases, they may react oddly in conversations, not respond, or talk to themselves.
Autism
Autistic people may display profoundly asocial tendencies, due to differences in how autistic and allistic (non-autistic) people communicate. These different communication styles can cause mutual friction between the two neurotypes, known as the double empathy problem. Autistic people tend to express emotions differently and less intensely than allistic people, and often do not pick up on allistic social cues or linguistic pragmatics (including eye contact, facial expressions, tone of voice, body language, and implicatures) used to convey emotions and hints.
Connecting with others is important to overall health. An increased difficulty in accurately reading social cues by others can affect this desire for people with autism. The risk of adverse social experiences is high for those with autism, and so they may prefer to be avoidant in social situations rather than experience anxiety over social performance. Social deficits in people with autism is directly correlated with the increased prevalence of social anxiety in this community. As they are in a steep minority, there is risk of not having access to like-minded peers in their community, which can lead them to withdrawal and social isolation.
Mood Disorders
Depression
Asociality can be observed in individuals with major depressive disorder or dysthymia, as individuals lose interest in everyday activities and hobbies they used to enjoy, this may include social activities, resulting in social withdrawal and withdrawal tendencies.
SST can be adapted to the treatment of depression with a focus on assertiveness training. Depressed patients often benefit from learning to set limits with others, to obtain satisfaction for their own needs, and to feel more self-confident in social interactions. Research suggests that patients who are depressed because they tend to withdraw from others can benefit from SST by learning to increase positive social interactions with others instead of withdrawing from social interactions.
Social Anxiety Disorder
Asocial behaviour is observed in people with social anxiety disorder (SAD), who experience perpetual and irrational fears of humiliating themselves in social situations. They often have panic attacks and severe anxiety as a result, which can occasionally lead to agoraphobia. The disorder is common in children and young adults, diagnosed on average between the ages of 8 and 15. If left untreated, people with SAD exhibit asocial behaviour into adulthood, avoiding social interactions and career choices that require interpersonal skills. SST can help people with social phobia or shyness to improve their communication and social skills so that they will be able to mingle with others or go to job interviews with greater ease and self-confidence.
Traumatic Brain Injury
Traumatic brain injuries (TBI) can also lead to asociality and social withdrawal.
Management
Treatments
Social Skills Training
Social skills training (SST) is an effective technique aimed towards anyone with “difficulty relating to others,” a common symptom of shyness, marital and family conflicts, or developmental disabilities; as well as of many mental and neurological disorders including adjustment disorders, anxiety disorders, attention-deficit/hyperactivity disorder, social phobia, alcohol dependence, depression, bipolar disorder, schizophrenia, avoidant personality disorder, paranoid personality disorder, obsessive-compulsive disorder, and schizotypal personality disorder.
Fortunately for people who display difficulty relating to others, social skills can be learned, as they are not simply inherent to an individual’s personality or disposition. Therefore, there is hope for anyone who wishes to improve their social skills, including those with psychosocial or neurological disorders. Nonetheless, it is important to note that asociality may still be considered neither a character flaw nor an inherently negative trait.
SST includes improving eye contact, speech duration, frequency of requests, and the use of gestures, as well as decreasing automatic compliance to the requests of others. SST has been shown to improve levels of assertiveness (positive and negative) in both men and women.
Additionally, SST can focus on receiving skills (e.g. accurately perceiving problem situations), processing skills (e.g. considering several response alternatives), and sending skills (delivering appropriate verbal and non-verbal responses).
Metacognitive Interpersonal Therapy
Metacognitive interpersonal therapy is a method of treating and improving the social skills of people with personality disorders that are associated with asociality. Through metacognitive interpersonal therapy, clinicians seek to improve their patients’ metacognition, meaning the ability to recognise and read the mental states of themselves. The therapy differs from SST in that the patient is trained to identify their own thoughts and feelings as a means of recognising similar emotions in others. Metacognitive interpersonal therapy has been shown to improve interpersonal and decision-making skills by encouraging awareness of suppressed inner states, which enables patients to better relate to other people in social environments.
The therapy is often used to treat patients with two or more co-occurring personality disorders, commonly including obsessive-compulsive and avoidant behaviours.
Coping Mechanisms
In order to cope with asocial behaviour, many individuals, especially those with avoidant personality disorder, develop an inner world of fantasy and imagination to entertain themselves when feeling rejected by peers. Asocial people may frequently imagine themselves in situations where they are accepted by others or have succeeded at an activity. Additionally, they may have fantasies relating to memories of early childhood and close family members.
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The efficacy of sertraline for depression is similar to that of other antidepressants, and the differences are mostly confined to side effects. Sertraline is better tolerated than the older tricyclic antidepressants, and it may work better than fluoxetine for some subtypes of depression. Sertraline is effective for panic disorder, social anxiety disorder, generalised anxiety disorder (GAD), and obsessive-compulsive disorder (OCD). However, for OCD, cognitive behavioural therapy (CBT), particularly in combination with sertraline, is a better treatment. Although approved for post-traumatic stress disorder, sertraline leads to only modest improvement in this condition. Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.
Sertraline shares the common side effects and contraindications of other SSRIs, with high rates of nausea, diarrhoea, insomnia, and sexual side effects, but it appears not to lead to much weight gain, and its effects on cognitive performance are mild. Similar to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidal thoughts and behaviour in people under the age of 25. It should not be used together with MAO inhibitor medication: this combination causes serotonin syndrome. Sertraline taken during pregnancy is associated with a significant increase in congenital heart defects in newborns.
Sertraline was invented and developed by scientists at Pfizer and approved for medical use in the United States in 1991. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2016, sertraline was the most commonly prescribed psychiatric medication in the US and in 2019, it was the twelfth most commonly prescribed medication in the US, with over 37 million prescriptions.
Brief History
The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds, including lometraline, based on the structures of the neuroleptics thiothixene and pinoxepin. Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogues was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioural scientist Albert Weissman. The most potent and selective (+)-isomer was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type – in that sense their inquiry was not “very goal driven”, and the discovery of the sertraline molecule was serendipitous. According to Welch, they worked outside the mainstream at Pfizer, and even “did not have a formal project team”. The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.
Sertraline was approved by the US Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. During the discussion, Paul Leber, the director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a “tough decision”, since the treatment effect on outpatients with depression had been “modest to minimal”. Other experts emphasized that the drug’s effect on inpatients had not differed from placebo and criticised poor design of the clinical trials by Pfizer. For example, 40% of participants dropped out of the trials, significantly decreasing their validity.
Until 2002, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe OCD. In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18. However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents. In 2005, the FDA added a boxed warning concerning paediatric suicidal behaviour to all antidepressants, including sertraline. In 2007, labelling was again changed to add a warning regarding suicidal behaviour in young adults ages 18 to 24.
Medical Uses
Sertraline has been approved for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder, and social anxiety disorder (SAD). Sertraline is not approved for use in children except for those with OCD.
Depression
Multiple controlled clinical trials established efficacy of sertraline for the treatment of depression. Sertraline is also an effective antidepressant in the routine clinical practice. Continued treatment with sertraline prevents both a relapse of the current depressive episode and future episodes (recurrence of depression).
In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia, a more chronic variety of depression, and comparable to imipramine in that respect. Sertraline also improves the depression of dysthymic patients to a greater degree than psychotherapy.
Limited paediatric data also demonstrates reduction in depressive symptoms in the paediatric population though remains a second line therapy after fluoxetine.
Comparison with Other Antidepressants
In general, sertraline efficacy is similar to that of other antidepressants. For example, a meta-analysis of 12 new-generation antidepressants showed that sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with depression. Comparative clinical trials demonstrated that sertraline is similar in efficacy against depression to moclobemide, nefazodone, escitalopram, bupropion, citalopram, fluvoxamine, paroxetine, venlafaxine, and mirtazapine. Sertraline may be more efficacious for the treatment of depression in the acute phase (first 4 weeks) than fluoxetine.
There are differences between sertraline and some other antidepressants in their efficacy in the treatment of different subtypes of depression and in their adverse effects. For severe depression, sertraline is as good as clomipramine but is better tolerated. Sertraline appears to work better in melancholic depression than fluoxetine, paroxetine, and mianserin and is similar to the tricyclic antidepressants such as amitriptyline and clomipramine. In the treatment of depression accompanied by OCD, sertraline performs significantly better than desipramine on the measures of both OCD and depression. Sertraline is equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it is better tolerated. Compared with amitriptyline, sertraline offered a greater overall improvement in quality of life of depressed patients.
Depression in Elderly
Sertraline used for the treatment of depression in elderly (older than 60) patients is superior to placebo and comparable to another SSRI fluoxetine, and tricyclic antidepressants (TCAs) amitriptyline, nortriptyline and imipramine. Sertraline has much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurs more frequently with sertraline. In addition, sertraline appears to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup. Accordingly, a meta-analysis of antidepressants in older adults found that sertraline, paroxetine and duloxetine were better than placebo. On the other hand, in a 2003 trial the effect size was modest, and there was no improvement in quality of life as compared to placebo. With depression in dementia, there is no benefit of sertraline treatment compared to either placebo or mirtazapine.
Obsessive-Compulsive Disorder
Sertraline is effective for the treatment of OCD in adults and children. It was better tolerated and, based on intention-to-treat analysis, performed better than the gold standard of OCD treatment clomipramine. Continuing sertraline treatment helps prevent relapses of OCD with long-term data supporting its use for up to 24 months. It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression. The onset of action is also slower for OCD than for depression. The treatment recommendation is to start treatment with a half of maximal recommended dose for at least two months. After that, the dose can be raised to the maximal recommended in the cases of unsatisfactory response.
CBT alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments.
Panic Disorder
Sertraline is superior to placebo for the treatment of panic disorder. The response rate was independent of the dose. In addition to decreasing the frequency of panic attacks by about 80% (vs. 45% for placebo) and decreasing general anxiety, sertraline resulted in improvement of quality of life on most parameters. The patients rated as “improved” on sertraline reported better quality of life than the ones who “improved” on placebo. The authors of the study argued that the improvement achieved with sertraline is different and of a better quality than the improvement achieved with placebo. Sertraline is equally effective for men and women, and for patients with or without agoraphobia. Previous unsuccessful treatment with benzodiazepines does not diminish its efficacy. However, the response rate was lower for the patients with more severe panic. Starting treatment simultaneously with sertraline and clonazepam, with subsequent gradual discontinuation of clonazepam, may accelerate the response.
Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine or imipramine. While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine, imipramine, clonazepam, alprazolam, and fluvoxamine) indicates approximate equivalence of these medications.
Other Anxiety Disorders
Sertraline has been successfully used for the treatment of social anxiety disorder. All three major domains of the disorder (fear, avoidance, and physiological symptoms) respond to sertraline. Maintenance treatment, after the response is achieved, prevents the return of the symptoms. The improvement is greater among the patients with later, adult onset of the disorder. In a comparison trial, sertraline was superior to exposure therapy, but patients treated with the psychological intervention continued to improve during a year-long follow-up, while those treated with sertraline deteriorated after treatment termination. The combination of sertraline and CBT appears to be more effective in children and young people than either treatment alone.
Sertraline has not been approved for the treatment of generalised anxiety disorder; however, several guidelines recommend it as a first-line medication referring to good quality controlled clinical trials.
Premenstrual Dysphoric Disorder
Sertraline is effective in alleviating the symptoms of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome. Significant improvement was observed in 50-60% of cases treated with sertraline vs. 20-30% of cases on placebo. The improvement began during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement was reflected in better family functioning, social activity and general quality of life. Work functioning and physical symptoms, such as swelling, bloating and breast tenderness, were less responsive to sertraline. Taking sertraline only during the luteal phase, that is, the 12-14 days before menses, was shown to work as well as continuous treatment. Continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50-100 mg) is also effective.
Other Indications
Sertraline is approved for the treatment of post-traumatic stress disorder (PTSD). National Institute of Clinical Excellence recommends it for patients who prefer drug treatment to a psychological one. Other guidelines also suggest sertraline as a first-line option for pharmacological therapy. When necessary, long-term pharmacotherapy can be beneficial. There are both negative and positive clinical trial results for sertraline, which may be explained by the types of psychological traumas, symptoms, and comorbidities included in the various studies. Positive results were obtained in trials that included predominantly women (75%) with a majority (60%) having physical or sexual assault as the traumatic event. Contrary to the above suggestions, a meta-analysis of sertraline clinical trials for PTSD found it to be not significantly better than placebo. Another meta-analysis relegated sertraline to the second line, proposing trauma focused psychotherapy as a first-line intervention. The authors noted that Pfizer had declined to submit the results of a negative trial for the inclusion into the meta-analysis making the results unreliable.
Sertraline when taken daily can be useful for the treatment of premature ejaculation. A disadvantage of sertraline is that it requires continuous daily treatment to delay ejaculation significantly.
A 2019 systematic review suggested that sertraline may be a good way to control anger, irritability and hostility in depressed patients and patients with other comorbidities.
Contraindications
Sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide. Sertraline concentrate contains alcohol and is therefore contraindicated with disulfiram. The prescribing information recommends that treatment of the elderly and patients with liver impairment “must be approached with caution”. Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose.
Side Effects
Nausea, ejaculation failure, insomnia, diarrhoea, dry mouth, somnolence, dizziness, tremor, headache, excessive sweating, fatigue, and decreased libido are the common adverse effects associated with sertraline with the greatest difference from placebo. Those that most often resulted in interruption of the treatment are nausea, diarrhoea and insomnia. The incidence of diarrhoea is higher with sertraline – especially when prescribed at higher doses – in comparison with other SSRIs.
Over more than six months of sertraline therapy for depression, people showed a nonsignificant weight increase of 0.1%. Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg). Although the difference did not reach statistical significance, the average weight gain was lower for fluoxetine (1%) but higher for citalopram, fluvoxamine and paroxetine (2.5%). Of the sertraline group, 4.5% gained a large amount of weight (defined as more than 7% gain). This result compares favourably with placebo, where, according to the literature, 3-6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group.
Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination. In spite of lower subjective rating, that is, feeling that they performed worse, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 years as compared to healthy controls. In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention and alertness stayed unchanged. Divided attention was improved and verbal memory under interference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance. The unique effect of sertraline on dopaminergic neurotransmission may be related to these effects on cognition and vigilance.
Sertraline has a low level of exposure of an infant through the breast milk and is recommended as the preferred option for the antidepressant therapy of breast-feeding mothers. There is 29-42% increase in congenital heart defects among children whose mothers were prescribed sertraline during pregnancy, with sertraline use in the first trimester associated with 2.7-fold increase in septal heart defects.
Abrupt interruption of sertraline treatment may result in withdrawal or discontinuation syndrome. Dizziness, insomnia, anxiety, agitation, and irritability are its common symptoms. It typically occurs within a few days from drug discontinuation and lasts a few weeks. The withdrawal symptoms for sertraline are less severe and frequent than for paroxetine, and more frequent than for fluoxetine. In most cases symptoms are mild, short-lived, and resolve without treatment. More severe cases are often successfully treated by temporary reintroduction of the drug with a slower tapering off rate.
Sertraline and SSRI antidepressants in general may be associated with bruxism and other movement disorders. Sertraline appears to be associated with microscopic colitis, a rare condition of unknown aetiology.
Sexual
Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal disorder, erectile dysfunction and difficulty achieving orgasm. While nefazodone and bupropion do not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties versus 18% before the treatment. Sexual arousal disorder, defined as “inadequate lubrication and swelling for women and erectile difficulties for men”, occurred in 12% of people on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline sometimes counteracted these side effects, so that sexual desire and overall satisfaction with sex stayed the same as before the sertraline treatment. However, under the action of placebo the desire and satisfaction slightly improved. Some people continue experiencing sexual side effects after they stop taking SSRIs.
Suicide
The US Food and Drug Administration (FDA) requires all antidepressants, including sertraline, to carry a boxed warning stating that antidepressants increase the risk of suicide in persons younger than 25 years. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 100% increase of suicidal thoughts and behaviour in children and adolescents, and a 50% increase – in the 18-24 age group.
Suicidal ideation and behaviour in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidal behaviour with a marginal statistical significance by 37% or 50% depending on the statistical technique used. The authors of the FDA analysis note that “given the large number of comparisons made in this review, chance is a very plausible explanation for this difference”. The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behaviour. Similarly, the analysis conducted by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo.
Overdose
Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalised patients or to aid in the medicolegal investigation of fatalities. As with most other SSRIs its toxicity in overdose is considered relatively low.
Interactions
As with other SSRIs, sertraline may increase the risk of bleeding with NSAIDs (non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, mefenamic acid), antiplatelet drugs, anticoagulants, omega-3 fatty acids, vitamin E, and garlic supplements due to sertraline’s inhibitory effects on platelet aggregation via blocking serotonin transporters on platelets. Sertraline, in particular, may potentially diminish the efficacy of levothyroxine.
Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro. Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol. This effect is dose-dependent; for example, co-administration with 50 mg of sertraline resulted in 20% greater exposure to desipramine, while 150 mg of sertraline led to a 70% increase. In a placebo-controlled study, the concomitant administration of sertraline and methadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.
Sertraline had a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which are CYP2C9 or CYP2C19 substrates; the clinical relevance of this effect was unclear. As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam, carbamazepine, clonazepam, and terfenadine; neither did it affect metabolism of the CYP1A2 substrate clozapine.
Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolised in the liver. Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy, and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.
CYP2C19 inhibitor esomeprazole increased sertraline concentrations in blood plasma by approximately 40%.
Clinical reports indicate that interaction between sertraline and the MAOIs isocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.
Sertraline may interact with grapefruit juice.
Pharmacology
Pharmacodynamics
Sertraline is a selective serotonin reuptake inhibitor (SSRI). By binding serotonin transporter (SERT) it inhibits neuronal reuptake of serotonin and potentiates serotonergic activity in the central nervous system. Over time, this leads to a downregulation of pre-synaptic 5-HT1A receptors, which is associated with an improvement in passive stress tolerance, and delayed downstream increase in expression of brain-derived neurotrophic factor (BDNF), which may contribute to a reduction in negative affective biases. It does not significantly affect norepinephrine transporter (NET), serotonin, dopamine, adrenergic, histamine, acetylcholine, GABA or benzodiazepine receptors.
Sertraline also shows relatively high activity as an inhibitor of the dopamine transporter (DAT) and antagonist of the sigma σ1 receptor (but not the σ2 receptor). However, sertraline affinity for its main target (SERT) is much greater than its affinity for σ1 receptor and DAT. Although there could be a role for the σ1 receptor in the pharmacology of sertraline, the significance of this receptor in its actions is unclear. Similarly, the clinical relevance of sertraline’s blockade of the dopamine transporter is uncertain.
Pharmacokinetics
Absorption
Following a single oral dose of sertraline, mean peak blood levels of sertraline occur between 4.5 and 8.4 hours. Bioavailability is likely linear and dose-proportional over a dose range of 150 to 200 mg. Concomitant intake of sertraline with food slightly increases sertraline peak levels and total exposure. There is an approximate 2-fold accumulation of sertraline with continuous administration and steady-state levels are reached within one week.
Distribution
Sertraline is highly plasma protein bound (98.5%) across a concentration range of 20 to 500 ng/mL. Despite the high plasma protein binding, sertraline and its metabolite desmethylsertraline at respective tested concentrations of 300 ng/mL and 200 ng/mL were found not to interfere with the plasma protein binding of warfarin and propranolol, two other highly plasma protein-bound drugs.
Metabolism
Sertraline is subject to extensive first-pass metabolism, as indicated by a small study of radiolabelled sertraline in which less than 5% of plasma radioactivity was unchanged sertraline in two males. The principal metabolic pathway for sertraline is N-demethylation into desmethylsertraline (N-desmethylsertraline) mainly by CYP2B6. Reduction, hydroxylation, and glucuronide conjugation of both sertraline and desmethylsertraline also occur. Desmethylsertraline, while pharmacologically active, is substantially (50-fold) weaker than sertraline as a serotonin reuptake inhibitor and its influence on the clinical effects of sertraline is thought to be negligible. Based on in vitro studies, sertraline is metabolized by multiple cytochrome 450 isoforms; however, it appears that in the human body CYP2C19 plays the most important role, followed by CYP2B6. In addition to the cytochrome P450 system, sertraline can be oxidatively deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo.
Elimination
The elimination half-life of sertraline is on average 26 hours, with a range of 13 to 45 hours. The half-life of sertraline is longer in women (32 hours) than in men (22 hours), which leads to 1.5-fold higher exposure to sertraline in women compared to men. The elimination half-life of desmethylsertraline is 62 to 104 hours.
In a small study of two males, sertraline was excreted to similar degrees in urine and faeces (40 to 45% each within 9 days). Unchanged sertraline was not detectable in urine, whereas 12 to 14% unchanged sertraline was present in faeces.
Pharmacogenomics
CYP2C19 and CYP2B6 are thought to be the key cytochrome P450 enzymes involved in the metabolism of sertraline. Relative to CYP2C19 normal (extensive) metabolisers, poor metabolisers have 2.7-fold higher levels of sertraline and intermediate metabolisers have 1.4-fold higher levels. In contrast, CYP2B6 poor metabolisers have 1.6-fold higher levels of sertraline and intermediate metabolisers have 1.2-fold higher levels.
Society and Culture
Generic Availability
The US patent for Zoloft expired in 2006, and sertraline is available in generic form and is marketed under many brand names worldwide.
In May 2020, the FDA placed Zoloft on the list of drugs currently facing a shortage.
Other Uses
Lass-Flörl et al., 2003 finds sertraline significantly inhibits phospholipase B in the fungal genus Candida, reducing virulence. It is also a very effective leishmanicide. Specifically, Palit & Ali 2008 find that sertraline kills almost all promastigotes of Leishmania donovani.
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Metacognition is an awareness of one’s thought processes and an understanding of the patterns behind them. The term comes from the root word meta, meaning “beyond”, or “on top of”. Metacognition can take many forms, such as reflecting on one’s ways of thinking and knowing when and how to use particular strategies for problem-solving. There are generally two components of metacognition:
Knowledge about cognition; and
Regulation of cognition.
Metamemory, defined as knowing about memory and mnemonic strategies, is an especially important form of metacognition. Academic research on metacognitive processing across cultures is in the early stages, but there are indications that further work may provide better outcomes in cross-cultural learning between teachers and students.
Writings on metacognition date back at least as far as two works by the Greek philosopher Aristotle (384-322 BC): On the Soul and the Parva Naturalia.
Definitions
This higher-level cognition was given the label metacognition by American developmental psychologist John H. Flavell (1976).
The term metacognition literally means ‘above cognition’, and is used to indicate cognition about cognition, or more informally, thinking about thinking. Flavell defined metacognition as knowledge about cognition and control of cognition. For example, a person is engaging in metacognition if they notice that they are having more trouble learning A than B, or if it strikes them that they should double-check C before accepting it as fact. J.H. Flavell (1976, p. 232). Andreas Demetriou’s theory (one of the neo-Piagetian theories of cognitive development) used the term hyper-cognition to refer to self-monitoring, self-representation, and self-regulation processes, which are regarded as integral components of the human mind. Moreover, with his colleagues, he showed that these processes participate in general intelligence, together with processing efficiency and reasoning, which have traditionally been considered to compose fluid intelligence.
Metacognition also involves thinking about one’s own thinking process such as study skills, memory capabilities, and the ability to monitor learning. This concept needs to be explicitly taught along with content instruction.
Metacognitive knowledge is about one’s own cognitive processes and the understanding of how to regulate those processes to maximize learning.
Some types of metacognitive knowledge would include:
Type
Outline
Content Knowledge (Declarative Knowledge)
Content knowledge (declarative knowledge) which is understanding one’s own capabilities, such as a student evaluating their own knowledge of a subject in a class. It is notable that not all metacognition is accurate. Studies have shown that students often mistake lack of effort with understanding in evaluating themselves and their overall knowledge of a concept.[10] Also, greater confidence in having performed well is associated with less accurate metacognitive judgment of the performance.
Task Knowledge (Procedural Knowledge)
Task knowledge (procedural knowledge), which is how one perceives the difficulty of a task which is the content, length, and the type of assignment. The study mentioned in Content knowledge also deals with a person’s ability to evaluate the difficulty of a task related to their overall performance on the task. Again, the accuracy of this knowledge was skewed as students who thought their way was better/easier also seemed to perform worse on evaluations, while students who were rigorously and continually evaluated reported to not be as confident but still did better on initial evaluations.
Strategic Knowledge (Conditional Knowledge)
Strategic knowledge (conditional knowledge) which is one’s own capability for using strategies to learn information. Young children are not particularly good at this; it is not until students are in upper elementary school that they begin to develop an understanding of effective strategies.
Metacognition is a general term encompassing the study of memory-monitoring and self-regulation, meta-reasoning, consciousness/awareness and autonoetic consciousness/self-awareness. In practice these capacities are used to regulate one’s own cognition, to maximise one’s potential to think, learn and to the evaluation of proper ethical/moral rules. It can also lead to a reduction in response time for a given situation as a result of heightened awareness, and potentially reduce the time to complete problems or tasks.
In the domain of experimental psychology, an influential distinction in metacognition (proposed by T.O. Nelson & L. Narens) is between Monitoring – making judgements about the strength of one’s memories – and Control – using those judgments to guide behaviour (in particular, to guide study choices). Dunlosky, Serra, and Baker (2007) covered this distinction in a review of metamemory research that focused on how findings from this domain can be applied to other areas of applied research.
In the domain of cognitive neuroscience, metacognitive monitoring and control has been viewed as a function of the prefrontal cortex, which receives (monitors) sensory signals from other cortical regions and implements control using feedback loops (see chapters by Schwartz & Bacon and Shimamura, in Dunlosky & Bjork, 2008).
Metacognition is studied in the domain of artificial intelligence and modelling. Therefore, it is the domain of interest of emergent systemics.
Components
Metacognition is classified into three components:
Metacognitive knowledge (also called metacognitive awareness) is what individuals know about themselves and others as cognitive processors.
Metacognitive regulation is the regulation of cognition and learning experiences through a set of activities that help people control their learning.
Metacognitive experiences are those experiences that have something to do with the current, on-going cognitive endeavour.
Metacognition refers to a level of thinking that involves active control over the process of thinking that is used in learning situations. Planning the way to approach a learning task, monitoring comprehension, and evaluating the progress towards the completion of a task: these are skills that are metacognitive in their nature.
Metacognition includes at least three different types of metacognitive awareness when considering metacognitive knowledge:
Declarative knowledge: refers to knowledge about oneself as a learner and about what factors can influence one’s performance. Declarative knowledge can also be referred to as “world knowledge”.
Procedural knowledge: refers to knowledge about doing things. This type of knowledge is displayed as heuristics and strategies. A high degree of procedural knowledge can allow individuals to perform tasks more automatically. This is achieved through a large variety of strategies that can be accessed more efficiently.
Conditional knowledge: refers to knowing when and why to use declarative and procedural knowledge. It allows students to allocate their resources when using strategies. This in turn allows the strategies to become more effective.
Similar to metacognitive knowledge, metacognitive regulation or “regulation of cognition” contains three skills that are essential.
Planning: refers to the appropriate selection of strategies and the correct allocation of resources that affect task performance.
Monitoring: refers to one’s awareness of comprehension and task performance
Evaluating: refers to appraising the final product of a task and the efficiency at which the task was performed. This can include re-evaluating strategies that were used.
Similarly, maintaining motivation to see a task to completion is also a metacognitive skill. The ability to become aware of distracting stimuli – both internal and external – and sustain effort over time also involves metacognitive or executive functions. The theory that metacognition has a critical role to play in successful learning means it is important that it be demonstrated by both students and teachers.
Students who underwent metacognitive training including pretesting, self evaluation, and creating study plans performed better on exams. They are self-regulated learners who utilise the “right tool for the job” and modify learning strategies and skills based on their awareness of effectiveness. Individuals with a high level of metacognitive knowledge and skill identify blocks to learning as early as possible and change “tools” or strategies to ensure goal attainment. Swanson (1990) found that metacognitive knowledge can compensate for IQ and lack of prior knowledge when comparing fifth and sixth grade students’ problem solving. Students with a high-metacognition were reported to have used fewer strategies, but solved problems more effectively than low-metacognition students, regardless of IQ or prior knowledge. In one study examining students who send text messages during college lectures, it was suggested that students with higher metacognitive abilities were less likely than other students to have their learning affected by using a mobile phone in class.
The fundamental cause of the trouble is that in the modern world the stupid are cocksure while the intelligent are full of doubt. Bertrand Russell.
Metacognologists are aware of their own strengths and weaknesses, the nature of the task at hand, and available “tools” or skills. A broader repertoire of “tools” also assists in goal attainment. When “tools” are general, generic, and context independent, they are more likely to be useful in different types of learning situations.
Another distinction in metacognition is executive management and strategic knowledge. Executive management processes involve planning, monitoring, evaluating and revising one’s own thinking processes and products. Strategic knowledge involves knowing what (factual or declarative knowledge), knowing when and why (conditional or contextual knowledge) and knowing how (procedural or methodological knowledge). Both executive management and strategic knowledge metacognition are needed to self-regulate one’s own thinking and learning.
Finally, there is no distinction between domain-general and domain-specific metacognitive skills. This means that metacognitive skills are domain-general in nature and there are no specific skills for certain subject areas. The metacognitive skills that are used to review an essay are the same as those that are used to verify an answer to a math question.
Social Metacognition
Although metacognition has thus far been discussed in relation to the self, recent research in the field has suggested that this view is overly restrictive. Instead, it is argued that metacognition research should also include beliefs about others’ mental processes, the influence of culture on those beliefs, and on beliefs about ourselves. This “expansionist view” proposes that it is impossible to fully understand metacognition without considering the situational norms and cultural expectations that influence those same conceptions. This combination of social psychology and metacognition is referred to as social metacognition.
Social metacognition can include ideas and perceptions that relate to social cognition. Additionally, social metacognition can include judging the cognition of others, such as judging the perceptions and emotional states of others. This is in part because the process of judging others is similar to judging the self. However, individuals have less information about the people they are judging; therefore, judging others tends to be more inaccurate. Having similar cognitions can buffer against this inaccuracy and can be helpful for teams or organisations, as well as interpersonal relationships.
Social Metacognition and the Self Concept
An example of the interaction between social metacognition and self-concept can be found in examining implicit theories about the self. Implicit theories can cover a wide range of constructs about how the self operates, but two are especially relevant here; entity theory and incrementalist theory. Entity theory proposes that an individual’s self-attributes and abilities are fixed and stable, while incrementalist theory proposes that these same constructs can be changed through effort and experience. Entity theorists are susceptible to learned helplessness because they may feel that circumstances are outside their control (i.e. there is nothing that could have been done to make things better), thus they may give up easily. Incremental theorists react differently when faced with failure: they desire to master challenges, and therefore adopt a mastery-oriented pattern. They immediately began to consider various ways that they could approach the task differently, and they increase their efforts. Cultural beliefs can act on this as well. For example, a person who has accepted a cultural belief that memory loss is an unavoidable consequence of old age may avoid cognitively demanding tasks as they age, thus accelerating cognitive decline. Similarly, a woman who is aware of the stereotype that purports that women are not good at mathematics may perform worse on tests of mathematical ability or avoid mathematics altogether. These examples demonstrate that the metacognitive beliefs people hold about the self – which may be socially or culturally transmitted – can have important effects on persistence, performance, and motivation.
Attitudes as a Function of Social Metacognition
The way that individuals think about attitude greatly affects the way that they behave. Metacognitions about attitudes influence how individuals act, and especially how they interact with others.
Some metacognitive characteristics of attitudes include importance, certainty, and perceived knowledge, and they influence behaviour in different ways. Attitude importance is the strongest predictor of behaviour and can predict information seeking behaviours in individuals. Attitude importance is also more likely to influence behaviour than certainty of the attitude. When considering a social behaviour like voting a person may hold high importance but low certainty. This means that they will likely vote, even if they are unsure whom to vote for. Meanwhile, a person who is very certain of who they want to vote for, may not actually vote if it is of low importance to them. This also applies to interpersonal relationships. A person might hold a lot of favourable knowledge about their family, but they may not maintain close relations with their family if it is of low importance.
Metacognitive characteristics of attitudes may be key to understanding how attitudes change. Research shows that the frequency of positive or negative thoughts is the biggest factor in attitude change. A person may believe that climate change is occurring but have negative thoughts toward it such as “If I accept the responsibilities of climate change, I must change my lifestyle”. These individuals would not likely change their behaviour compared to someone that thinks positively about the same issue such as “By using less electricity, I will be helping the planet”.
Another way to increase the likelihood of behaviour change is by influencing the source of the attitude. An individual’s personal thoughts and ideas have a much greater impact on the attitude compared to ideas of others. Therefore, when people view lifestyle changes as coming from themselves, the effects are more powerful than if the changes were coming from a friend or family member. These thoughts can be re-framed in a way that emphasizes personal importance, such as “I want to stop smoking because it is important to me” rather than “quitting smoking is important to my family”. More research needs to be conducted on culture differences and importance of group ideology, which may alter these results.
Social Metacognition and Stereotypes
People have secondary cognitions about the appropriateness, justifiability, and social judgability of their own stereotypic beliefs. People know that it is typically unacceptable to make stereotypical judgments and make conscious efforts not to do so. Subtle social cues can influence these conscious efforts. For example, when given a false sense of confidence about their ability to judge others, people will return to relying on social stereotypes. Cultural backgrounds influence social metacognitive assumptions, including stereotypes. For example, cultures without the stereotype that memory declines with old age display no age differences in memory performance.
When it comes to making judgements about other people, implicit theories about the stability versus malleability of human characteristics predict differences in social stereotyping as well. Holding an entity theory of traits increases the tendency for people to see similarity among group members and utilise stereotyped judgments. For example, compared to those holding incremental beliefs, people who hold entity beliefs of traits use more stereotypical trait judgements of ethnic and occupational groups as well as form more extreme trait judgments of new groups. When an individual’s assumptions about a group combine with their implicit theories, more stereotypical judgements may be formed. Stereotypes that one believes others hold about them are called metastereotypes.
Animal Metacognition
In Nonhuman Primates
Chimpanzees
Beran, Smith, and Perdue (2013) found that chimpanzees showed metacognitive monitoring in the information-seeking task. In their studies, three language-trained chimpanzees were asked to use the keyboard to name the food item in order to get the food. The food in the container was either visible to them or they had to move toward the container to see its contents. Studies shown that chimpanzees were more often to check what was in the container first if the food in the container was hidden. But when the food was visible to them, the chimpanzees were more likely to directly approach the keyboard and reported the identity of the food without looking again in the container. Their results suggested that chimpanzees know what they have seen and show effective information-seeking behaviour when information is incomplete.
Rhesus Macaques (Macaca Mulatta)
Morgan et al. (2014) investigated whether rhesus macaques can make both retrospective and prospective metacognitive judgements on the same memory task. Risk choices were introduced to assess the monkey’s confidence about their memories. Two male rhesus monkeys (Macaca mulatta) were trained in a computerised token economy task first in which they can accumulate tokens to exchange food rewards. Monkeys were presented with multiple images of common objects simultaneously and then a moving border appearing on the screen indicating the target. Immediately following the presentation, the target images and some distractors were shown in the test. During the training phase, monkeys received immediate feedback after they made responses. They can earn two tokens if they make correct choices but lost two tokens if they were wrong.
In Experiment 1, the confidence rating was introduced after they completed their responses in order to test the retrospective metamemory judgements. After each response, a high-risk and a low-risk choice were provided to the monkeys. They could earn one token regardless of their accuracy if they choose the low-risk option. When they chose high-risk, they were rewarded with three tokens if their memory response was correct on that trial but lost three tokens if they made incorrect responses. Morgan and colleagues (2014) found a significant positive correlation between memory accuracy and risk choice in two rhesus monkeys. That is, they were more likely to select the high-risk option if they answered correctly in the working memory task but select the low-risk option if they were failed in the memory task.
Then Morgan et al. (2014) examine monkeys’ prospective metacognitive monitoring skills in Experiment 2. This study employed the same design except that two monkeys were asked to make low-risk or high-risk confidence judgement before they make actual responses to measure their judgements about future events. Similarly, the monkeys were more often to choose high-risk confidence judgment before answering correctly in working memory task and tended to choose the low-risk option before providing an incorrect response. These two studies indicated that rhesus monkeys can accurately monitor their performance and provided evidence of metacognitive abilities in monkeys.
In Rats
In addition to nonhuman primates, other animals are also shown metacognition. Foote and Crystal (2007) provided the first evidence that rats have the knowledge of what they know in a perceptual discrimination task. Rats were required to classify brief noises as short or long. Some noises with intermediate durations were difficult to discriminate as short or long. Rats were provided with an option to decline to take the test on some trials but were forced to make responses on other trials. If they chose to take the test and respond correctly, they would receive a high reward but no reward if their classification of noises was incorrect. But if the rats decline to take the test, they would be guaranteed a smaller reward. The results showed that rats were more likely to decline to take the test when the difficulty of noise discrimination increased, suggesting rats knew they do not have the correct answers and declined to take the test to receive the reward. Another finding is that the performance was better when they had chosen to take the test compared with if the rats were forced to make responses, proving that some uncertain trials were declined to improve the accuracy.
These responses pattern might be attributed to actively monitor their own mental states. Alternatively, external cues such as environmental cue associations could be used to explain their behaviours in the discrimination task. Rats might have learned the association between intermediate stimuli and the decline option over time. Longer response latencies or some features inherent to stimuli can serve as discriminative cues to decline tests. Therefore, Templer, Lee, and Preston (2017) utilised an olfactory-based delayed match to sample (DMTS) memory task to assess whether rats were capable of metacognitive responding adaptively. Rats were exposed to sample odour first and chose to either decline or take the four-choice memory test after a delay. The correct choices of odour were associated with high reward and incorrect choices have no reward. The decline options were accompanied by a small reward.
In experiment 2, some “no-sample” trials were added in the memory test in which no odour was provided before the test. They hypothesized that rats would decline more often when there was no sample odour presented compared with odour presented if rats could internally assess the memory strength. Alternatively, if the decline option was motivated by external environmental cues, the rats would be less likely to decline the test because no available external cues were presented. The results showed that rats were more likely to decline the test in no-sample trials relative to normal sample trials, supporting the notion that rats can track their internal memory strength.
To rule out other potential possibilities, they also manipulated memory strength by providing the sampled odour twice and varying the retention interval between the learning and the test. Templer and colleagues (2017) found rats were less likely to decline the test if they had been exposed to the sample twice, suggesting that their memory strength for these samples was increased. Longer delayed sample test was more often declined than short delayed test because their memory was better after the short delay. Overall, their series of studies demonstrated that rats could distinguish between remembering and forgetting and rule out the possibilities that decline use was modulated by the external cues such as environmental cue associations.
In Pigeons
Research on metacognition of pigeons has shown limited success. Inman and Shettleworth (1999) employed the delayed match to sample (DMTS) procedure to test pigeons’ metacognition. Pigeons were presented with one of three sample shapes (a triangle, a square, or a star) and then they were required to peck the matched sample when three stimuli simultaneously appeared on the screen at the end of the retention interval. A safe key was also presented in some trials next to three sample stimuli which allow them to decline that trial. Pigeons received a high reward for pecking correct stimuli, a middle-level reward for pecking the safe key, and nothing if they pecked the wrong stimuli. Inman and Shettleworth’s (1999) first experiment found that pigeons’ accuracies were lower and they were more likely to choose the safe key as the retention interval between presentation of stimuli and test increased. However, in Experiment 2, when pigeons were presented with the option to escape or take the test before the test phase, there was no relationship between choosing the safe key and longer retention interval. Adams and Santi (2011) also employed the DMTS procedure in a perceptual discrimination task during which pigeons were trained to discriminate between durations of illumination. Pigeons did not choose the escape option more often as the retention interval increased during initial testing. After extended training, they learned to escape the difficult trials. However, these patterns might be attributed to the possibility that pigeons learned the association between escape responses and longer retention delay.
In addition to DMTS paradigm, Castro and Wasserman (2013) proved that pigeons can exhibit adaptive and efficient information-seeking behaviour in the same-different discrimination task. Two arrays of items were presented simultaneously in which the two sets of items were either identical or different from one another. Pigeons were required to distinguish between the two arrays of items in which the level of difficulty was varied. Pigeons were provided with an “Information” button and a “Go” button on some trials that they could increase the number of items in the arrays to make the discrimination easier or they can prompt to make responses by pecking the Go button. Castro and Wasserman found that the more difficult the task, the more often pigeons chose the information button to solve the discrimination task. This behavioural pattern indicated that pigeons could evaluate the difficulty of the task internally and actively search for information when is necessary.
In Dogs
Dogs have shown a certain level of metacognition that they are sensitive to information they have acquired or not. Belger & Bräuer (2018) examined whether dogs could seek additional information when facing uncertain situations. The experimenter put the reward behind one of the two fences in which dogs can see or cannot see where the reward was hidden. After that, dogs were encouraged to find the reward by walking around one fence. The dogs checked more frequently before selecting the fence when they did not see the baiting process compared with when they saw where the reward was hidden. However, contrary to apes, dogs did not show more checking behaviours when the delay between baiting the reward and selecting the fence was longer. Their findings suggested that dogs have some aspect of information-searching behaviours but less flexibly compared to apes.
In Dolphins
Smith et al. (1995) evaluated whether dolphins have the ability of metacognitive monitoring in an auditory threshold paradigm. A bottlenosed dolphin was trained to discriminate between high-frequency tones and low-frequency tones. An escape option was available on some trials associated with a small reward. Their studies showed that dolphins could appropriately use the uncertain response when the trials were difficult to discriminate.
Debate
There is consensus that nonhuman primates, especially great apes and rhesus monkeys, exhibit metacognitive control and monitoring behaviours. But less convergent evidence was found in other animals such as rats and pigeons. Some researchers criticised these methods and posited that these performances might be accounted for by low-level conditioning mechanisms. Animals learned the association between reward and external stimuli through simple reinforcement models. However, many studies have demonstrated that the reinforcement model alone cannot explain animals’ behavioural patterns. Animals have shown adaptive metacognitive behaviour even with the absence of concrete reward.
Strategies
Metacognitive-like processes are especially ubiquitous when it comes to the discussion of self-regulated learning. Self-regulation requires metacognition by looking at one’s awareness of their learning and planning further learning methodology. Attentive metacognition is a salient feature of good self-regulated learners, but does not guarantee automatic application. Reinforcing collective discussion of metacognition is a salient feature of self-critical and self-regulating social groups. The activities of strategy selection and application include those concerned with an ongoing attempt to plan, check, monitor, select, revise, evaluate, etc.
Metacognition is ‘stable’ in that learners’ initial decisions derive from the pertinent facts about their cognition through years of learning experience. Simultaneously, it is also ‘situated’ in the sense that it depends on learners’ familiarity with the task, motivation, emotion, and so forth. Individuals need to regulate their thoughts about the strategy they are using and adjust it based on the situation to which the strategy is being applied. At a professional level, this has led to emphasis on the development of reflective practice, particularly in the education and health-care professions.
Recently, the notion has been applied to the study of second language learners in the field of TESOL and applied linguistics in general (e.g. Wenden, 1987; Zhang, 2001, 2010). This new development has been much related to Flavell (1979), where the notion of metacognition is elaborated within a tripartite theoretical framework. Learner metacognition is defined and investigated by examining their person knowledge, task knowledge and strategy knowledge.
Wenden (1991) has proposed and used this framework and Zhang (2001) has adopted this approach and investigated second language learners’ metacognition or metacognitive knowledge. In addition to exploring the relationships between learner metacognition and performance, researchers are also interested in the effects of metacognitively-oriented strategic instruction on reading comprehension (e.g. Garner, 1994, in first language contexts, and Chamot, 2005; Zhang, 2010). The efforts are aimed at developing learner autonomy, interdependence and self-regulation.
Metacognition helps people to perform many cognitive tasks more effectively. Strategies for promoting metacognition include self-questioning (e.g. “What do I already know about this topic? How have I solved problems like this before?”), thinking aloud while performing a task, and making graphic representations (e.g. concept maps, flow charts, semantic webs) of one’s thoughts and knowledge. Carr, 2002, argues that the physical act of writing plays a large part in the development of metacognitive skills.
Strategy Evaluation matrices (SEM) can help to improve the knowledge of cognition component of metacognition. The SEM works by identifying the declarative (Column 1), procedural (Column 2) and conditional (Column 3 and 4) knowledge about specific strategies. The SEM can help individuals identify the strength and weaknesses about certain strategies as well as introduce them to new strategies that they can add to their repertoire.
A regulation checklist (RC) is a useful strategy for improving the regulation of cognition aspect of one’s metacognition. RCs help individuals to implement a sequence of thoughts that allow them to go over their own metacognition. King (1991) found that fifth-grade students who used a regulation checklist outperformed control students when looking at a variety of questions including written problem solving, asking strategic questions, and elaborating information.
Examples of strategies that can be taught to students are word analysis skills, active reading strategies, listening skills, organisational skills and creating mnemonic devices.
Walker and Walker have developed a model of metacognition in school learning termed Steering Cognition, which describes the capacity of the mind to exert conscious control over its reasoning and processing strategies in relation to the external learning task. Studies have shown that pupils with an ability to exert metacognitive regulation over their attentional and reasoning strategies used when engaged in maths, and then shift those strategies when engaged in science or then English literature learning, associate with higher academic outcomes at secondary school.
Metastrategic Knowledge
“Metastrategic knowledge” (MSK) is a sub-component of metacognition that is defined as general knowledge about higher order thinking strategies. MSK had been defined as “general knowledge about the cognitive procedures that are being manipulated”. The knowledge involved in MSK consists of “making generalizations and drawing rules regarding a thinking strategy” and of “naming” the thinking strategy.
The important conscious act of a metastrategic strategy is the “conscious” awareness that one is performing a form of higher order thinking. MSK is an awareness of the type of thinking strategies being used in specific instances and it consists of the following abilities:
Making generalisations and drawing rules regarding a thinking strategy;
Naming the thinking strategy,
Explaining when, why and how such a thinking strategy should be used;
When it should not be used;
What are the disadvantages of not using appropriate strategies; and
What task characteristics call for the use of the strategy.
MSK deals with the broader picture of the conceptual problem. It creates rules to describe and understand the physical world around the people who utilise these processes called higher-order thinking. This is the capability of the individual to take apart complex problems in order to understand the components in problem. These are the building blocks to understanding the “big picture” (of the main problem) through reflection and problem solving.
Action
Both social and cognitive dimensions of sporting expertise can be adequately explained from a metacognitive perspective according to recent research. The potential of metacognitive inferences and domain-general skills including psychological skills training are integral to the genesis of expert performance. Moreover, the contribution of both mental imagery (e.g. mental practice) and attentional strategies (e.g. routines) to our understanding of expertise and metacognition is noteworthy. The potential of metacognition to illuminate our understanding of action was first highlighted by Aidan Moran who discussed the role of meta-attention in 1996. A recent research initiative, a research seminar series called META funded by the BPS, is exploring the role of the related constructs of meta-motivation, meta-emotion, and thinking and action (metacognition).
Mental Illness
Sparks of Interest
In the context of mental health, metacognition can be loosely defined as the process that “reinforces one’s subjective sense of being a self and allows for becoming aware that some of one’s thoughts and feelings are symptoms of an illness”. The interest in metacognition emerged from a concern for an individual’s ability to understand their own mental status compared to others as well as the ability to cope with the source of their distress. These insights into an individual’s mental health status can have a profound effect on overall prognosis and recovery. Metacognition brings many unique insights into the normal daily functioning of a human being. It also demonstrates that a lack of these insights compromises ‘normal’ functioning. This leads to less healthy functioning. In the autism spectrum, it is speculated that there is a profound deficit in Theory of Mind. In people who identify as alcoholics, there is a belief that the need to control cognition is an independent predictor of alcohol use over anxiety. Alcohol may be used as a coping strategy for controlling unwanted thoughts and emotions formed by negative perceptions. This is sometimes referred to as self medication.
Implications
Adrian Wells’ and Gerald Matthews’ theory proposes that when faced with an undesired choice, an individual can operate in two distinct modes: “object” and “metacognitive”. Object mode interprets perceived stimuli as truth, where metacognitive mode understands thoughts as cues that have to be weighted and evaluated. They are not as easily trusted. There are targeted interventions unique of each patient, that gives rise to the belief that assistance in increasing metacognition in people diagnosed with schizophrenia is possible through tailored psychotherapy. With a customised therapy in place clients then have the potential to develop greater ability to engage in complex self-reflection. This can ultimately be pivotal in the patient’s recovery process. In the obsessive-compulsive spectrum, cognitive formulations have greater attention to intrusive thoughts related to the disorder. “Cognitive self-consciousness” are the tendencies to focus attention on thought. Patients with OCD exemplify varying degrees of these “intrusive thoughts”. Patients also with generalised anxiety disorder (GAD) also show negative thought process in their cognition.
Cognitive-attentional syndrome (CAS) characterises a metacognitive model of emotion disorder (CAS is consistent with the attention strategy of excessively focusing on the source of a threat). This ultimately develops through the client’s own beliefs. Metacognitive therapy attempts to correct this change in the CAS. One of the techniques in this model is called attention training (ATT). It was designed to diminish the worry and anxiety by a sense of control and cognitive awareness. ATT also trains clients to detect threats and test how controllable reality appears to be.
Following the work of Asher Koriat, who regards confidence as central aspect of metacognition, metacognitive training for psychosis aims at decreasing overconfidence in patients with schizophrenia and raising awareness of cognitive biases. According to a meta-analysis, this type of intervention improves delusions and hallucinations.
Works of Art as Metacognitive Artefacts
The concept of metacognition has also been applied to reader-response criticism. Narrative works of art, including novels, movies and musical compositions, can be characterised as metacognitive artefacts which are designed by the artist to anticipate and regulate the beliefs and cognitive processes of the recipient, for instance, how and in which order events and their causes and identities are revealed to the reader of a detective story. As Menakhem Perry has pointed out, mere order has profound effects on the aesthetical meaning of a text. Narrative works of art contain a representation of their own ideal reception process. They are something of a tool with which the creators of the work wish to attain certain aesthetical and even moral effects.
Mind Wandering
There is an intimate, dynamic interplay between mind wandering and metacognition. Metacognition serves to correct the wandering mind, suppressing spontaneous thoughts and bringing attention back to more “worthwhile” tasks.
Organisational Metacognition
The concept of metacognition has also been applied to collective teams and organisations in general, termed organisational metacognition.
Educational psychology: Branch of psychology concerned with the scientific study of human learning.
Educational technology: Use of technology in education to improve learning and teaching.
Epistemology: Branch of philosophy concerning knowledge.
Goal orientation.
Introspection: Examining one’s own thoughts and feelings.
Learning styles: Largely debunked theories that aim to account for differences in individuals’ learning.
Meta-emotion.
Metaknowledge.
Metaphilosophy: Philosophy of philosophy.
Münchhausen trilemma: A thought experiment used to demonstrate the impossibility of proving any truth.
Metatheory: Theory whose subject matter is itself a theory.
Mentalisation.
Mindstream: Buddhist concept of continuity of mind.
Mirror test: Animal self-awareness test to determine self-recognition in a mirror.
Phenomenology (philosophy): Philosophical method and schools of philosophy.
Phenomenology (psychology): Psychological study of subjective experience.
Psychological effects of Internet use.
Second-order cybernetics: Recursive application of cybernetics to itself and the reflexive practice of cybernetics according to this critique.
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Common side effects include nausea, trouble sleeping, sexual problems, shakiness, feeling tired, and sweating. Serious side effects include an increased risk of suicide in those under the age of 25, serotonin syndrome, glaucoma, and QT prolongation. It should not be used in persons who take or have recently taken a MAO inhibitor. Antidepressant discontinuation syndrome may occur when stopped. There are concerns that use during pregnancy may harm the foetus.
Citalopram was approved for medical use in the United States in 1998. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication. In 2019, it was the 30th most commonly prescribed medication in the United States, with more than 21 million prescriptions.
Brief History
Citalopram was first synthesized in 1972 by chemist Klaus Bøgesø and his research group at the pharmaceutical company Lundbeck and was first marketed in 1989 in Denmark. It was first marketed in the US in 1998. The original patent expired in 2003, allowing other companies to legally produce and market generic versions.
Medical Uses
Depression
In the United States, citalopram is approved to treat major depressive disorder. Citalopram appears to have comparable efficacy and superior tolerability relative to other antidepressants. In the National Institute for Health and Clinical Excellence ranking of ten antidepressants for efficacy and cost-effectiveness, citalopram is fifth in effectiveness (after mirtazapine, escitalopram, venlafaxine, and sertraline) and fourth in cost-effectiveness. The ranking results were based on a 2009 meta-analysis by Andrea Cipriani; an update of the analysis in 2018 produced broadly similar results.
Evidence for effectiveness of citalopram for treating depression in children is uncertain.
Panic Disorder
Citalopram is licensed in the UK and other European countries for panic disorder, with or without agoraphobia.
Other
Citalopram may be used off-label to treat anxiety, and dysthymia, premenstrual dysphoric disorder, body dysmorphic disorder, and obsessive-compulsive disorder (OCD).
It appears to be as effective as fluvoxamine and paroxetine in OCD. Some data suggest the effectiveness of intravenous infusion of citalopram in resistant OCD. Citalopram is well tolerated and as effective as moclobemide in social anxiety disorder. There are studies suggesting that citalopram can be useful in reducing aggressive and impulsive behaviour. It appears to be superior to placebo for behavioural disturbances associated with dementia. It has also been used successfully for hypersexuality in early Alzheimer’s disease.
A meta-analysis, including studies with fluoxetine, paroxetine, sertraline, escitalopram, and citalopram versus placebo, showed SSRIs to be effective in reducing symptoms of premenstrual syndrome, whether taken continuously or just in the luteal phase. For alcoholism, citalopram has produced a modest reduction in alcoholic drink intake and increase in drink-free days in studies of alcoholics, possibly by decreasing desire or reducing the reward.
While on its own citalopram is less effective than amitriptyline in the prevention of migraines, in refractory cases, combination therapy may be more effective.
Citalopram and other SSRIs can be used to treat hot flashes.
A 2009 multisite randomised controlled study found no benefit and some adverse effects in autistic children from citalopram, raising doubts whether SSRIs are effective for treating repetitive behaviour in children with autism.
Some research suggests citalopram interacts with cannabinoid protein-couplings in the rat brain, and this is put forward as a potential cause of some of the drug’s antidepressant effect.
Administration
Citalopram is typically taken in one dose, either in the morning or evening. It can be taken with or without food. Its absorption does not increase when taken with food, but doing so can help prevent nausea. Nausea is often caused when the 5HT3 receptors actively absorb free serotonin, as this receptor is present within the digestive tract. The 5HT3 receptors stimulate vomiting. This side effect, if present, should subside as the body adjusts to the medication.
Citalopram is considered safe and well tolerated in the therapeutic dose range. Distinct from some other agents in its class, it exhibits linear pharmacokinetics and minimal drug interaction potential, making it a better choice for the elderly or comorbid patients.
Adverse Effects
Sexual dysfunction is often a side effect with SSRIs.
Citalopram theoretically causes side effects by increasing the concentration of serotonin in other parts of the body (e.g. the intestines). Other side effects, such as increased apathy and emotional flattening, may be caused by the decrease in dopamine release associated with increased serotonin. Citalopram is also a mild antihistamine, which may be responsible for some of its sedating properties.
Other common side effects of citalopram include drowsiness, insomnia, nausea, weight changes (usually weight gain), increase in appetite, vivid dreaming, frequent urination, dry mouth, increased sweating, trembling, diarrhoea, excessive yawning, severe tinnitus, and fatigue. Less common side effects include bruxism, vomiting, cardiac arrhythmia, blood pressure changes, dilated pupils, anxiety, mood swings, headache, hyperactivity and dizziness. Rare side effects include convulsions, hallucinations, severe allergic reactions and photosensitivity. If sedation occurs, the dose may be taken at bedtime rather than in the morning. Some data suggests citalopram may cause nightmares. Citalopram is associated with a higher risk of arrhythmia than other SSRIs.
Withdrawal symptoms can occur when this medicine is suddenly stopped, such as paraesthesia, sleeping problems (difficulty sleeping and intense dreams), feeling dizzy, agitated or anxious, nausea, vomiting, tremors, confusion, sweating, headache, diarrhoea, palpitations, changes in emotions, irritability, and eye or eyesight problems. Treatment with citalopram should be reduced gradually when treatment is finished.
Citalopram and other SSRIs can induce a mixed state, especially in those with undiagnosed bipolar disorder. According to an article published in 2020, one of the other rare side effects of Citalopram could be triggering visual snow syndrome; which does not resolve after the discontinuation of the medicine.
Sexual Dysfunction
Some people experience persistent sexual side effects after they stop taking SSRIs. This is known as Post-SSRI Sexual Dysfunction (PSSD). Common symptoms in these cases include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. The prevalence of PSSD is unknown, and there is no established treatment.
Abnormal Heart Rhythm
In August 2011, the US Food and Drug Administration (FDA) announced, “Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day”. A further clarification issued in March 2012, restricted the maximum dose to 20 mg for subgroups of patients, including those older than 60 years and those taking an inhibitor of cytochrome P450 2C19.7.
Endocrine Effects
As with other SSRIs, citalopram can cause an increase in serum prolactin level. Citalopram has no significant effect on insulin sensitivity in women of reproductive age and no changes in glycaemic control were seen in another trial.
Exposure in Pregnancy
Antidepressant exposure (including citalopram) during pregnancy is associated with shorter duration of gestation (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g), and lower Apgar scores (by <0.4 points). Antidepressant exposure is not associated with an increased risk of spontaneous abortion. It is uncertain whether there is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy.
Interactions
Citalopram should not be taken with St John’s wort, tryptophan or 5-HTP as the resulting drug interaction could lead to serotonin syndrome. With St John’s wort, this may be caused by compounds in the plant extract reducing the efficacy of the hepatic cytochrome P450 enzymes that process citalopram. It has also been suggested that such compounds, including hypericin, hyperforin and flavonoids, could have SSRI-mimetic effects on the nervous system, although this is still subject to debate. One study found that Hypericum extracts had similar effects in treating moderate depression as citalopram, with fewer side effects.
Tryptophan and 5-HTP are precursors to serotonin. When taken with an SSRI, such as citalopram, this can lead to levels of serotonin that can be lethal. This may also be the case when SSRIs are taken with SRAs (serotonin releasing agents) such as in the case of MDMA. It is possible that SSRIs could reduce the effects associated due to an SRA, since SSRIs stop the reuptake of Serotonin by blocking SERT. This would allow less serotonin in and out of the transporters, thus decreasing the likelihood of neurotoxic effects. However, these concerns are still disputed as the exact pharmacodynamic effects of citalopram and MDMA have yet to be fully identified.[citation needed]
SSRIs, including citalopram, can increase the risk of bleeding, especially when coupled with aspirin, NSAIDs, warfarin, or other anticoagulants. Citalopram is contraindicated in individuals taking MAOIs, owing to a potential for serotonin syndrome.
Taking citalopram with omeprazole may cause higher blood levels of citalopram. This is a potentially dangerous interaction, so dosage adjustments may be needed or alternatives may be prescribed.
SSRI discontinuation syndrome has been reported when treatment is stopped. It includes sensory, gastrointestinal symptoms, dizziness, lethargy, and sleep disturbances, as well as psychological symptoms such as anxiety/agitation, irritability, and poor concentration. Electric shock-like sensations are typical for SSRI discontinuation. Tapering off citalopram therapy, as opposed to abrupt discontinuation, is recommended in order to diminish the occurrence and severity of discontinuation symptoms. Some doctors choose to switch a patient to Prozac (fluoxetine) when discontinuing citalopram as fluoxetine has a much longer half-life (i.e. stays in the body longer compared to citalopram). This may avoid many of the severe withdrawal symptoms associated with citalopram discontinuation. This can be done either by administering a single 20 mg dose of fluoxetine or by beginning on a low dosage of fluoxetine and slowly tapering down. Either of these prescriptions may be written in liquid form to allow a very slow and gradual tapering down in dosage. Alternatively, a patient wishing to stop taking citalopram may visit a compounding pharmacy where their prescription may be re-arranged into progressively smaller dosages.
Overdose
Overdosage may result in vomiting, sedation, disturbances in heart rhythm, dizziness, sweating, nausea, tremor, and rarely amnesia, confusion, coma, or convulsions. Overdose deaths have occurred, sometimes involving other drugs, but also with citalopram as the sole agent. Citalopram and N-desmethylcitalopram may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalised patients or to assist in a medicolegal death investigation. Blood or plasma citalopram concentrations are usually in a range of 50-400 μg/l in persons receiving the drug therapeutically, 1000-3000 μg/l in patients who survive acute overdosage and 3-30 mg/l in those who do not survive. It is the most dangerous of SSRIs in overdose.
Suicidality
In the United States, citalopram carries a boxed warning stating it may increase suicidal thinking and behaviour in those under age 24.
Stereochemistry
Citalopram has one stereocentre, to which a 4-fluoro phenyl group and an N, N-dimethyl-3-aminopropyl group bind. As a result of this chirality, the molecule exists in (two) enantiomeric forms (mirror images). They are termed S-(+)-citalopram and R-(–)-citalopram.
Citalopram is sold as a racemic mixture, consisting of 50% (R)-(−)-citalopram and 50% (S)-(+)-citalopram. Only the (S)-(+) enantiomer has the desired antidepressant effect. Lundbeck now markets the (S)-(+) enantiomer, the generic name of which is escitalopram. Whereas citalopram is supplied as the hydrobromide, escitalopram is sold as the oxalate salt (hydrooxalate). In both cases, the salt forms of the amine make these otherwise lipophilic compounds water-soluble.
Metabolism
Citalopram is metabolised in the liver mostly by CYP2C19, but also by CYP3A4 and CYP2D6. Metabolites desmethylcitalopram and didesmethylcitalopram are significantly less energetic and their contribution to the overall action of citalopram is negligible. The half-life of citalopram is about 35 hours. Approximately 80% is cleared by the liver and 20% by the kidneys. The elimination process is slower in the elderly and in patients with liver or kidney failure. With once-daily dosing, steady plasma concentrations are achieved in about a week. Potent inhibitors of CYP2C19 and 3A4 might decrease citalopram clearance. Tobacco smoke exposure was found to inhibit the biotransformation of citalopram in animals, suggesting that the elimination rate of citalopram is decreased after tobacco smoke exposure. After intragastric administration, the half-life of the racemic mixture of citalopram was increased by about 287%.
Society and Culture
Brand Names
Citalopram is sold under these brand names:
Akarin (Denmark, Nycomed).
C Pram S (India).
Celapram (Australia and New Zealand).
Celexa (US and Canada, Forest Laboratories, Inc.).
Celica (Australia).
Ciazil (Australia and New Zealand).
Cilate (South Africa).
Cilift (South Africa).
Cimal (South America, by Roemmers and Recalcine).
Cipralex (South Africa).
Cipram (Denmark and Turkey, H. Lundbeck A/S).
Cipramil (Australia, Brazil, Belgium, Chile, Finland, Germany, Netherlands, Iceland, Ireland, Israel, New Zealand, Norway, Russia, South Africa, Sweden, and the United Kingdom).
Cipraned, Cinapen (Greece).
Ciprapine (Ireland).
Ciprotan (Ireland).
Citabax, Citaxin (Poland).
Cital (Poland).
Citalec (Czech Republic and Slovakia).
Citalex (Iran and Serbia).
Citalo (Australia, Egypt, and Pakistan).
Citalopram (Canada, Denmark, Finland, Germany, Ireland, New Zealand, Spain, Sweden, Switzerland, United Kingdom, the US).
Citol (Russia).
Citox (Mexico).
Citrol (Europe and Australia).
Citta (Brazil).
Dalsan (Eastern Europe).
Denyl (Brazil).
Elopram (Italy).
Estar (Pakistan).
Humorup (Argentina).
Humorap (Peru, Bolivia).
Lopraxer (Greece).
Oropram (Iceland, Actavis).
Opra (Russia).
Pram (Russia).
Pramcit (Pakistan).
Procimax (Brazil).
Recital (Israel, Thrima Inc. for Unipharm Ltd.).
Sepram (Finland).
Seropram (various European countries, including Czech Republic).
Szetalo (India).
Talam (Europe and Australia).
Temperax (Argentina, Chile, and Peru).
Vodelax (Turkey).
Zentius (South America, by Roemmers and Recalcine).
Zetalo (India).
Cipratal (Kuwait, GCC).
Zylotex (Portugal).
European Commission Fine
On 19 June 2013, the European Commission imposed a fine of €93.8 million on the Danish pharmaceutical company Lundbeck, plus a total of €52.2 million on several generic pharmaceutical-producing companies. This was in response to Lundbeck entering an agreement with the companies to delay their sales of generic citalopram after Lundbeck’s patent on the drug had expired, thus reducing competition in breach of European antitrust law.
Thought suppression is a psychological defence mechanism. It is a type of motivated forgetting in which an individual consciously attempts to stop thinking about a particular thought.
It is often associated with obsessive-compulsive disorder (OCD). OCD is when a person will repeatedly (usually unsuccessfully) attempt to prevent or “neutralise” intrusive distressing thoughts centred on one or more obsessions. It is also thought to be a cause of memory inhibition, as shown by research using the think/no think paradigm. Thought suppression is relevant to both mental and behavioural levels, possibly leading to ironic effects that are contrary to intention. Ironic process theory is one cognitive model that can explain the paradoxical effect.
When an individual tries to suppress thoughts under a high cognitive load, the frequency of those thoughts increases and becomes more accessible than before. Evidence shows that people can prevent their thoughts from being translated into behaviour when self-monitoring is high; this does not apply to automatic behaviours though, and may result in latent, unconscious actions. This phenomenon is made paradoxically worse by increasing the amount of distractions a person has, although the experiments in this area can be criticised for using impersonal concurrent tasks, which may or may not properly reflect natural processes or individual differences.
Empirical Work (1980s)
In order for thought suppression and its effectiveness to be studied, researchers have had to find methods of recording the processes going on in the mind. One experiment designed with this purpose was performed by Wegner, Schneider, Carter & White. They asked participants to avoid thinking of a specific target (e.g. a white bear) for five minutes, but if they did, they were told then to ring a bell. After this, participants were told that for the next five minutes they were to think about the target. There was evidence that unwanted thoughts occurred more frequently in those who used thought suppression compared to those who were not. Furthermore, there was also evidence that during the second stage, those who had used thought suppression had a higher frequency of target thoughts than did those who had not used thought suppression; later coined the rebound effect. This effect has been replicated and can even be done with implausible targets, such as the thought of a “green rabbit”. From these implications, Wegner eventually developed the “ironic process theory”.
Improved Methodology (1990s)
To better elucidate the findings of thought suppression, several studies have changed the target thought. Roemer and Borkovec found that participants who suppressed anxious or depressing thoughts showed a significant rebound effect. Furthermore, Wenzlaff, Wegner, & Roper demonstrated that anxious or depressed subjects were less likely to suppress negative, unwanted thoughts. Despite Rassin, Merkelbach and Muris reporting that this finding is moderately robust in the literature, some studies were unable to replicate results. However, this may be explained by a consideration of individual differences.
Recent research found that for individuals with low anxiety and high desirability traits (repressors), suppressed anxious autobiographical events initially intruded fewer times than in other groups (low, high, and high defensive anxious groups), but intruded more often after one week. This difference in coping style may account for the disparities within the literature. That said, the problem remains that the cause of the paradoxical effect may be in the thought tapping measures used (e.g. bell ringing). Evidence from Brown (1990) that showed participants were very sensitive to frequency information prompted Clarke, Ball and Pape to obtain participants’ aposterio estimates of the number of intrusive target thoughts and found the same pattern of paradoxical results. However, even though such a method appears to overcome the problem, it and all the other methodologies use self-report as the primary form of data-collection. This may be problematic because of response distortion or inaccuracy in self-reporting.
Behavioural Domain
Thought suppression also has the capability to change human behaviour. Macrae, Bodenhausen, Milne, and Jetten found that when people were asked not to think about the stereotypes of a certain group (e.g. a “skinhead”), their written descriptions about a group member’s typical day contained less stereotypical thoughts. However, when they were told they were going to meet an individual they had just written about, those in the suppression group sat significantly farther away from the “skinhead” (just by virtue of his clothes being present). These results show that even though there may have been an initial enhancement of the stereotype, participants were able to prevent this from being communicated in their writing; this was not true for their behaviour though.
Further experiments have documented similar findings. In one study from 1993, when participants were given cognitively demanding concurrent tasks, the results showed a paradoxical higher frequency of target thoughts than controls. However other controlled studies have not shown such effects. For example, Wenzlaff and Bates found that subjects concentrating on a positive task experienced neither paradoxical effects nor rebound effects – even when challenged with cognitive load. Wenzlaff and Bates also note that the beneficiality of concentration in their study participants was optimised when the subjects employed positive thoughts.
Some studies have shown that when test subjects are under what Wegner refers to as a “cognitive load” (for instance, using multiple external distractions to try to suppress a target thought), the effectiveness of thought suppression appears to be reduced. However, in other studies in which focused distraction is used, long term effectiveness may improve. That is, successful suppression may involve less distractors. For example, in 1987 Wegner, Schneider, Carter & White found that a single, pre-determined distracter (e.g. a red Volkswagen) was sufficient to eliminate the paradoxical effect post-testing. Evidence from Bowers and Woody in 1996 is supportive of the finding that hypnotised individuals produce no paradoxical effects. This rests on the assumption that deliberate “distracter activity” is bypassed in such an activity.
Cognitive Dynamics
When the cognitive load is increased, thought suppression typically becomes less effective. For example, in the white bear experiment, many general distractions in the environment (for instance a lamp, a light bulb, a desk etc.) might later serve as reminders of the object being suppressed (these are also referred to as “free distraction”). Some studies, however, are unable to find this effect for emotional thoughts in hypnotized individuals when one focused distraction is provided. In an attempt to account for these findings, a number of theorists have produced cognitive models of thought suppression. Wegner suggested in 1989 that individuals distract themselves using environmental items. Later, these items become retrieval cues for the thought attempting to be suppressed. This iterative process leaves the individual surrounded by retrieval cues, ultimately causing the rebound effect. Wegner hypothesized that multiple retrieval cues not being forged explains, in part, the effectiveness of focused distraction (i.e. a reduction of mental load). This is because there may be an ideal balance between the two processes; if the cognitive demand that is not too heavy, then the monitoring processes will not supersede it.
Individual differences may also play a role in regards to the ironic thought process.
Thought suppression has been seen as a form of “experiential avoidance”. Experiential avoidance is when an individual attempts to suppress, change, or control unwanted internal experiences (thoughts, feelings, bodily sensations, memories, etc.). This line of thinking supports relational frame theory.
Other Methodologies
Thought suppression has been shown to be a cause of inhibition in several ways. Two commonly-used methods to study this relationship are the list method and the item method. In this list method, participants study two lists of words, one after the other. After studying the first list, some participants are told to forget everything that they have just learned, while others are not given this instruction. After studying both lists, participants are asked to recall the words on both lists. These experiments typically find that participants who were told to forget the first list do not remember as many words from that list, suggesting that they have been suppressed due to the instruction to forget. In the item method, participants study individual words rather than lists. After each word is shown, participants are told to either remember or forget the word. As in experiments using the list method, the words followed by the instruction to forget are more poorly remembered. Some researchers believe that these two methods result in different types of forgetting. According to these researchers, the list method results in inhibition of the forgotten words, but the item method results in some words being remembered better than the others, without a specific relation to forgetting.
Think/No Think Paradigm
A paradigm from 2009 to study how suppression relates to inhibition is the think/no think paradigm. In these experiments, participants study pairs of words. An example of a possible word pair is roach-ordeal. After all the word pairs are learned, the participants see the first word of the pair and are either told to think about the second word (think phase) or not to think about the second word (no think phase). The no think phase is when suppression occurs. Some pairs were never presented after the initial study portion of the study, and these trials serve as the control group. At the end of the experiment, the participants try to remember all of the word pairs based on the first word. Studies could also use the “independent probe” method, which gives the category and first letter of the second word of the pair. Typically, regardless of the method used, results show that the no-think trials result in worse memory than the think trials, which supports the idea that suppression leads to inhibition in memory. Although this methodology was first done using word pairs, experiments have been conducted using pictures and autobiographical memories as stimuli, with the same results.
Research has also shown that doing difficult counting tasks at the same time as a think/no think task leads to less forgetting in the no think condition, which suggests that suppression takes active mental energy to be successful. Furthermore, the most forgetting during the no think phase occurs when there is a medium amount of brain activation while learning the words. The words are never learned if there is too little activation, and the association between the two words is too strong to be suppressed during the no think phase if there is too much activation. However, with medium activation, the word pairs are learned but able to be suppressed during the no think phase.
fMRI studies have shown two distinct patterns of brain activity during suppression tasks. The first is that there is less activity in the hippocampus, the brain area responsible for forming memories. The second is an increase of brain activity in the dorsolateral prefrontal cortex, especially in cases where suppression is harder. Researchers think that this region works to prevent memory formation by preventing the hippocampus from working.
This methodology can also be used to study thought substitution by adding an instruction during the no think phase for participants to think of a different word rather than the word being suppressed. This research shows that thought substitution can lead to increased levels of forgetting compared to suppression without a thought substitution instruction. This research also suggests that thought substitution, while used as a suppression strategy during the no think phase, may work differently than suppression. Some researchers argue that thinking of something different during the no think phase forms a new association with the first word than the original word pair, which results in interference when using this strategy, which is different than the inhibition that results from simply not thinking about something.
Dream Influence
Dreams occur mainly during the rapid eye movement (REM) sleep and are composed of images, ideas, emotions, and sensations. Although more research needs to be done on this subject, dreams are said to be linked to the unconscious mind. Thought suppression has an influence on the subject matter of the unconscious mind and by trying to restrain particular thoughts, there is a high chance of them showing up in one’s dreams.
Ironic Control Theory
Ironic control theory, also known as “ironic process theory”, states that thought suppression “leads to an increased occurrence of the suppressed content in waking states”. The irony lies in the fact that although people try not to think about a particular subject, there is a high probability that it will appear in one’s dreams regardless. There is a difference for individuals who have a higher tendency of suppression; they are more prone to psychopathological responses such as “intrusive thoughts, including depression, anxiety and obsessional thinking”. Due to these individuals having higher instances of thought suppression, they experience dream rebound more often.
Cognitive load also plays a role in ironic control theory. Studies have shown that a greater cognitive load results in an increased possibility of dream rebound occurring. In other words, when one tries to retain a heavy load of information before going to sleep, there is a high chance of that information manifesting itself within the dream. There is a greater degree of dream rebound in those with a higher cognitive load opposed to those whose load was absent. With the enhancement of a high cognitive load, ironic control theory states thought suppression is more likely to occur and lead to dream rebound.
Dream Rebound
Dream rebound is when suppressed thoughts manifest themselves in one’s dreams. Self-control is a form of thought suppression and when one dreams, that suppressed item has a higher chance of appearing in the dream. For example, when an individual is attempting to quit smoking, they may dream about themselves smoking a cigarette. Emotion suppression has also been found to trigger dream rebound. Recurrence of emotional experiences act as pre-sleep suggestions, ultimately leading to the suppressed thoughts presenting themselves within the dream. One effecting factor of dream rebound is the changes in the prefrontal lobes during rapid-eye movement sleep. Suppressed thoughts are more accessible during REM sleep, as a result of operating processes having a diminished effectiveness. This leads to pre-sleep thoughts becoming more available “with an increased activity of searching for these suppressed thought[s]”. There are other hypotheses regarding REM sleep and dream rebound. For instance, weak semantic associations, post REM sleep, are more accessible than any other time due to weak ironic monitoring processes becoming stronger. More research is needed to further understand what exactly causes dream rebound.
Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA).
It is used for the treatment of obsessive-compulsive disorder (OCD), panic disorder, major depressive disorder (MDD), and chronic pain. It may increase the risk of suicide in those under the age of 25. It is taken by mouth. It has also been used to treat premature ejaculation.
Common side effects include dry mouth, constipation, loss of appetite, sleepiness, weight gain, sexual dysfunction, and trouble urinating. Serious side effects include an increased risk of suicidal behaviour in those under the age of 25, seizures, mania, and liver problems. If stopped suddenly a withdrawal syndrome may occur with headaches, sweating, and dizziness. It is unclear if it is safe for use in pregnancy. Its mechanism of action is not entirely clear but is believed to involve increased levels of serotonin.
Clomipramine was discovered in 1964 by the Swiss drug manufacturer Ciba-Geigy. It is on the World Health Organisation’s List of Essential Medicines. It is available as a generic medication.
Brief History
Clomipramine was developed by Geigy as a chlorinated derivative of Imipramine. It was first referenced in the literature in 1961 and was patented in 1963. The drug was first approved for medical use in Europe in the treatment of depression in 1970, and was the last of the major TCAs to be marketed. In fact, clomipramine was initially considered to be a “me-too drug” by the FDA, and in relation to this, was declined licensing for depression in the United States. As such, to this day, clomipramine remains the only TCA that is available in the United States that is not approved for the treatment of depression, in spite of the fact that it is a highly effective antidepressant. Clomipramine was eventually approved in the United States for the treatment of OCD in 1989 and became available in 1990. It was the first drug to be investigated and found effective in the treatment of OCD. The first reports of benefits in OCD were in 1967, and the first double-blind, placebo-controlled clinical trial of clomipramine for OCD was conducted in 1976, with more rigorous clinical studies that solidified its effectiveness conducted in the 1980s. It remained the “gold standard” for the treatment of OCD for many years until the introduction of the SSRIs, which have since largely superseded it due to greatly improved tolerability and safety (although notably not effectiveness). Clomipramine is the only TCA that has been shown to be effective in the treatment of OCD and that is approved by the US Food and Drug Administration (FDA) for the treatment of OCD; the other TCAs failed clinical trials for this indication, likely due to insufficient serotonergic activity.
Medical Uses
Clomipramine has a number of uses in medicine including in the treatment of:
OCD which is its only US Food and Drug Administration (FDA)-labelled indication. Other regulatory agencies (such as the TGA of Australia and the MHRA of the UK) have also approved clomipramine for this indication.
MDD a popular off-label use in the US. It is approved by the Australian TGA and the United Kingdom MHRA for this indication. Some have suggested the possible superior efficacy of clomipramine compared to other antidepressants in the treatment of MDD, although at the current time the evidence is insufficient to adequately substantiate this claim.
Chronic pain with or without organic disease, particularly headache of the tension type.
Sleep paralysis, with or without narcolepsy.
Enuresis (involuntary urinating in sleep) in children. The effect may not be sustained following treatment, and alarm therapy may be more effective in both the short-term and the long-term. Combining a tricyclic (such as clomipramine) with anticholinergic medication, may be more effective for treating enuresis than the tricyclic alone.
In a meta-analysis of various trials involving fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft) to test their relative efficacies in treating OCD, clomipramine was found to be the most effective.
Contraindications
Contraindications include:
Known hypersensitivity to clomipramine, or any of the excipients or cross-sensitivity to tricyclic antidepressants of the dibenzazepine group.
Recent myocardial infarction.
Any degree of heart block or other cardiac arrhythmias.
Mania.
Severe liver disease.
Narrow angle glaucoma.
Urinary retention.
It must not be given in combination or within 3 weeks before or after treatment with a monoamine oxidase inhibitor (Moclobemide included, however clomipramine can be initiated sooner at 48 hours following discontinuation of moclobemide).
Pregnancy and Lactation
Clomipramine use during pregnancy is associated with congenital heart defects in the newborn. It is also associated with reversible withdrawal effects in the newborn. Clomipramine is also distributed in breast milk and hence nursing while taking clomipramine is advised against.
Side Effects
Clomipramine has been associated with the following side effects:
Very common (>10% frequency):
Accommodation defect.
Blurred vision.
Nausea.
Dry mouth (Xerostomia).
Constipation.
Fatigue.
Weight gain.
Increased appetite.
Dizziness.
Tremor.
Headache.
Myoclonus.
Drowsiness.
Somnolence.
Restlessness.
Micturition disorder.
Sexual dysfunction (erectile dysfunction and loss of libido).
Hyperhidrosis (profuse sweating).
Common (1-10% frequency):
Weight loss.
Orthostatic hypotension.
Sinus tachycardia.
Clinically irrelevant ECG changes (e.g. T- and ST-wave changes) in patients of normal cardiac status.
Palpitations.
Tinnitus (hearing ringing in one’s ears).
Mydriasis (dilated pupils).
Vomiting.
Abdominal disorders.
Diarrhoea.
Decreased appetite.
Increased transaminases.
Increased Alkaline phosphatase.
Speech disorders.
Paraesthesia.
Muscle hypertonia.
Dysgeusia.
Memory impairment.
Muscular weakness.
Disturbance in attention.
Confusional state.
Disorientation.
Hallucinations (particularly in elderly patients and patients with Parkinson’s disease).
Galactorrhoea (lactation that is not associated with pregnancy or breastfeeding).
Breast enlargement.
Yawning.
Hot flush.
Dermatitis allergic (skin rash, urticaria).
Photosensitivity reaction.
Pruritus (itching).
Uncommon (0.1-1% frequency):
Convulsions.
Ataxia.
Arrhythmias.
Elevated blood pressure.
Activation of psychotic symptoms.
Very rare (<0.01% frequency):
Pancytopaenia: An abnormally low amount of all the different types of blood cells in the blood (including platelets, white blood cells and red blood cells).
Leukopenia: A low white blood cell count.
Agranulocytosis: A more severe form of leukopenia; a dangerously low neutrophil count which leaves one open to life-threatening infections due to the role of the white blood cells in defending the body from invaders.
Thrombocytopenia: An abnormally low amount of platelets in the blood which are essential to clotting and hence this leads to an increased tendency to bruise and bleed, including, potentially, internally.
Eosinophilia: An abnormally high number of eosinophils – the cells that fight off parasitic infections – in the blood.
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH): A potentially fatal reaction to certain medications that is due to an excessive release of antidiuretic hormone – a hormone that prevents the production of urine by increasing the reabsorption of fluids in the kidney – this results in the development of various electrolyte abnormalities (e.g. hyponatraemia [low blood sodium], hypokalaemia [low blood potassium], hypocalcaemia [low blood calcium]).
Glaucoma.
Oedema (local or generalised).
Alopecia (hair loss).
Hyperpyrexia (a high fever that is above 41.5 °C).
Hepatitis (liver swelling) with or without jaundice: The yellowing of the eyes, the skin, and mucous membranes due to impaired liver function.
Abnormal ECG.
Anaphylactic and anaphylactoid reactions including hypotension.
Neuroleptic malignant syndrome (NMS): A potentially fatal side effect of antidopaminergic agents such as antipsychotics, tricyclic antidepressants and antiemetics (drugs that relieve nausea and vomiting). NMS develops over a period of days or weeks and is characterised by the following symptoms:
Tremor.
Muscle rigidity.
Mental status change (such as confusion, delirium, mania, hypomania, agitation, coma, etc.).
Hyperthermia (high body temperature).
Tachycardia (high heart rate).
Blood pressure changes.
Diaphoresis (sweating profusely).
Diarrhoea.
Alveolitis allergic (pneumonitis) with or without eosinophilia.
Purpura.
Conduction disorder (e.g. widening of QRS complex, prolonged QT interval, PR/PQ interval changes, bundle-branch block, torsade de pointes, particularly in patients with hypokalaemia).
Withdrawal
Withdrawal symptoms may occur during gradual or particularly abrupt withdrawal of tricyclic antidepressant drugs. Possible symptoms include: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, anxiety, dizziness and worsening of psychiatric status. Differentiating between the return of the original psychiatric disorder and clomipramine withdrawal symptoms is important. Clomipramine withdrawal can be severe. Withdrawal symptoms can also occur in neonates when clomipramine is used during pregnancy. A major mechanism of withdrawal from tricyclic antidepressants is believed to be due to a rebound effect of excessive cholinergic activity due to neuroadaptations as a result of chronic inhibition of cholinergic receptors by tricyclic antidepressants. Restarting the antidepressant and slow tapering is the treatment of choice for tricyclic antidepressant withdrawal. Some withdrawal symptoms may respond to anticholinergics, such as atropine or benztropine mesylate.
Clomipramine overdose usually presents with the following symptoms:
Signs of central nervous system depression such as:
Stupor.
Coma.
Drowsiness.
Restlessness.
Ataxia.
Mydriasis.
Convulsions.
Enhanced reflexes.
Muscle rigidity.
Athetoid and choreoathetoid movements.
Serotonin syndrome: A condition with many of the same symptoms as neuroleptic malignant syndrome but has a significantly more rapid onset.
Cardiovascular effects including:
Arrhythmias (including Torsades de pointes).
Tachycardia.
QTc interval prolongation.
Conduction disorders.
Hypotension.
Shock.
Heart failure.
Cardiac arrest.
Apnoea.
Cyanosis.
Respiratory depression.
Vomiting.
Fever.
Sweating.
Oliguria.
Anuria.
There is no specific antidote for overdose and all treatment is purely supportive and symptomatic. Treatment with activated charcoal may be used to limit absorption in cases of oral overdose. Anyone suspected of overdosing on clomipramine should be hospitalised and kept under close surveillance for at least 72 hours. Clomipramine has been reported as being less toxic in overdose than most other TCAs in one meta-analysis but this may well be due to the circumstances surrounding most overdoses as clomipramine is more frequently used to treat conditions for which the rate of suicide is not particularly high such as OCD. In another meta-analysis, however, clomipramine was associated with a significant degree of toxicity in overdose.
Interactions
Clomipramine may interact with a number of different medications, including the monoamine oxidase inhibitors which include isocarboxazid, moclobemide, phenelzine, selegiline and tranylcypromine, antiarrhythmic agents (due to the effects of TCAs like clomipramine on cardiac conduction. There is also a potential pharmacokinetic interaction with quinidine due to the fact that clomipramine is metabolised by CYP2D6 in vivo), diuretics (due to the potential for hypokalaemia (low blood potassium) to develop which increases the risk for QT interval prolongation and torsades de pointes), the selective serotonin reuptake inhibitors (SSRIs; due to both potential additive serotonergic effects leading to serotonin syndrome and the potential for a pharmacokinetic interaction with the SSRIs that inhibit CYP2D6 [e.g. fluoxetine and paroxetine]) and serotonergic agents such as triptans, other tricyclic antidepressants, tramadol, etc. (due to the potential for serotonin syndrome). Its use is also advised against in those concurrently on CYP2D6 inhibitors due to the potential for increased plasma levels of clomipramine and the resulting potential for CNS and cardiotoxicity.
Pharmacology
Pharmacodynamics
Clomipramine is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin-norepinephrine reuptake inhibitor (SNRI); that is, it blocks the reuptake of these neurotransmitters back into neurons by preventing them from interacting with their transporters, thereby increasing their extracellular concentrations in the synaptic cleft and resulting in increased serotonergic and noradrenergic neurotransmission. In addition, clomipramine also has antiadrenergic, antihistamine, antiserotonergic, antidopaminergic, and anticholinergic activities. It is specifically an antagonist of the α1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, the dopamine D1, D2, and D3 receptors, and the muscarinic acetylcholine receptors (M1-M5). Like other TCAs, clomipramine weakly blocks voltage-dependent sodium channels as well.
Although clomipramine shows around 100- to 200-fold preference in affinity for the serotonin transporter (SERT) over the norepinephrine transporter (NET), its major active metabolite, desmethylclomipramine (norclomipramine), binds to the NET with very high affinity (Ki = 0.32 nM) and with dramatically reduced affinity for the SERT (Ki = 31.6 nM). Moreover, desmethylclomipramine circulates at concentrations that are approximately twice those of clomipramine. In accordance, occupancy of both the SERT and the NET has been shown with clomipramine administration in positron emission tomography studies with humans and non-human primates. As such, clomipramine is in fact a fairly balanced SNRI rather than only a serotonin reuptake inhibitor (SRI).
The antidepressant effects of clomipramine are thought to be due to reuptake inhibition of serotonin and norepinephrine, while serotonin reuptake inhibition only is thought to be responsible for the effectiveness of clomipramine in the treatment of OCD. Conversely, antagonism of the H1, α1-adrenergic, and muscarinic acetylcholine receptors is thought to contribute to its side effects. Blockade of the H1 receptor is specifically responsible for the antihistamine effects of clomipramine and side effects like sedation and somnolence (sleepiness). Antagonism of the α1-adrenergic receptor is thought to cause orthostatic hypotension and dizziness. Inhibition of muscarinic acetylcholine receptors is responsible for the anticholinergic side effects of clomipramine like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. In overdose, sodium channel blockade in the brain is believed to cause the coma and seizures associated with TCAs while blockade of sodium channels in the heart is considered to cause cardiac arrhythmias, cardiac arrest, and death. On the other hand, sodium channel blockade is also thought to contribute to the analgesic effects of TCAs, for instance in the treatment of neuropathic pain.
The exceptionally strong serotonin reuptake inhibition of clomipramine likely precludes the possibility of its antagonism of serotonin receptors (which it binds to with more than 100-fold lower affinity than the SERT) resulting in a net decrease in signalling by these receptors. In accordance, while serotonin receptor antagonists like cyproheptadine and chlorpromazine are effective as antidotes against serotonin syndrome, clomipramine is nonetheless capable of inducing this syndrome. In fact, while all TCAs are SRIs and serotonin receptor antagonists to varying extents, the only TCAs that are associated with serotonin syndrome are clomipramine and to a lesser extent its dechlorinated analogue imipramine, which are the two most potent SRIs of the TCAs (and in relation to this have the highest ratios of serotonin reuptake inhibition to serotonin receptor antagonism). As such, whereas other TCAs can be combined with monoamine oxidase inhibitors (with caution due to the risk of hypertensive crisis from NET inhibition; sometimes done in treatment-resistant depressives), clomipramine cannot be due to the risk of serotonin syndrome and death. Unlike the case of its serotonin receptor antagonism, orthostatic hypotension is a common side effect of clomipramine, suggesting that its blockade of the α1-adrenergic receptor is strong enough to overcome the stimulatory effects on the α1-adrenergic receptor of its NET inhibition.
Serotonergic Activity
Clomipramine is a very strong SRI. Its affinity for the SERT was reported in one study using human tissues to be 0.14 nM, which is considerably higher than that of other TCAs. For example, the TCAs with the next highest affinities for the SERT in the study were imipramine, amitriptyline, and dosulepin (dothiepin), with Ki values of 1.4 nM, 4.3 nM, and 8.3 nM, respectively. In addition, clomipramine has a terminal half-life that is around twice as long as that of amitriptyline and imipramine. In spite of these differences however, clomipramine is used clinically at the same usual dosages as other serotonergic TCAs (100-200 mg/day). It achieves typical circulating concentrations that are similar in range to those of other TCAs but with an upper limit that is around twice that of amitriptyline and imipramine. For these reasons, clomipramine is the most potent SRI among the TCAs and is far stronger as an SRI than other TCAs at typical clinical dosages. In addition, clomipramine is more potent as an SRI than any SSRIs, it is more potent than paroxetine, which is the strongest SSRI.
A positron emission tomography study found that a single low dose of 10 mg clomipramine to healthy volunteers resulted in 81.1% occupancy of the SERT, which was comparable to the 84.9% SERT occupancy by 50 mg fluvoxamine. In the study, single doses of 5 to 50 mg clomipramine resulted in 67.2 to 94.0% SERT occupancy while single doses of 12.5 to 50 mg fluvoxamine resulted in 28.4 to 84.9% SERT occupancy. Chronic treatment with higher doses was able to achieve up to 100.0% SERT occupancy with clomipramine and up to 93.6% SERT occupancy with fluvoxamine. Other studies have found 83% SERT occupancy with 20 mg/day paroxetine and 77% SERT occupancy with 20 mg/day citalopram. These results indicate that very low doses of clomipramine are able to substantially occupy the SERT and that clomipramine achieves higher occupancy of the SERT than SSRIs at comparable doses. Moreover, clomipramine may be able to achieve more complete occupancy of the SERT at high doses, at least relative to fluvoxamine.
If the ratios of the 80% SERT occupancy dosage and the approved clinical dosage range are calculated and compared for SSRIs, SNRIs, and clomipramine, it can be deduced that clomipramine is by far the strongest SRI used medically. The lowest approved dosage of clomipramine can be estimated to be roughly comparable in SERT occupancy to the maximum approved dosages of the strongest SSRIs and SNRIs. Because their mechanism of action was originally not known and dose-ranging studies were never conducted, first-generation antipsychotics were dramatically overdosed in patients. It has been suggested that the same may have been true for clomipramine and other TCAs.
Obsessive-Compulsive Disorder
Clomipramine was the first drug that was investigated for and found to be effective in the treatment of OCD. In addition, it was the first drug to be approved by the Food and Drug Administration (FDA) in the United States for the treatment of OCD. The effectiveness of clomipramine in the treatment of OCD is far greater than that of other TCAs, which are comparatively weak SRIs; a meta-analysis found pre- versus post-treatment effect sizes of 1.55 for clomipramine relative to a range of 0.67 for imipramine and 0.11 for desipramine. In contrast to other TCAs, studies have found that clomipramine and SSRIs, which are more potent SRIs, have similar effectiveness in the treatment of OCD. However, multiple meta-analyses have found that clomipramine nonetheless retains a significant effectiveness advantage relative to SSRIs; in the same meta-analysis mentioned previously, the effect sizes of SSRIs in the treatment of OCD ranged from 0.81 for fluoxetine to 1.36 for sertraline (relative to 1.55 for clomipramine). However, the effectiveness advantage for clomipramine has not been apparent in head-to-head comparisons of clomipramine versus SSRIs for OCD. The differences in effectiveness findings could be due to differences in methodologies across non-head-to-head studies.
Relatively high doses of SSRIs are needed for effectiveness in the treatment of OCD. Studies have found that high dosages of SSRIs above the normally recommended maximums are significantly more effective in OCD treatment than lower dosages (e.g. 250 to 400 mg/day sertraline versus 200 mg/day sertraline). In addition, the combination of clomipramine and SSRIs has also been found to be significantly more effective in alleviating OCD symptoms, and clomipramine is commonly used to augment SSRIs for this reason. Studies have found that intravenous clomipramine, which is associated with very high circulating concentrations of the drug and a much higher ratio of clomipramine to its metabolite desmethylclomipramine, is more effective than oral clomipramine in the treatment of OCD. There is a case report of complete remission from OCD for approximately one month following a massive overdose of fluoxetine, an SSRI with a uniquely long duration of action. Taken together, stronger serotonin reuptake inhibition has consistently been associated with greater alleviation of OCD symptoms, and since clomipramine, at the clinical dosages in which it is employed, is effectively the strongest SRI used medically, this may underlie its unique effectiveness in the treatment of OCD.
In addition to serotonin reuptake inhibition, clomipramine is also a mild but clinically significant antagonist of the dopamine D1, D2, and D3 receptors at high concentrations. Addition of antipsychotics, which are potent dopamine receptor antagonists, to SSRIs, has been found to significantly augment their effectiveness in the treatment of OCD. As such, besides strong serotonin reuptake inhibition, clomipramine at high doses might also block dopamine receptors to treat OCD symptoms, and this could additionally or alternatively be involved in its possible effectiveness advantage over SSRIs.
Although clomipramine is probably more effective in the treatment of OCD compared to SSRIs, it is greatly inferior to them in terms of tolerability and safety due to its lack of selectivity for the SERT and promiscuous pharmacological activity. In addition, clomipramine has high toxicity in overdose and can potentially result in death, whereas death rarely, if ever, occurs with overdose of SSRIs. It is for these reasons that clomipramine, in spite of potentially superior effectiveness to SSRIs, is now rarely used as a first-line agent in the treatment of OCD, with SSRIs being used as first-line therapies instead and clomipramine generally being reserved for more severe cases and as a second-line agent.
Pharmacokinetics
The oral bioavailability of clomipramine is approximately 50%. Peak plasma concentrations occur around 2-6 hours (with an average of 4.7 hours) after taking clomipramine orally and are in the range of 56-154 ng/mL (178-489 nmol/L). Steady-state concentrations of clomipramine are around 134-532 ng/mL (426-1,690 nmol/L), with an average of 218 ng/mL (692 nmol/L), and are reached after 7 to 14 days of repeated dosing. Steady-state concentrations of the active metabolite, desmethylclomipramine, are around 230-550 ng/mL (730-1,750 nmol/L). The volume of distribution (Vd) of clomipramine is approximately 17 L/kg. It binds approximately 97-98% to plasma proteins, primarily to albumin. Clomipramine is metabolised in the liver mainly by CYP2D6. It has a terminal half-life of 32 hours, and its N-desmethyl metabolite, desmethylclomipramine, has a terminal half-life of approximately 69 hours. Clomipramine is mostly excreted in urine (60%) and faeces (32%).
Chemistry
Clomipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine, desipramine, and trimipramine. Clomipramine is a derivative of imipramine with a chlorine atom added to one of its rings and is also known as 3-chloroimipramine. It is a tertiary amine TCA, with its side chain-demethylated metabolite desmethylclomipramine being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, dosulepin (dothiepin), doxepin, and trimipramine. The chemical name of clomipramine is 3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H23ClN2 with a molecular weight of 314.857 g/mol. The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely. The CAS Registry Number of the free base is 303-49-1 and of the hydrochloride is 17321-77-6.
Society and Culture
Generic Names
Clomipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while clomipramine hydrochloride is its USAN, USP, BANM, and JAN. Clomipramina is its generic name in Spanish, Portuguese and Italian and its DCIT, while clomipramin is its generic name in German and clomipraminum is its generic name in Latin.
Brand Names
Clomipramine is marketed throughout the world mainly under the brand names Anafranil and Clomicalm for use in humans and animals, respectively.
Veterinary Uses
In the US, clomipramine is only licensed to treat separation anxiety in dogs for which it is sold under the brand name Clomicalm. It has proven effective in the treatment of OCD in cats and dogs. In dogs, it has also demonstrated similar efficacy to fluoxetine in treating tail chasing. In dogs some evidence suggests its efficacy in treating noise phobia.
Clomipramine has also demonstrated efficacy in treating urine spraying in cats. Various studies have been done on the effects of clomipramine on cats to reduce urine spraying/marking behaviour. It has been shown to be able to reduce this behaviour by up to 75% in a trial period of four weeks.
Cognitive models generally fall into the category of executive dysfunction or modulatory control. Neuroanatomically, functional and structural neuroimaging studies implicate the prefrontal cortex (PFC), basal ganglia (BG), insula, and posterior cingulate cortex (PCC). Genetic and neurochemical studies implicate glutamate and monoamine neurotransmitters, especially serotonin and dopamine.
The cortico-basal ganglia-thalamo-cortical loop (CBGTC) model is based on the observation that the basal ganglia loops related to the OFC and ACC are implicated in OCD by neuroimaging studies, although the directionality of volumetric and functional changes is not consistent. Causal evidence from OCD secondary to neuropsychiatric disorders supports the CBGTC model. Obsessions may arise from failure of the circuit to gate information that is normally implicitly processed, leading to representation in explicit processing systems such as the dlPFC and hippocampus, and thereby resulting in obsessions.
Abnormal affect in OCD has been hypothesized to result from dysfunction in the OFC, ventral striatum, and amygdala. OCD is characterised by high levels of anxiety, high rates of comorbidity with major depressive disorder, and blunted response to reward. This is reflected by reduced amygdala and ventral striatum response to positive stimuli, and elevated amygdala response to fearful stimuli. Furthermore, deep brain stimulation of the nucleus accumbens is an effective treatment of OCD, and symptom improvement correlates with reduced binding of dopamine receptors. The reduced binding, due to the ability of the radioligand tracers to be displaced by endogenous dopamine, is taken to reflect increased basal dopamine release. Affective dysregulation due to blunted reward, and elevated fear sensitivity may promote compulsivity by assigning excessive motivational salience to avoidance behaviour.
The ventral striatum is important in action selection, and receives inputs from the medial OFC that signal various aspects of value for stimulus association outcomes. By assigning abnormal values to certain behaviours, OFC may lead to compulsive behaviour through modulating action selection in the ventral striatum. A number of abnormalities have been found in the OFC, including reduced volume, increased resting state activity, and reduced activity during cognitive tasks. The difference between resting and cognitive paradigms may be due to increased signal to noise ratio, a possible mechanism of aberrant valuation. OFC-striatum connectivity also predicts symptom severity, although the opposite has been found in some studies.
Besides abnormal valuation of stimuli or tasks, compulsions may be driven by dysfunction in error monitoring that leads to excessive uncertainty.
OCD has also been conceptualised as resulting from dysfunction in response inhibition, and fear extinction. While hyperactivation of the OFC as a whole during resting is observed in OCD, hyperactivation of the lateral OFC and hypoactivation of the mOFC is seen. This is congruent with the localization of fear/avoidance behaviours to the lOFC and emotional regulation to the mOFC. Hyperactivity of the dACC during monitoring task, along with hyperactivity of the lOFC and amygadala may all contribute to generating obsessions, reduced regulation by the mOFC may enable them.
One model suggests that obsessions do not drive compulsions, but are rather byproducts of compulsions, as evidenced by some studies reporting excessive reliance on habit. Dysfunctional habit based learning may be a driver behind neuroimaging studies of memory reporting increased hippocampus activity. The conscious processing of information that is normally implicitly processing may be the underlying cause of obsessions.
Functional Neuroimaging
Functional neuroimaging studies have implicated multiple regions in OCD. Symptom provocation is associated with increased likelihood of activation in the bilateral orbitofrontal cortex (OFC), right anterior PFC, left dorsolateral prefrontal cortex (dlPFC), bilateral anterior cingulate cortex (ACC), left precuneus, right premotor cortex, left superior temporal gyrus (STG), bilateral external globus pallidus, left hippocampus, right insula, left caudate, right posterior cingulate cortex (PCC), and right superior parietal lobule. The medial portion of the orbitofrontal cortex connects with the paralimbic-limbic system, including the insular cortex, cingulate gryus, amygdala, and hypothalamus. This area is involved in encoding the representation of the value of an expected outcome, which is used to anticipate positive and negative consequences that are likely to follow a given action. During affective tasks hyperactivation has been observed in the ACC, insula and head of the caudate and putamen, regions implicated in salience, arousal, and habit. Hypoactivation during affective tasks is observed in the medial prefrontal cortex (mPFC) and posterior caudate, which are implicated in behavioural and cognitive control. During non-affective tasks, hyperactivation has been observed in the precuneus and PCC, while hypoactivation has been observed in the pallidum, ventral anterior thalamus and posterior caudate. An older meta analysis found hyperactivity in the OFC and ACC. An ALE meta analysis of various functional neuroimaging paradigms observed various abnormalities during Go/no go, interference, and task switching paradigms. Decreased likelihood of activation in right putamen and cerebellum was reported during Go/no go. During interference tasks, likelihood of activation was reported in the left superior frontal gyrus, right precentral gyrus, and left cingulate gyrus, to be decreased, and in the right caudate to be increased. Task switching was associated with extensive decreased likelihood of activation in the middle, medial, inferior, superior frontal gyri, caudate, cingulate and precuneus. A separate ALE meta analysis found consistent abnormalities in orbitofrontal, striatal, lateral frontal, anterior cingulate, middle occipital and parietal, and cerebellar regions.
Structural Neuroimaging
Differences in grey matter, white matter and structural connectivity have been observed in OCD. One meta-analysis reported grey matter increases in the bilateral lenticular nuclei, and grey matter decreases in the ACC (anterior cingulate cortex) and mPFC (medial prefrontal cortex).[14] Another meta-analysis reported that global volumes are not decreased, but the left ACC and OFC demonstrate decreased volume, while the thalamus but not basal ganglia have increased volumes. An ALE meta analysis found increased grey matter in the left postcentral gyrus, middle frontal region, putamen, thalamus, left ACC, and culmen, while decreased grey matter was reported in the right temporal gyrus and left insula extending to the inferior frontal gyrus.
Overlapping abnormalities in white matter volume and diffusivity have been reported. Increased white matter volume and decreased Fractional anisotropy has been observed in anterior midline tracts, interpreted as indicating increased crossings. However, given these effects were most pronounced in medicated adults, it is possible that medication plays a role An ALE meta analysis has observed increased FA in the superior longitudinal fasiculus and corpus callosum, and decreased FA in inferior longitudinal and cingulum fibres.
Neurochemistry
Glutamate, an excitatory neurotransmitter has been implicated in OCD. MRS studies have observed decreased Glx (glutamate, glutamine and GABA) in the striatum. However, increased Glx has been reported in the ACC. Furthermore, increased cerebrospinal fluid (CSF) glutamate and glycine have been found. Various preclinical models have supported glutamate signalling dysfunction in OCD, and treatment with glutamatergic agents such as the glutamate-inhibiting riluzole has been reported to be efficacious.
Reduced dopamine D1 receptors and dopamine D2 receptors in the striatum have been reported in people with OCD, along with both increased and decreased reports of dopamine transporter (DAT) binding. While antipsychotics are sometimes used to treat refractory OCD, they frequently fail in treating or exacerbate OCD symptoms. Treatment with deep brain stimulation is effective in OCD, and response correlates with increased dopamine in the nucleus accumbens. Combined this evidence suggests that OCD may be associated with both increased and decreased dopamine signalling, or that a unidirectional model may not be adequate.
Drug challenge studies have implicated 5-HT2A and 5-HT2A in OCD. Administration of meta-Chlorophenylpiperazine (mCPP), a non selective serotonin (5-HT) release and receptor agonist with a preference for 5-HT2C has been reported to exacerbate OCD symptoms. Psilocybin, a 5-HT2C, 5-HT2A and 5-HT1A receptor agonist has been associated with acute improvement of OCD symptoms. In vivo neuroimaging has found abnormalities with 5-HT2A and serotonin transporter (5-HTT). Inconsistent binding potentials have been observed for 5-HT2A, with both decreased and increased and binding potentials being reported. Inconsistent results have been reported in with respect to 5-HTT as well, with increased, decreased and no changes being reported.
Oestrogen and OCD
Aromatase is an enzyme expressed in several gonadic tissue sites. It is the rate limiting step in the conversion of androgens to oestrogen. This conversion can significantly impact oestrogen levels in brain areas. These OCD-linked effects have been demonstrated by Aromatase knockout mice (ArKO), who lack a functional enzyme to convert androgens to oestrogen. This ArKO knockout strategy has provided a model to examine the physiological impact of lower than normal amounts of oestrogen.
Studies with ArKO mice have been used to show that varying levels of oestrogen affect the onset of OCD behaviours. Lower amounts of oestrogen are associated with an increase of OCD behaviours in males more than females.
Variation in oestrogen can lead to increased levels of OCD symptoms within women as well. The disorder itself has a later onset in women, and tends to show two distinct peaks of onset. The first peak occurs around puberty and the second around the age of childbearing. These peaks correlate with time periods where oestrogen levels are highest in women.
The obsessive-compulsive spectrum is a model of medical classification where various psychiatric, neurological and/or medical conditions are described as existing on a spectrum of conditions related to obsessive-compulsive disorder (OCD).
“The disorders are thought to lie on a spectrum from impulsive to compulsive where impulsivity is said to persist due to deficits in the ability to inhibit repetitive behavior with known negative consequences, while compulsivity persists as a consequence of deficits in recognizing completion of tasks.”
OCD is a mental disorder characterised by obsessions and/or compulsions. An obsession is defined as “a recurring thought, image, or urge that the individual cannot control”. Compulsion can be described as a “ritualistic behaviour that the person feels compelled to perform”. The model suggests that many conditions overlap with OCD in symptomatic profile, demographics, family history, neurobiology, comorbidity, clinical course and response to various pharmacotherapies. Conditions described as being on the spectrum are sometimes referred to as obsessive-compulsive spectrum disorders.
Conditions
The following conditions have been hypothesized by various researchers as existing on the spectrum:
However, recently there is a growing support for proposals to narrow down this spectrum to only include body dysmorphic disorder, hypochondriasis, tic disorders, and trichotillomania.
Body dysmorphic disorder is defined by an obsession with an imagined defect in physical appearance, and compulsive rituals in an attempt to conceal the perceived defect. Typical complaints include perceived facial flaws, perceived deformities of body parts and body size abnormalities. Some compulsive behaviours observed include mirror checking, ritualised application of makeup to hide the perceived flaw, excessive hair combing or cutting, excessive physician visits and plastic surgery. Body dysmorphic disorder is not gender specific and onset usually occurs in teens and young adults.
Hypochondriasis
Hypochondriasis is excessive preoccupancy or worry about having a serious illness. These thoughts cause a person a great deal of anxiety and stress. The prevalence of this disorder is the same for men and women. Hypochondriasis is normally recognised in early adult age. Those that suffer with hypochondriasis are constantly thinking of their body functions, minor bumps and bruises as well as body images. Hypochondriacs go to numerous outpatient facilities for confirmation of their own diagnosis. Hypochondriasis is the belief that something is wrong but it is not known to be a delusion.
Tic Disorders
Tourette’s syndrome is a neurological disorder characterised by recurrent involuntary movements (motor tics) and involuntary noises (vocal tics). The reason Tourette’s syndrome and other tic disorders are being considered for placement in the obsessive compulsive spectrum is because of the phenomenology and co-morbidity of the disorders with obsessive compulsive disorder. Within the population of patients with OCD up to 40% have a history of a tic disorder and 60% of people with Tourette’s syndrome have obsessions and/or compulsions. Plus 30% of people with Tourette’s syndrome have clinically diagnosable OCD. Course of illness is another factor that suggests correlation because it has been found that tics displayed in childhood are a predictor of obsessive and compulsive symptoms in late adolescence and early adulthood. However, the association of Tourette’s and tic disorders with OCD is challenged by neuropsychology and pharmaceutical treatment. Whereas OCD is treated with SSRI, tics are treated with dopamine blockers and alpha-2 agonists.
Trichotillomania is an impulse control disorder which causes an individual to pull out their hair from various parts of their body without a purpose. The cause for trichotillomania remains unknown. Like OCD, trichotillomania isn’t a nervous condition but stress can trigger this habit. For some people pulling their hair out of boredom is normal, but that isn’t the case for someone that is dealing with trichotillomania. Emotions do not affect the behaviour but these behaviours are more prevalent in those that suffer with depression. Review articles recommend behavioural interventions such as habit reversal training and decoupling.
While racing thoughts are most commonly described in people with bipolar disorder and sleep apnoea, they are also common with anxiety disorders, OCD, and other psychiatric disorders such as attention deficit hyperactivity disorder. Racing thoughts are also associated with sleep deprivation, hyperthyroidism and the use of amphetamines.
Description
Racing thoughts may be experienced as background or take over a person’s consciousness. Thoughts, music, and voices might be zooming through one’s mind as they jump tangentially from one to the next. There also might be a repetitive pattern of voice or of pressure without any associated “sound”. It is a very overwhelming and irritating feeling, and can result in losing track of time. In some cases, it may also be frightening to the person experiencing it, as there is a loss of control. If one is experiencing these thoughts at night when going to sleep, they may suddenly awaken, startled and confused by the very random and sudden nature of the thoughts.
Racing thoughts differ in manifestation according to the individual’s perspective. These manifestations can vary from unnoticed or minor distractions to debilitating stress, preventing the sufferer from maintaining a thought.
Generally, racing thoughts are described by an individual who has had an episode where the mind uncontrollably brings up random thoughts and memories and switches between them very quickly. Sometimes they are related, as one thought leads to another; other times they seem completely random. A person suffering from an episode of racing thoughts has no control over their train of thought, and it stops them from focusing on one topic or prevents sleeping.
Associated Conditions
The causes of racing thoughts are most often associated with anxiety disorders, but many influences can cause these rapid, racing thoughts. There are also many associated conditions, in addition to anxiety disorders, which can be classified as having secondary relationships with causing racing thoughts. The conditions most commonly linked to racing thoughts are bipolar disorder, anxiety disorder, attention deficit hyperactivity disorder, sleep deprivation, amphetamine dependence, and hyperthyroidism.
Anxiety Disorders
Racing thoughts associated with anxiety disorders can be caused by many different conditions, such as obsessive-compulsive disorder (OCD), panic disorder, generalised anxiety disorder, or posttraumatic stress disorder.
In people with OCD, racing thoughts can be brought on by stressors, or triggers, causing disturbing thoughts in the individual. These disturbing thoughts, then, result in compulsions characterising OCD in order to lower the stress and gain some sort of control over these stressful, racing thoughts.
Panic disorder is an anxiety disorder characterised by repeated panic attacks of fear or nervousness, lasting several minutes. During these panic attacks, the response is out of proportion to the situation. The racing thoughts may feel catastrophic and intense, but they are a symptom of the panic attack and must be controlled in order to soothe the panic and minimise the panic attack.
Generalised anxiety disorder (GAD) is a neurological anxiety disorder that involves uncontrollable and excessive worrying about irrational topics or problems. These stressful thoughts must be present for at least six months in order to be diagnosed as GAD. Along with other symptoms, racing thoughts is one of the most common ones. With GAD, there is an inability to relax or let thoughts or worries go, persistent worrying and obsessions about small concerns that are out of proportion to the result, and even worrying about their excessive worrying.
Bipolar Disorder
Racing thoughts can be brought on by bipolar disorder, defined by mood instability that range from extreme emotional highs, mania, to severe depression. During the manic phase of bipolar disorder is when racing thoughts usually occur. Disjointed, constantly changing thoughts with no underlying theme can be a sign of the manic phase of bipolar disorder. Manic thoughts can prevent performance of daily routines due to their rapid, unfocused and overwhelming nature. Racing thoughts in people with bipolar disorder are generally accompanied with other symptoms associated with this disorder.
Amphetamines
Amphetamines are used as a stimulant to trigger the central nervous system, increasing heart rate and blood pressure while decreasing appetite. Since amphetamines are a stimulant, use of these drugs result in a state that resembles the manic phase of bipolar disorder and also produces similar symptoms, as stated above.
Attention Deficit Hyperactivity Disorder
Racing thoughts associated with ADHD is most common in adults. With ADHD, racing thoughts can occur and tend to cause insomnia. Racing thoughts in people with ADHD tend to be rapid, unstable thoughts which do not follow any sort of pattern, similar to racing thoughts in people with bipolar disorder. Medications used to treat ADHD, such as Adderall or Methylphenidate, can be prescribed to patients with ADHD to calm these racing thoughts, most commonly in the morning when people wake up but just as well in the evening before sleep.
Lack of Sleep
Racing thoughts, also referred to as “racing mind”, may prevent a person from falling asleep. Chronic sleep apnoea and prolonged disturbed sleep patterns may also induce racing thoughts. Treatment for sleep apnoea and obstructive airway disorder can improve airflow and improve sleep resulting in improved brain and REM (rapid eye movement) function and reduced racing thought patterns.
Hyperthyroidism
Hyperthyroidism is a condition in which the thyroid gland produces too much thyroid hormone, thyroxin. This overabundance of thyroxin causes irregular and rapid heartbeat, irritability, weight loss, nervousness, anxiety and racing thoughts. The anxiety and inability to focus is very common in hyperthyroidism and leads to racing thoughts, as well as panic attacks and difficulty concentrating.
Frequency
Anxiety disorder, the most common mental illness in the United States, affects 40 million people, ages 10 and older; this accounts for 18% of the US population. Most people suffering from anxiety disorder report some form of racing thoughts symptom.
The prevalence of OCD in every culture studied is at least 2% of the population, and the majority of those have obsessions, or racing thoughts. With these reports, estimates of more than 2 million people in the United States (as of 2000) suffer from racing thoughts.
Treatment
There are various treatments available to calm racing thoughts, some of which involve medication. One type of treatment involves writing out the thoughts onto paper. Some treatments suggest using activities, such as painting, cooking, and other hobbies, to keep the mind busy and distract from the racing thoughts. Exercise may be used to tire the person, thereby calming their mind. When racing thoughts are anxiety induced during panic or anxiety attacks, it is recommended that the person wait it out. Using breathing and meditation techniques to calm the breath and mind simultaneously is another tool for handling racing thoughts induced by anxiety attacks. Mindfulness meditation has also shown to help with racing thoughts by allowing practitioners to face their thoughts head-on, without reacting.
While all of these techniques can be useful to cope with racing thoughts, it may prove necessary to seek medical attention and counsel. Since racing thoughts are associated with many other underlying mental illnesses, such as bipolar disorder, anxiety disorder, and ADHD, medications used commonly to treat these disorders will help calm racing thoughts in patients.
Treatment for the underlying causes of racing thoughts is helpful and useful in order to calm the racing thoughts more permanently. For example, in people with ADHD, medications used to promote focus and calm distracting thoughts, will help them with their ADHD.
Some obstructive airway disorders may be relieved with nasal septoplasty which can improve sleep and lead to a reduction of racing mind. Insomnia may increase racing thoughts and those effected will find sleep apnoea treatment and nasal surgery helpful to eliminate their racing thoughts.
It is important to look at the underlying defect that may be causing racing thoughts in order to prevent them in the long-term.
The Yale–Brown Obsessive Compulsive Scale (Y-BOCS) is a test to rate the severity of obsessive-compulsive disorder (OCD) symptoms.
The scale, which was designed by Wayne K. Goodman and his colleagues, is used extensively in research and clinical practice to both determine severity of OCD and to monitor improvement during treatment. This scale, which measures obsessions separately from compulsions, specifically measures the severity of symptoms of obsessive-compulsive disorder without being biased towards or against the type of content the obsessions or compulsions might present. Following the original publication the total score is usually computed from the subscales for obsessions (items 1-5) and compulsions (items 6-10) but other algorithms exist.
Accuracy and Modifications
Goodman and his colleagues have developed the Yale-Brown Obsessive-Compulsive Scale-Second Edition (Y-BOCS-II) in an effort to modify the original scale which, according to Goodman, “[has become] the gold standard measure of obsessive-compulsive disorder (OCD) symptom severity”. In creating the Y-BOCS-II, changes were made “to the Severity Scale item content and scoring framework, integrating avoidance into the scoring of Severity Scale items, and modifying the Symptom Checklist content and format”. After reliability tests, Goodman concluded that “Taken together, the Y-BOCS-II has excellent psychometric properties in assessing the presence and severity, of obsessive-compulsive symptoms. Although the Y-BOCS remains a reliable and valid measure, the Y-BOCS-II may provide an alternative method of assessing symptom presence and severity.”
Studies have been conducted by members of the Iranian Journal of Psychiatry & Clinical Psychology to determine the accuracy of the Yale-Brown Obsessive Compulsive Scale (specifically as it appears in its Persian format). The members applied the scale to a group of individuals and, after ensuring a normal distribution of data, a series of reliability tests were performed. According to the authors, “[the] results supported satisfactory validity and reliability of translated form of Yale-Brown Obsessive-Compulsive Scale for research and clinical diagnostic applications”.
Children’s Version
The children’s version of the Y-BOCS, or the Children’s Yale-Brown Obsessive Compulsive Scales (CY-BOCS), is a clinician-report questionnaire designed to assess symptoms of obsessive compulsive disorder from childhood through early adolescence.
The CY-BOCS contains 70 questions and takes about 15-25 minutes. Each question is designed to ask about symptoms of obsessive compulsive behaviour, though the exact breakdown of questions is unknown. For each question, children rate the degree to which the question applies on a scale of 0-4. Based on research, this assessment has been found to be statistically valid and reliable, but not necessarily helpful.
Other Versions
The CY-BOCS has been adapted into several self- and parent-report versions, designed to be completed by parent and child working together, although most have not been psychometrically validated. However, these versions still ask the child to rate the severity of their obsessive compulsive behaviours and the degree to which each has been impairing. While this measure has been found to be useful in a clinic setting, scores and interpretations are taken with a grain of salt, given the lack of validation.
Another version, which is parent-focused, is similar to the original CY-BOCS and is administered to both parent and child by the clinician. This version was distributed by Solvay Pharmaceuticals in the late 1990s, creating an association between the measure and a number of pharmaceutical groups that has caused it to be avoided by most clinicians. Severity cut-off scores for this version have not been empirically determined.
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