Tag: GAD: Generalised Anxiety Disorder

What is Buspirone?

Published on by Andrew Marshall6 Comments

Introduction

Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalised anxiety disorder. Benefits support its short-term use. It is taken orally (by mouth), and takes two to six weeks to be fully effective.

Refer to Azapirone.

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating. Serious side effects may include movement disorders, serotonin syndrome, and seizures. Its use in pregnancy appears to be safe but has not been well studied, and use during breastfeeding has not been well studied. It is a serotonin 5-HT1A receptor agonist.

Buspirone was first made in 1968 and approved for medical use in the United States in 1986. It is available as a generic medication. In 2020, it was the 55th most-commonly prescribed medication in the United States, with more than 12 million prescriptions.

Brief History

Buspirone was first synthesized by a team at Mead Johnson in 1968 but was not patented until 1980. It was initially developed as an antipsychotic acting on the D2 receptor but was found to be ineffective in the treatment of psychosis; it was then used as an anxiolytic instead. In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD. The patent expired in 2001, and buspirone is now available as a generic drug.

Medical Uses

Anxiety

Buspirone is used for the short-term and long-term treatment of anxiety disorders or symptoms of anxiety. It is generally preferred over benzodiazepines because it does not activate the receptors that make drugs like alprazolam addictive.

Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2–4 weeks to manifest itself. The drug has been shown to be similarly effective in the treatment of generalised anxiety disorder (GAD) to benzodiazepines including diazepam, alprazolam, lorazepam, and clorazepate. Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD, although there is some limited evidence that it may be useful in the treatment of social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).

Other Uses

Sexual Dysfunction

There is some evidence that buspirone on its own may be useful in the treatment of hypoactive sexual desire disorder (HSDD) in women. Buspirone may also be effective in treating antidepressant-induced sexual dysfunction.

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawal, barbiturate withdrawal, or alcohol withdrawal/delirium tremens.

SSRI and SNRI antidepressants such as paroxetine and venlafaxine may cause jaw pain/jaw spasm reversible syndrome (although it is not common), and buspirone appears to be successful in treating bruxism on SSRI/SNRI-induced jaw clenching.

Contraindications

Buspirone has these contraindications:

  • Hypersensitivity to buspirone
  • Metabolic acidosis, as in diabetes
  • Should not be used with MAO inhibitors
  • Severely compromised liver and/or kidney function

Side Effects

Known side effects associated with buspirone include dizziness, headaches, nausea, tinnitus, and paraesthesia. Buspirone is relatively well tolerated, and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects. In addition, buspirone does not produce euphoria and is not a drug of abuse. Dyskinesia, akathisia, myoclonus, parkinsonism, and dystonia were reported associated with buspirone. It is unclear if there is a risk of tardive dyskinesia or other movement disorders with buspirone.

Overdose

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available. In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed. Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals. One death has been reported in a co-ingestion of 450 mg buspirone with alprazolam, diltiazem, alcohol, cocaine.

Interactions

Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:

  • Itraconazole: Increased plasma level of buspirone
  • Rifampicin: Decreased plasma levels of buspirone
  • Nefazodone: Increased plasma levels of buspirone
  • Haloperidol: Increased plasma levels of buspirone
  • Carbamazepine: Decreased plasma levels of buspirone
  • Grapefruit: Significantly increases the plasma levels of buspirone.
  • Fluvoxamine: Moderately increase plasma levels of buspirone.
  • Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).

Pharmacology

Pharmacodynamics

Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity. It is a partial agonist of both presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and postsynaptic 5-HT1A receptors. It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons. Buspirone also has lower affinities for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors.

In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity. It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonises postsynaptic D2 receptors only at higher doses. In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals. Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.

A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself and is known to act as a potent α2-adrenergic receptor antagonist. This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals. In addition, 1-PP may play an important role in the antidepressant effects of buspirone. Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor. However, buspirone has been reported to have shown “significant and selective intrinsic efficacy” at the α1-adrenergic receptor expressed in a “tissue- and species-dependent manner”.

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.

Pharmacokinetics

Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism. The time to peak plasma levels following ingestion is 0.9 to 1.5 hours. It is reported to have an elimination half-life of 2.8 hours, although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours. Buspirone is metabolised primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed. Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans. The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo. As such, it is likely to play an important role in the therapeutic effects of buspirone. 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.

Chemistry

Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain.

Analogues

Structural analogues of buspirone include other azapirones like gepirone, ipsapirone, perospirone, and tandospirone.

A number of analogues are recorded.

Synthesis

A number of more modern methods of synthesis have also been reported (list not exhaustive).

Alkylation of 1-(2-pyrimidyl)piperazine 20980-22-7 with 3-chloro-1-cyanopropane (4-chlorobutyronitrile) 628-20-6 gives 33386-14-0. the reduction of the nitrile group is performed either by catalytic hydrogenation or with LAH giving 33386-20-8. The primary amine is then reacted with 3,3-tetramethyleneglutaric anhydride 5662-95-3 in order to yield Buspirone (6).

Society and Culture

Generic names

Buspirone is the INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and DCITTooltip Denominazione Comune Italiana of buspirone, while buspirone hydrochloride is its USANTooltip United States Adopted Name, BANMTooltip British Approved Name, and JANTooltip Japanese Accepted Name.

Brand Name

Buspirone was primarily sold under the brand name Buspar. Buspar is currently listed as discontinued by the US Food and Drug Administration (FDA). In 2010, in response to a citizen petition, the FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness.

2019 Shortage

Due to interrupted production at a Mylan Pharmaceuticals plant in Morgantown, West Virginia, the US experienced a shortage of buspirone in 2019.

Research

Some tentative research supports other uses such as the treatment of depression and behavioural problems following brain damage.

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What is Sertraline?

Published on by Andrew Marshall8 Comments

Introduction

Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.

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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What is Metacognition?

Published on by Andrew Marshall1 Comment

Introduction

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:

TypeOutline
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:

  1. Metacognitive knowledge (also called metacognitive awareness) is what individuals know about themselves and others as cognitive processors.
  2. Metacognitive regulation is the regulation of cognition and learning experiences through a set of activities that help people control their learning.
  3. 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:

  1. 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”.
  2. 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.
  3. 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.

  1. Planning: refers to the appropriate selection of strategies and the correct allocation of resources that affect task performance.
  2. Monitoring: refers to one’s awareness of comprehension and task performance
  3. 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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What is Alprazolam?

Published on by Andrew Marshall8 Comments

Introduction

Alprazolam, sold under the brand name Xanax, among others, is a fast-acting tranquiliser of medium duration in the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.

It is most commonly used in short-term management of anxiety disorders, specifically panic disorder or generalised anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken by mouth.

Common side effects include sleepiness, depression, headaches, feeling tired, dry mouth, and memory problems. Some of the sedation and tiredness may improve within a few days. Due to concerns about misuse, some do not recommend alprazolam as an initial treatment for panic disorder. Withdrawal or rebound symptoms may occur if use is suddenly decreased; gradually decreasing the dose over weeks or months may be required. Other rare risks include suicide, and a two fold increased risk of all cause mortality. Alprazolam, like other benzodiazepines, acts through the GABAA receptor.

Alprazolam was patented in 1971 and approved for medical use in the United States in 1981. Alprazolam is a Schedule IV controlled substance and is a common drug of abuse. It is available as a generic medication. In 2019, it was the 41st most commonly prescribed medication in the United States, with more than 17 million prescriptions.

Medical Uses

Alprazolam is mostly used in short term management of anxiety disorders, panic disorders, and nausea due to chemotherapy. Alprazolam may also be indicated for the treatment of GAD, as well as for the treatment of anxiety conditions with co-morbid depression. The US Food and Drug Administration (FDA) label advises that the physician should periodically reassess the usefulness of the drug.

Panic Disorder

Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks. However, it is not a first line treatment since the development of selective serotonin reuptake inhibitors. Alprazolam is no longer recommended in Australia for the treatment of panic disorder due to concerns regarding tolerance, dependence, and abuse. Most evidence shows that the benefits of alprazolam in treating panic disorder last only 4 to 10 weeks. However, people with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit.

In the United States, alprazolam is FDA-approved for the treatment of panic disorder with or without agoraphobia. Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence.

Anxiety Disorders

Anxiety associated with depression is responsive to alprazolam. Clinical studies have shown that the effectiveness is limited to 4 months for anxiety disorders. However, the research into antidepressant properties of alprazolam is poor and has only assessed its short-term effects against depression. In one study, some long term, high-dosage users of alprazolam developed reversible depression. In the US, alprazolam is FDA-approved for the management of anxiety disorders (a condition corresponding most closely to the Diagnostic and Statistical Manual DSM-IV-TR diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. In the UK, alprazolam is recommended for the short-term treatment (2-4 weeks) of severe acute anxiety.

Nausea due to Chemotherapy

Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting.

Contraindications

Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly people, people with substance use disorder history (particularly alcohol dependence), and people with comorbid psychiatric disorders. The use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with: myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies (e.g. cirrhosis), severe sleep apnoea, pre-existing respiratory depression, marked neuromuscular respiratory, acute pulmonary insufficiency, chronic psychosis, hypersensitivity or allergy to alprazolam or other benzodiazepines, and borderline personality disorder (where it may induce suicidality and dyscontrol).

Like all central nervous system depressants, alprazolam in larger-than-normal doses can cause significant deterioration in alertness and increase drowsiness, especially in those unaccustomed to the drug’s effects.

Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination and drowsiness.

Side Effects

Sedative drugs, including alprazolam, have been associated with an increased risk of death.

Possible side effects include:

  • Anterograde amnesia and concentration problems.
  • Ataxia, slurred speech.
  • Disinhibition.
  • Drowsiness, dizziness, lightheadedness, fatigue, unsteadiness, and impaired coordination, vertigo.
  • Dry mouth (infrequent).
  • Hallucinations (rare).
  • Jaundice (very rare).
  • Seizures (less common).
  • Skin rash, respiratory depression, constipation.
  • Suicidal ideation or suicide.
  • Urinary retention (infrequent).
  • Muscle weakness.

In September 2020, the FDA required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Paradoxical Reactions

Although unusual, the following paradoxical reactions have been shown to occur:

  • Aggression.
  • Mania, agitation, hyperactivity, and restlessness.
  • Rage, hostility.
  • Twitches and tremor.

Food and Drug Interactions

Alprazolam is primarily metabolised via CYP3A4. Combining CYP3A4 inhibitors such as cimetidine, erythromycin, norfluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of alprazolam, which may result in its accumulation and increased severity of its side effects.

Imipramine and desipramine have been reported to increase an average of 31% and 20% respectively by the concomitant administration of alprazolam tablets. Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.

Alcohol is one of the most common interactions; alcohol and alprazolam taken in combination have a synergistic effect on one another, which can cause severe sedation, behavioural changes, and intoxication. The more alcohol and alprazolam taken, the worse the interaction. Combination of alprazolam with the herb kava can result in the development of a semi-comatose state. Plants in the genus Hypericum (including St. John’s wort) conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.

Pregnancy and Breastfeeding

Benzodiazepines cross the placenta, enter the foetus, and are also excreted in breast milk. Chronic administration of diazepam, another benzodiazepine, to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.

The use of alprazolam during pregnancy is associated with congenital abnormalities, and use in the last trimester may cause foetal drug dependence and withdrawal symptoms in the post-natal period as well as neonatal flaccidity and respiratory problems. However, in long-term users of benzodiazepines, abrupt discontinuation due to concerns of teratogenesis has a high risk of causing extreme withdrawal symptoms and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines.

Overdose

Refer to Benzodiazepine Overdose.

The maximum recommended daily dose is 10 milligrams per day.

Overdoses of alprazolam can be mild to severe depending on the quantity ingested and if other drugs are taken in combination.

Alprazolam overdoses cause excess central nervous system (CNS) depression and may include one or more of the following symptoms:

  • Coma and death if alprazolam is combined with other substances.
  • Fainting.
  • Hypotension (low blood pressure).
  • Hypoventilation (shallow breathing).
  • Impaired motor functions.
  • Dizziness.
  • Impaired balance.
  • Impaired or absent reflexes.
  • Muscle weakness.
  • Orthostatic hypotension (fainting while standing up too quickly).
  • Somnolence (drowsiness).

Dependence and Withdrawal

Refer to Benzodiazepine Dependence and Benzodiazepine Withdrawal Syndrome.

The potential for misuse among those taking it for medical reasons is controversial, with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs. Others state that there is a substantial risk of misuse and dependence in both patients and non-medical users and that the short half-life and rapid onset of action may increase the risk of misuse. Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behaviour.

Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA (gamma-aminobutyric acid) receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABAA receptors and, thus, of GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and thus making the drugs less potent.

Withdrawal and rebound symptoms commonly occur and necessitate a gradual reduction in dosage to minimise withdrawal effects when discontinuing.

Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pre-treatment levels. If the symptoms are more severe or frequent, the person may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the person actually being drug dependent.

Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment. There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a person stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.

In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required.

Some common symptoms of alprazolam discontinuation include malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness.

Those taking more than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures, as well as marked delirium similar to that produced by the anticholinergic tropane alkaloids of Datura (scopolamine and atropine). The discontinuation of this medication may also cause a reaction called rebound anxiety.

In a 1983 study, only 5% of patients who had abruptly stopped taking long-acting benzodiazepines after less than 8 months demonstrated withdrawal symptoms, but 43% of those who had been taking them for more than 8 months did. With alprazolam – a short-acting benzodiazepine – taken for 8 weeks, 65% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.

The benzodiazepines diazepam and oxazepam have been found to produce fewer withdrawal reactions than alprazolam, temazepam, or lorazepam. Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines, and method of discontinuation.

Pharmacology

Alprazolam is a positive allosteric modulator of the GABA type A receptor. When it binds to the receptor, effects of GABA are enhanced leading to inhibition of neurones in the brain. This results in effects including reduced anxiety, muscle relaxant, antidepressant and anticonvulsant activity. The activity of alprazolam in the central nervous system is dose dependent.

Mechanism of Action

Alprazolam is classed as a high-potency triazolobenzodiazepine: a benzodiazepine with a triazole ring attached to its structure. As a benzodiazepine, alprazolam produces a variety of therapeutic and adverse effects by binding to the GABAA benzodiazepine receptor site and modulating its function; GABA receptors are the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. Binding of alprazolam to the GABAA receptor, a chloride ion channel, enhances the effects of GABA, a neurotransmitter. When GABA binds the GABAA receptor the channel opens and chloride enters the cell which makes it more resistant to depolarisation. Therefore, alprazolam has a depressant effect on synaptic transmission to reduce anxiety.

The GABAA receptor is made up of 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Alprazolam and other triazolobenzodiazepines such as triazolam that have a triazole ring fused to their diazepine ring appear to have antidepressant properties. This is perhaps due to the similarities shared with tricyclic antidepressants, as they have two benzene rings fused to a diazepine ring. Alprazolam causes a marked suppression of the hypothalamic-pituitary-adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic; however, it is used mainly as an anxiolytic.

Giving alprazolam, as compared to lorazepam, has been demonstrated to elicit a statistically significant increase in extracellular dopamine D1 and D2 concentrations in the striatum.

Pharmacokinetics

Alprazolam is taken orally, and is absorbed well – 80% of alprazolam binds to proteins in the serum (the majority binding to albumin). The concentration of alprazolam peaks after one to two hours.

Alprazolam is metabolised in the liver, mostly by the enzyme cytochrome P450 3A4 (CYP3A4). Two major metabolites are produced: 4-hydroxyalprazolam and α-hydroxyalprazolam, as well as an inactive benzophenone. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they have little to no contribution to the effects of alprazolam.

The metabolites, as well as some unmetabolised alprazolam, are filtered out by the kidneys and are excreted in the urine.

Chemistry

Physical Properties

Alprazolam is a triazole and benzodiazepine derivative substituted with a phenyl group at position 6, with a chlorine atom at position 8 and with a methyl group at position 1. It is an analogue of triazolam, the difference between them being the absence of a chlorine atom in the ‘ortho’ position of the phenyl ring. It is slightly soluble in chloroform, soluble in alcohol, slightly soluble in acetone and insoluble in water. It has a melting point in the temperature range 228-229.5 °C.

Synthesis

For the synthesis of alprazolam the same method can be used as for triazolam, excepting that it starts from 2-amino-5-chlorobenzophenone. However, an alternative easier synthesis starting with 2,6-dichloro-4-phenylquinoline has been suggested, in which it reacts with hydrazine giving 6-chloro-2-hydrazino-4-phenylquinoline. Boiling the mixture with triethyl orthoacetate results in cyclization with the formation of the triazole ring. The product undergoes oxidative degradation in the presence of periodate and ruthenium dioxide in acetone solution, giving 2-[4-(3′-methyl-1,2,4-triazolo)]-5-chlorobenzophenone. Oxy-methylation with formaldehyde results in a product that is treated with phosphorus tribromide, when 2-[4-(3′-methyl-5′-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone is obtained. By substituting the bromine atom with an amino group conferred by ammonia, it forms alprazolam triazolobenzophenone, following which an intermolecular heterocyclisation takes place to obtain alprazolam.

Detection

Quantification of alprazolam in blood and plasma samples may be necessary to confirm a diagnosis of intoxication in hospitalised patients, or to provide evidence in the case of crimes e.g., impaired driving arrest, or to assist in a thorough forensic investigation, e.g. in a medicolegal death investigation. Blood or plasma alprazolam concentrations are usually in a range of 10-100 μg/L in persons receiving the drug therapeutically, 100-300 μg/L in those arrested for impaired driving, and 300–2000 μg/L in victims of acute overdosage. Most of the commercial immunoassays used for the benzodiazepine class of drugs cross-react with alprazolam, but confirmation and quantitative determination are usually done by chromatographic techniques.

Forms of Alprazolam

Alprazolam regular release and orally disintegrating tablets are available as 0.25 mg, 0.5 mg, 1 mg, and 2 mg tablets, while extended release tablets are available as 0.5 mg, 1 mg, 2 mg, and 3 mg. Liquid alprazolam is available in a 1 mg/mL oral concentrate. Inactive ingredients in alprazolam tablets and solutions include microcrystalline cellulose, corn starch, docusate sodium, povidone, sodium starch glycollate, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, and sodium benzoate. In addition, the 0.25 mg tablet contains D&C Yellow No. 10 and the 0.5 mg tablet contains FD&C Yellow No. 6 and D&C Yellow No. 10.

Society and Culture

Patent

Alprazolam is covered under US Patent 3,987,052, which was filed on 29 October 1969, granted on 19 October 1976, and expired in September 1993.

Recreational Use

Refer to Benzodiazepine Use Disorder.

There is a risk of misuse and dependence in both patients and non-medical users of alprazolam; alprazolam’s high affinity binding, high potency, and rapid onset increase its abuse potential. The physical dependence and withdrawal syndrome of alprazolam also add to its addictive nature. In the small subgroup of individuals who escalate their doses there is usually a history of alcohol or other substance use disorders. Despite this, most prescribed alprazolam users do not use their medication recreationally, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation. However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to “primary tranquiliser” (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise. In 2011, The New York Times reported, “The Centres for Disease Control and Prevention last year reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008.”

Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States. A large-scale nationwide US government study conducted by SAMHSA found that, in the US, benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital emergency and urgent care facilities. Men and women are equally likely to use benzodiazepines recreationally. The report found that alprazolam is the most common benzodiazepine for recreational use, followed by clonazepam, lorazepam, and diazepam. The number of emergency department visits due to benzodiazepines increased by 36% between 2004 and 2006.

Regarding the significant increases detected, it is worthwhile to consider that the number of pharmaceuticals dispensed for legitimate therapeutic uses may be increasing over time, and DAWN estimates are not adjusted to take such increases into account. Nor do DAWN estimates take into account the increases in the population or in ED use between 2004 and 2006.

Those at a particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence and people with borderline personality disorder.

Alprazolam, along with other benzodiazepines, is often used with other recreational drugs. These uses include aids to relieve the panic or distress of dysphoric (“bad trip”) reactions to psychedelic drugs, such as LSD, and the drug-induced agitation and insomnia in the “comedown” stages of stimulant use, such as amphetamine, cocaine, and MDMA allowing sleep. Alprazolam may also be used with other depressant drugs, such as ethanol, heroin, and other opioids, in an attempt to enhance their psychological effects. Alprazolam may be used in conjunction with cannabis, with users citing a synergistic effect achieved after consuming the combination.

The poly-drug use of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an overdose, which may cause fatal respiratory depression.

A 1990 study found that diazepam has a higher misuse potential relative to many other benzodiazepines and that some data suggest that alprazolam and lorazepam resemble diazepam in this respect.

Anecdotally, injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolisation) and decay of muscle tissue (rhabdomyolysis). Alprazolam is not very soluble in water – when crushed in water it does not fully dissolve (40 µg/ml of H2O at pH 7). There have also been anecdotal reports of alprazolam being snorted.[111] Due to the low weight of a dose, alprazolam, in one case, was distributed on blotter paper in a manner similar to LSD.

Slang terms for alprazolam vary from place to place. Some of the more common terms are modified versions of the trade name “Xanax”, such as Xannies (or Xanies) and the phonetic equivalent of Zannies; references to their drug classes, such as benzos or downers; or remark upon their shape or colour (most commonly a straight, perforated tablet or an oval-shaped pill): bars, ladders, Xanbars, Xans, Z-bars, handle bars, beans, footballs, planks, poles, sticks, blues, or blue footballs.

Availability

Alprazolam is available in English-speaking countries under the following brand names:

  • Alprax, Alprocontin, Alzam, Alzolam, Anzilum, Apo-Alpraz, Helex, Kalma, Mylan-Alprazolam, Niravam, Novo-Alprazol, Nu-Alpraz, Pacyl, Restyl, Tranax, Trika, Xycalm, Xanax, Xanor, Zolam, Zopax.

In December 2013, in anticipation of the rescheduling of alprazolam to Schedule 8 in Australia, Pfizer Australia announced they would be discontinuing the Xanax brand in Australia as it was no longer commercially viable.

Alprazolam has varied legal status depending on jurisdiction:

  • In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act by the Drug Enforcement Administration.
  • Under the UK drug misuse classification system, benzodiazepines are Class C drugs (Schedule 4).
    • In the UK, alprazolam is not available on the NHS and can only be obtained on a private prescription.
  • In Ireland, alprazolam is a Schedule 4 medicine.
  • In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).
  • In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription.
  • In Germany, alprazolam can be prescribed normally in doses up to 1 mg.
    • Higher doses are scheduled as Anlage III drugs and require a special prescription form.
  • In Australia, alprazolam was originally a Schedule 4 (Prescription Only) medication; however, as of February 2014, it has become a Schedule 8 medication, subjecting it to more rigorous prescribing requirements.
  • In the Philippines, alprazolam is legally classified as a “dangerous drug” under the Comprehensive Dangerous Drugs Act of 2002, along with other schedule drugs listed in the 1971 Convention on Psychotropic Substances.
    • The importation of dangerous drugs including alprazolam, requires authorisation from the Philippine Drug Enforcement Agency.
  • Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.

What is Trifluoperazine?

Published on by Andrew Marshall2 Comments

Introduction

Trifluoperazine, sold under a number of brand names, is a typical antipsychotic primarily used to treat schizophrenia.

It may also be used short term in those with generalised anxiety disorder but is less preferred to benzodiazepines. It is of the phenothiazine chemical class.

Medical Uses

Schizophrenia

Trifluoperazine is an effective antipsychotic for people with schizophrenia. There is low-quality evidence that trifluoperazine increases the chance of being improved when compared to placebo when people are followed up for 19 weeks. There is low-quality evidence that trifluoperazine reduces the risk of relapse when compared with placebo when people are followed for 5 months. As of 2014 there was no good evidence for a difference between trifluoperazine and placebo with respect to the risk of experiencing intensified symptoms over a 16-week period nor in reducing significant agitation or distress.

There is no good evidence that trifluoperazine is more effective for schizophrenia than lower-potency antipsychotics like chlorpromazine, chlorprothixene, thioridazine and levomepromazine, but trifluoperazine appears to cause more adverse effects than these drugs.

Other

It appears to be effective for people with generalised anxiety disorder but the benefit-risk ratio was unclear as of 2005.

It has been experimentally used as a drug to kill eukaryotic pathogens in humans.

Side Effects

Its use in many parts of the world has declined because of highly frequent and severe early and late tardive dyskinesia, a type of extrapyramidal symptom. The annual development rate of tardive dyskinesia may be as high as 4%.

A 2004 meta-analysis of the studies on trifluoperazine found that it is more likely than placebo to cause extrapyramidal side effects such as akathisia, dystonia, and Parkinsonism. It is also more likely to cause somnolence and anticholinergic side effects such as red eye and xerostomia (dry mouth). All antipsychotics can cause the rare and sometimes fatal neuroleptic malignant syndrome. Trifluoperazine can lower the seizure threshold. The antimuscarinic action of trifluoperazine can cause excessive dilation of the pupils (mydriasis), which increases the chances of patients with hyperopia developing glaucoma.

Contraindications

Trifluoperazine is contraindicated in CNS depression, coma, and blood dyscrasias. Trifluoperazine should be used with caution in patients suffering from renal or hepatic impairment.

Mechanism of Action

Trifluoperazine has central antiadrenergic, antidopaminergic, and minimal anticholinergic effects. It is believed to work by blockading dopamine D1 and D2 receptors in the mesocortical and mesolimbic pathways, relieving or minimising such symptoms of schizophrenia as hallucinations, delusions, and disorganised thought and speech.

Names

Brand names include Eskazinyl, Eskazine, Jatroneural, Modalina, Stelazine, Stilizan, Terfluzine, Trifluoperaz, Triftazin.

In the United Kingdom and some other countries, trifluoperazine is sold and marketed under the brand ‘Stelazine’.

The drug is sold as tablet, liquid and ‘Trifluoperazine-injectable USP’ for deep intramuscular short-term use. GP studying pharmacological data has indicated cases of neck vertebrae irreversible fusing leading to NHS preparations being predominantly of the liquid form trifluoperazine as opposed to the tablet form as in Stela zine etc.

In the past, trifluoperazine was used in fixed combinations with the MAO inhibitor (antidepressant) tranylcypromine (tranylcypromine/trifluoperazine) to attenuate the strong stimulating effects of this antidepressant. This combination was sold under the brand name Jatrosom N. Likewise a combination with amobarbital (potent sedative/hypnotic agent) for the amelioration of psychoneurosis and insomnia existed under the brand name Jalonac. In Italy the first combination is still available, sold under the brand name Parmodalin (10 mg of tranylcypromine and 1 mg of trifluoperazine).

What is Venlafaxine?

Published on by Andrew Marshall20 Comments

Introduction

Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.

It is used to treat major depressive disorder (MDD), generalised anxiety disorder (GAD), panic disorder, and social phobia. It may also be used for chronic pain. It is taken by mouth.

Common side effects include loss of appetite, constipation, dry mouth, dizziness, sweating, and sexual problems. Severe side effects include an increased risk of suicide, mania, and serotonin syndrome. Antidepressant withdrawal syndrome may occur if stopped. There are concerns that use during the later part of pregnancy can harm the baby. How it works is not entirely clear, but it seems to be related to the potentiation of the activity of some neurotransmitters in the brain.

Venlafaxine was approved for medical use in the United States in 1993. It is available as a generic medication. In 2018, it was the 50th most commonly prescribed medication in the United States with more than 16 million prescriptions.

Medical Uses

Venlafaxine is used primarily for the treatment of depression, general anxiety disorder, social phobia, panic disorder, and vasomotor symptoms.

Venlafaxine has been used off label for the treatment of diabetic neuropathy and migraine prevention (in some people, however, venlafaxine can exacerbate or cause migraines). It may work on pain via effects on the opioid receptor. It has also been found to reduce the severity of ‘hot flashes’ in menopausal women and men on hormonal therapy for the treatment of prostate cancer.

Due to its action on both the serotoninergic and adrenergic systems, venlafaxine is also used as a treatment to reduce episodes of cataplexy, a form of muscle weakness, in patients with the sleep disorder narcolepsy. Some open-label and three double-blind studies have suggested the efficacy of venlafaxine in the treatment of attention deficit-hyperactivity disorder (ADHD). Clinical trials have found possible efficacy in those with post-traumatic stress disorder (PTSD). Case reports, open trials and blinded comparisons with established medications have suggested the efficacy of venlafaxine in the treatment of obsessive-compulsive disorder (OCD).

Depression

A comparative meta-analysis of 21 major antidepressants found that venlafaxine, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, and vortioxetine were more effective than other antidepressants, although the quality of many comparisons was assessed as low or very low.

Venlafaxine was similar in efficacy to the atypical antidepressant bupropion; however, the remission rate was lower for venlafaxine. In a double-blind study, patients who did not respond to an SSRI were switched to either venlafaxine or another SSRI (citalopram); similar improvement was observed in both groups.

Studies of venlafaxine in children have not established its efficacy.

Studies have shown that the extended release is superior to the immediate release form of venlafaxine.

A meta-analysis shown that efficacity of venlafaxine is not correlated with baseline severity of depression.

Dosage

Venlafaxine has been shown to have an optimal efficacity and tolerability towards the lower end of their licensed dose range.

Contraindications

Venlafaxine is not recommended in patients hypersensitive to it, nor should it be taken by anyone who is allergic to the inactive ingredients, which include gelatin, cellulose, ethylcellulose, iron oxide, titanium dioxide and hypromellose. It should not be used in conjunction with a monoamine oxidase inhibitor (MAOI), as it can cause potentially fatal serotonin syndrome.

Adverse Effects

Refer to Adverse Effects of Venlafaxine.

Venlafaxine can increase eye pressure, so those with glaucoma may require more frequent eye checks.

A 2017 meta-analysis estimated venlafaxine discontinuation rate to 9.4%.

Suicide

The US Food and Drug Administration (FDA) requires all antidepressants, including venlafaxine, to carry a black box warning with a generic warning about a possible suicide risk.

A 2014 meta analysis of 21 clinical trials of venlafaxine for the treatment of depression in adults found that compared to placebo, venlafaxine reduced the risk of suicidal thoughts and behaviour.

A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk by 60% (statistically significant), as compared to no treatment. At the same time, fluoxetine (Prozac) halved the suicide risk.

In another study, the data on more than 200,000 cases were obtained from the UK general practice research database. At baseline, patients prescribed venlafaxine had a greater number of risk factors for suicide (such as prior suicide attempts) than patients treated with other anti-depressants. The patients taking venlafaxine had significantly higher risk of completed suicide than the ones on fluoxetine or citalopram (Celexa). After adjusting for known risk factors, venlafaxine was associated with an increased risk of suicide relative to fluoxetine and dothiepin that was not statistically significant. A statistically significant greater risk for attempted suicide remained after adjustment, but the authors concluded that it could be due to residual confounding.[28]

An analysis of clinical trials by the FDA statisticians showed the incidence of suicidal behaviour among the adults on venlafaxine to be not significantly different from fluoxetine or placebo.

Venlafaxine is contraindicated in children, adolescents and young adults. According to the FDA analysis of clinical trials venlafaxine caused a statistically significant 5-fold increase in suicidal ideation and behaviour in persons younger than 25. In another analysis, venlafaxine was no better than placebo among children (7-11 years old), but improved depression in adolescents (12-17 years old). However, in both groups, hostility and suicidal behaviour increased in comparison to those receiving a placebo. In a study involving antidepressants that had failed to produce results in depressed teenagers, teens whose SSRI treatment had failed who were randomly switched to either another SSRI or to venlafaxine showed an increased rate of suicide on venlafaxine. Among teenagers who were suicidal at the beginning of the study, the rate of suicidal attempts and self-harm was significantly higher, by about 60%, after the switch to venlafaxine than after the switch to an SSRI.

Discontinuation Syndrome

Refer to Antidepressant Discontinuation Syndrome.

People stopping venlafaxine commonly experience discontinuation symptoms such as dysphoria, headaches, nausea, irritability, emotional lability, sensation of electric shocks, and sleep disturbance. Venlafaxine has a higher rate of moderate to severe discontinuation symptoms relative to other antidepressants (similar to the SSRI paroxetine).

The higher risk and increased severity of discontinuation syndrome symptoms relative to other antidepressants may be related to the short half-life of venlafaxine and its active metabolite. After discontinuing venlafaxine, the levels of both serotonin and norepinephrine decrease, leading to the hypothesis that the discontinuation symptoms could result from an overly rapid reduction of neurotransmitter levels.

Serotonin Syndrome

Refer to Serotonin Syndrome.

The development of a potentially life-threatening serotonin syndrome (also more recently classified as “serotonin toxicity”) may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited to SSRIs and SNRIs, many hallucinogens such as tryptamines and phenethylamines (e.g. LSD/LSA, DMT, MDMA, mescaline), dextromethorphan (DXM), tramadol, tapentadol, pethidine (meperidine) and triptans and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Venlafaxine-induced serotonin syndrome has also been reported when venlafaxine has been taken in isolation in overdose. An abortive serotonin syndrome state, in which some but not all of the symptoms of the full serotonin syndrome are present, has been reported with venlafaxine at mid-range dosages (150 mg per day). A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5 mg per day) has also been reported.

Pregnancy

There are few well-controlled studies of venlafaxine in pregnant women. A study released in May 2010 by the Canadian Medical Association Journal suggests use of venlafaxine doubles the risk of miscarriage. Consequently, venlafaxine should only be used during pregnancy if clearly needed. A large case-control study done as part of the National Birth Defects Prevention Study and published in 2012 found a significant association of venlafaxine use during pregnancy and several birth defects including anencephaly, cleft palate, septal heart defects and coarctation of the aorta. Prospective studies have not shown any statistically significant congenital malformations. There have, however, been some reports of self-limiting effects on newborn infants. As with other serotonin reuptake inhibitors (SRIs), these effects are generally short-lived, lasting only 3 to 5 days, and rarely resulting in severe complications.

Drug Interactions

Venlafaxine should be taken with caution when using St John’s wort. Venlafaxine may lower the seizure threshold, and co-administration with other drugs that lower the seizure threshold such as bupropion and tramadol should be done with caution and at low doses.

Bipolar Disorder

Venlafaxine is neither recommended nor approved for the treatment of major depressive episodes in bipolar disorder, as it can induce mania or mixed episodes. Venlafaxine appears to be more likely than the SSRIs and bupropion to induce mania and mixed episodes in bipolar patients.

Liver Injury

A rare but serious side effect of venlafaxine is liver injury. It reaches man and female patients with a median age of 44 years. Cessation of venlafaxine is one of the appropriate measure of management. The mechanism of venlafaxine related-liver injury is unclear but may be related to a CYP2D6 polymorphism.

Other

In rare cases, drug-induced akathisia (movement disorder) can occur after use in some people.

Venlafaxine should be used with caution in hypertensive patients. Venlafaxine must be discontinued if significant hypertension persists. It can also have undesirable cardiovascular effects.

Overdose

Most patients overdosing with venlafaxine develop only mild symptoms. Plasma venlafaxine concentrations in overdose survivors have ranged from 6 to 24 mg/l, while postmortem blood levels in fatalities are often in the 10-90 mg/l range. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose. It is usually reserved as a second-line treatment for depression due to a combination of its superior efficacy to the first-line treatments like fluoxetine, paroxetine and citalopram and greater frequency of side effects like nausea, headache, insomnia, drowsiness, dry mouth, constipation, sexual dysfunction, sweating and nervousness.

There is no specific antidote for venlafaxine, and management is generally supportive, providing treatment for the immediate symptoms. Administration of activated charcoal can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with benzodiazepines or other anticonvulsants. Forced diuresis, hzemodialysis, exchange transfusion, or hemoperfusion are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug’s high volume of distribution.

Mechanism of Action

Pharmacology

Venlafaxine is usually categorised as a serotonin-norepinephrine reuptake inhibitor (SNRI), but it has also been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It works by blocking the transporter “reuptake” proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin and norepinephrine. Additionally, in high doses it weakly inhibits the reuptake of dopamine, since dopamine is inactivated by norepinephrine reuptake in the frontal cortex. The frontal cortex largely lacks dopamine transporters; therefore venlafaxine can increase dopamine neurotransmission in this part of the brain.

Venlafaxine indirectly affects opioid receptors as well as the alpha2-adrenergic receptor, and was shown to increase pain threshold in mice. These benefits with respect to pain were reversed with naloxone, an opioid antagonist, thus supporting an opioid mechanism.

Pharmacokinetics

Venlafaxine is well absorbed, with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively metabolized in the liver via the CYP2D6 isoenzyme to desvenlafaxine (O-desmethylvenlafaxine, now marketed as a separate medication named Pristiq), which is just as potent an SNRI as the parent compound, meaning that the differences in metabolism between extensive and poor metabolisers are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe in CYP2D6 poor metabolisers. Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the kidneys. The half-life of venlafaxine is relatively short, so patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed dose can result in withdrawal symptoms.

Venlafaxine is a substrate of P-glycoprotein (P-gp), which pumps it out of the brain. The gene encoding P-gp, ABCB1, has the SNP rs2032583, with alleles C and T. The majority of people (about 70% of Europeans and 90% of East Asians) have the TT variant. A 2007 study found that carriers of at least one C allele (variant CC or CT) are 7.72 times more likely than non-carriers to achieve remission after 4 weeks of treatment with amitriptyline, citalopram, paroxetine or venlafaxine (all P-gp substrates). The study included patients with mood disorders other than major depression, such as bipolar II; the ratio is 9.4 if these other disorders are excluded. At the 6-week mark, 75% of C-carriers had remitted, compared to only 38% of non-carriers.

Chemistry

The IUPAC name of venlafaxine is 1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]cyclohexanol, though it is sometimes referred to as (±)-1-[a-[a-(dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol. It consists of two enantiomers present in equal quantities (termed a racemic mixture), both of which have the empirical formula of C17H27NO2. It is usually sold as a mixture of the respective hydrochloride salts, (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]cyclohexanol hydrochloride, C17H28ClNO2, which is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid analgesic tramadol, and more distantly to the newly released opioid tapentadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or RIMAs.

Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release (controlled release) version distributes the release of the drug into the gastrointestinal tract over a longer period than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of nausea as a side effect, resulting in better compliance.

Society and Culture

Venlafaxine was originally marketed as Effexor in most of the world; generic venlafaxine has been available since around 2008 and extended release venlaxafine has been available since around 2010.

As of January 2020 venlafaxine is marketed under many brand names worldwide, many with alternative extended release forms (not shown): Adefaxin, Alenthus, Altven, Alventa, Amfax, Anapresin, Ansifix, Arafaxina, Argofan, Arrow Venlafaxine, Axone, Axyven, Benolaxe, Blossom, Calmdown, Dalium, Defaxine, Depefex, Depretaxer, Deprevix, Deprexor, Deprixol, Depurol, Desinax, Dislaven, Dobupal, Duofaxin, Easyfor, Ectien, Eduxon, Efastad, Efaxin, Efaxine, Efectin, Efegen, Efevelon, Efevelone, Efexiva, Efexor, Effegad, Effexine, Effexor, Elafax, Elaxine, Elify, Enpress, Enlafax, Envelaf, Falven, Faxigen, Faxine, Faxiprol, Faxiven, Faxolet, Flavix, Flaxen, Fobiless, Ganavax, Idixor, Idoxen, Intefred, Illovex, Lafactin, Lafaxin, Lanvexin, Laroxin, Levest, Limbic, Linexel, Maxibral, Mazda, Melocin, Memomax, Mezine, Neoxacina, Neoxacina, Nervix, Norafexine, Norezor, Norpilen, Noviser, Nulev, Odiven, Olwexya, Oriven, Paxifar, Politid, Pracet, Prefaxine, Psiseven, Quilarex, Rafax, Senexon, Sentidol, Sentosa, Serosmine, Seroxine, Sesaren, Subelan, Sulinex, Sunveniz, Sunvex, Symfaxin, Tedema, Tifaxin, Tonpular, Trevilor, Tudor, Vafexin, Valosine, Vandral, Velaf, Velafax, Velahibin, Velaxin, Velept, Velpine, Venax, Venaxin, Venaxx, Vencarm, Vencontrol, Vendep, Venegis, Venex, Venexor, Venfalex, Venfax, Ven-Fax, Venfaxine, Venforin, Venforspine, Veniba, Veniz, Venjoy, Venla, Venlabax, Venlablue, Venlabrain, Venladep, Venladex, Venladoz, Venlaf, Venlafab, Venlafaxin, Venlafaxina, Venlafaxine, Venlagamma, Venlalic, Venlamax, Venlamylan, Venlaneo, Venlapine, Venla-Q, Venlasand, Venlatrin, Venlavitae, Venlax, Venlaxin, Venlaxine, Venlaxor, Venlazid, Venlectine, Venlifax, Venlift, Venlix, Venlobax, Venlofex, Venlor, Venorion, Venozap, Vensate, Ventab, Venxin, Venxor, Venzip, Vexamode, Vfax, Viepax, ViePax, Voxafen, Zacalen, Zanfexa, Zaredrop, Zarelis, Zarelix, and Zenexor.

What is Escitalopram?

Published on by Andrew Marshall11 Comments

Introduction

Escitalopram, sold under the brand names Cipralex and Lexapro, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder (MDD) or generalised anxiety disorder (GAD). It is taken by mouth.

Common side effects include trouble sleeping, nausea, sexual problems, and feeling tired. More serious side effects may include suicide in people under the age of 25. It is unclear if use during pregnancy or breastfeeding is safe. Escitalopram is the (S)-stereoisomer (left-handed version) of citalopram (which exists as a racemate), hence the name escitalopram. In other words, escitalopram is a chiral switch of citalopram.

Escitalopram was approved for medical use in the United States in 2002. Escitalopram is sometimes replaced by twice the dose of citalopram. In 2018, it was the 22nd most commonly prescribed medication in the United States with more than 25 million prescriptions.

Brief History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.

The FDA issued the approval of escitalopram for major depression in August 2002 and for GAD in December 2003. On 23 May 2006, the FDA approved a generic version of escitalopram by Teva. On 14 July of that year, however, the US District Court of Delaware decided in favour of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.

In 2006, Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram. This pushed the patent expiration date from 07 December 2009, to 14 September 2011. Together with the 6-month paediatric exclusivity, the final expiration date was 14 March 2012.

Medical Uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults. In European countries and the United Kingdom, it is approved for depression (MDD) and anxiety disorders, these include: GAD, social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia. In Australia it is approved for major depressive disorder.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo-controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.

Controversy existed regarding the effectiveness of escitalopram compared with its predecessor, citalopram. The importance of this issue followed from the greater cost of escitalopram relative to the generic mixture of isomers of citalopram, prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. As of 2012, reviews had concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and tolerability.

A 2011 review concluded that second-generation antidepressants appear equally effective, although they may differ in onset and side effects. Treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.

In 2018, a systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs showed escitalopram to be one of the most effective.

Anxiety Disorder

Escitalopram appears to be effective in treating general anxiety disorder, with relapse on escitalopram at 20% rather than placebo at 50%.

Escitalopram appears effective in treating social anxiety disorder.

Other

Escitalopram is effective in reducing the symptoms of premenstrual syndrome, whether taken continuously or in the luteal phase only. There are no good data available for escitalopram as treatment for seasonal affective disorder as of 2021.

Side Effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, and anorgasmia.

There is also evidence that SSRIs may cause an increase in suicidal ideation. An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications. The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses at 20 mg for adults and 10 mg for those older than 65 years or with liver impairment. There are concerns of higher rates of QT prolongation and torsades de pointes compared with other SSRIs. The US Food and Drug Administration (FDA) and Health Canada did not similarly order restrictions on escitalopram dosage, only on its predecessor citalopram.

Very Common Effects

Very common effects (>10% incidence) include:

  • Headache (24%).
  • Nausea (18%).
  • Ejaculation disorder (9-14%).
  • Somnolence (4-13%).
  • Insomnia (7-12%).

Common Effects

Common effects (1-10% incidence) include:

  • Insomnia.
  • Somnolence (sleepiness).
  • Dizziness.
  • Paraesthesia.
  • Tremor.
  • Decreased or increased appetite.
  • Anxiety.
  • Restlessness.
  • Abnormal dreams.
  • Libido decreased.
  • Anorgasmia.
  • Sinusitis (nasal congestion).
  • Yawning.
  • Diarrhoea.
  • Constipation.
  • Vomiting.
  • Dry mouth.
  • Excessive sweating.
  • Arthralgia (joint pain).
  • Myalgia (muscular aches and pains).
  • Fatigue.
  • Pyrexia (fever).
  • Impotence (erectile dysfunction).

Psychomotor Effects

The most common effect is fatigue or somnolence, particularly in older adults, although patients with pre-existing daytime sleepiness and fatigue may experience paradoxical improvement of these symptoms. Escitalopram has not been shown to affect serial reaction time, logical reasoning, serial subtraction, multitask, or MacWorth clock task performance.

Discontinuation Symptoms

Refer to Antidepressant Discontinuation Syndrome.

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as anhedonia (83%), “electric shock” sensations, colloquially called “brain shivers” or “brain zaps” by sufferers. Frequent symptoms in one study were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). Very slow tapering was recommended. There have been spontaneous reports of discontinuation of Lexapro and other SSRIs and SNRIs, especially when abrupt, leading to dysphoric mood, irritability, agitation, anxiety, headache, lethargy, emotional lability, insomnia, and hypomania. Other symptoms such as panic attacks, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), mania, worsening of depression, and suicidal ideation can emerge when the dose is adjusted down.

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 include genital anaesthesia, erectile dysfunction, anhedonia, decreased libido, premature ejaculation, vaginal lubrication issues, and nipple insensitivity in women. Rates are unknown, and there is no established treatment.

Pregnancy

Antidepressant exposure (including escitalopram) is associated with shorter duration of pregnancy (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. There is a tentative association of SSRI use during pregnancy with heart problems in the baby. The advantages of their use during pregnancy may thus outweigh the possible negative effects on the baby.

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects, such as agitation and tachycardia. However, dyskinesia, hypertonia, and clonus may occur in some cases. Therapeutic blood levels of escitalopram are usually in the range of 20-80 μg/L but may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolisers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.

Pharmacology

Mechanism of Action

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently available, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood brain barrier penetrability. In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor, its antidepressant-like effects were enhanced.

Interactions

Escitalopram, similarly to other SSRIs, inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazole, risperidone, tramadol, codeine, etc. As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected. Escitalopram should be taken with caution when using St. John’s wort. Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern. Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome has been reported.

Bupropion has been found to significantly increase citalopram plasma concentration and systemic exposure; as of April 2018 the interaction with escitalopram had not been studied, but some monographs warned of the potential interaction.

Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that also have the ability to prolong the QT interval. These drugs include antiarrhythmics, antipsychotics, tricyclic antidepressants, some antihistamines (astemizole, mizolastine) and some antiretrovirals (ritonavir, saquinavir, lopinavir). As an SSRI, escitalopram should generally not be given concurrently with MAOIs.

Chemistry

Escitalopram is the (S)-stereoisomer (left-handed version) of the racemate citalopram, which is responsible for its name: escitalopram. The (R)-stereoisomer (R-citalopram, the right-handed version) is not thought to have useful effects for treating depression.

Society and Culture

Allegations of Illegal Marketing

In 2004, separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers: a physician named Joseph Piacentile and a Forest salesman named Christopher Gobble. In February 2009, the suits were joined. Eleven states and the District of Columbia filed notices of intent to intervene as plaintiffs in the action.

The suits alleged that Forest illegally engaged in off-label promotion of Lexapro for use in children; hid the results of a study showing lack of effectiveness in children; paid kickbacks to physicians to induce them to prescribe Lexapro to children; and conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors. Forest denied the allegations but ultimately agreed to settle with the plaintiffs for over $313 million.

Brand Names

Escitalopram is sold under many brand names worldwide such as Cipralex, Lexapro, Mozarin, Aciprex, Depralin, Ecytara, Elicea, Nexpram, Pramatis, and Betesda.

Can the MHS: A Serve as a Clinically Useful Screening Tool for GAD?

Published on by Andrew MarshallLeave a comment

Research Paper Title

A Brief Online and Offline (Paper-and-Pencil) Screening Tool for Generalized Anxiety Disorder: The Final Phase in the Development and Validation of the Mental Health Screening Tool for Anxiety Disorders (MHS: A).

Background

Generalised anxiety disorder (GAD) can cause significant socioeconomic burden and daily life dysfunction; hence, therapeutic intervention through early detection is important.

Methods

This study was the final stage of a 3-year anxiety screening tool development project that evaluated the psychometric properties and diagnostic screening utility of the Mental Health Screening Tool for Anxiety Disorders (MHS: A), which measures GAD.

Results

A total of 527 Koreans completed online and offline (i.e., paper-and pencil) versions of the MHS: A, Beck Anxiety Inventory (BAI), Generalised Anxiety Disorder-7 (GAD-7), and Penn State Worry Questionnaire (PSWQ). The participants had an average age of 38.6 years and included 340 (64.5%) females. Participants were also administered the Mini-International Neuropsychiatric Interview (MINI).

Internal consistency, convergent/criterion validity, item characteristics, and test information were assessed based on the item response theory (IRT), and a factor analysis and cut-off score analyses were conducted. The MHS: A had good internal consistency and good convergent validity with other anxiety scales.

The two versions (online/offline) of the MHS: A were nearly identical (r = 0.908). It had a one-factor structure and showed better diagnostic accuracy (online/offline: sensitivity = 0.98/0.90, specificity = 0.80/0.83) for GAD detection than the GAD-7 and BAI. The IRT analysis indicated that the MHS: A was most informative as a screening tool for GAD.

Conclusions

The MHS: A can serve as a clinically useful screening tool for GAD in Korea. Furthermore, it can be administered both online and offline and can be flexibly used as a brief mental health screener, especially with the current rise in telehealth.

Reference

Kim, S-H., Park, K., Yoon, S., Choi, Y., Lee, S-H. & Choi, K-H. (2021) A Brief Online and Offline (Paper-and-Pencil) Screening Tool for Generalized Anxiety Disorder: The Final Phase in the Development and Validation of the Mental Health Screening Tool for Anxiety Disorders (MHS: A). Frontiers in Psychology. doi: 10.3389/fpsyg.2021.639366. eCollection 2021.

What is Avoidant Personality Disorder?

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Introduction

Avoidant personality disorder (AvPD) is a Cluster C personality disorder in which the main coping mechanism of those affected is avoidance of feared stimuli.

Those affected display a pattern of severe social anxiety, social inhibition, feelings of inadequacy and inferiority, extreme sensitivity to negative evaluation and rejection, and avoidance of social interaction despite a strong desire for intimacy.

People with AvPD often consider themselves to be socially inept or personally unappealing and avoid social interaction for fear of being ridiculed, humiliated, rejected, or disliked. They often avoid becoming involved with others unless they are certain they will be liked.

Childhood emotional neglect (in particular, the rejection of a child by one or both parents) and peer group rejection are associated with an increased risk for its development; however, it is possible for AvPD to occur without any notable history of abuse or neglect.

Brief History

The avoidant personality has been described in several sources as far back as the early 1900s, although it was not so named for some time. Swiss psychiatrist Eugen Bleuler described patients who exhibited signs of avoidant personality disorder in his 1911 work Dementia Praecox: Or the Group of Schizophrenias. Avoidant and schizoid patterns were frequently confused or referred to synonymously until Kretschmer (1921), in providing the first relatively complete description, developed a distinction.

Signs and Symptoms

Avoidant individuals are preoccupied with their own shortcomings and form relationships with others only if they believe they will not be rejected. They often view themselves with contempt, while showing a decreased ability to identify traits within themselves that are generally considered as positive within their societies. Loss and social rejection are so painful that these individuals will choose to be alone rather than risk trying to connect with others.

Some with this disorder fantasize about idealized, accepting and affectionate relationships because of their desire to belong. They often feel themselves unworthy of the relationships they desire, and shame themselves from ever attempting to begin them. If they do manage to form relationships, it is also common for them to pre-emptively abandon them out of fear of the relationship failing.

Individuals with the disorder tend to describe themselves as uneasy, anxious, lonely, unwanted and isolated from others. They often choose jobs of isolation in which they do not have to interact with others regularly. Avoidant individuals also avoid performing activities in public spaces for fear of embarrassing themselves in front of others.

Symptoms include:

  • Extreme shyness or anxiety in social situations, though the person feels a strong desire for close relationships;
  • Heightened attachment-related anxiety, which may include a fear of abandonment; and
  • Substance abuse and/or dependence.

Comorbidity

AvPD is reported to be especially prevalent in people with anxiety disorders, although estimates of comorbidity vary widely due to differences in (among others) diagnostic instruments. Research suggests that approximately 10-50% of people who have panic disorder with agoraphobia have avoidant personality disorder, as well as about 20-40% of people who have social anxiety disorder. In addition to this, AvPD is more prevalent in people who have comorbid social anxiety disorder and generalised anxiety disorder (GAD) than in those who have only one of the aforementioned conditions.

Some studies report prevalence rates of up to 45% among people with GAD and up to 56% of those with obsessive-compulsive disorder. Posttraumatic stress disorder is also commonly comorbid with AvPD.

Avoidants are prone to self-loathing and, in certain cases, self-harm. In particular, avoidants who have comorbid PTSD have the highest rates of engagement in self-harming behaviour, outweighing even those with borderline personality disorder (with or without PTSD). Substance use disorders are also common in individuals with AvPD – particularly in regard to alcohol, benzodiazepines and heroin – and may significantly affect a patient’s prognosis.

Earlier theorists proposed a personality disorder with a combination of features from borderline personality disorder and avoidant personality disorder, called “avoidant-borderline mixed personality” (AvPD/BPD).

Causes

Causes of AvPD are not clearly defined, but appear to be influenced by a combination of social, genetic and psychological factors. The disorder may be related to temperamental factors that are inherited.

Specifically, various anxiety disorders in childhood and adolescence have been associated with a temperament characterised by behavioural inhibition, including features of being shy, fearful and withdrawn in new situations. These inherited characteristics may give an individual a genetic predisposition towards AvPD.

Childhood emotional neglect and peer group rejection are both associated with an increased risk for the development of AvPD. Some researchers believe a combination of high-sensory-processing sensitivity coupled with adverse childhood experiences may heighten the risk of an individual developing AvPD.

Subtypes

Millon

Psychologist Theodore Millon notes that because most patients present a mixed picture of symptoms, their personality disorder tends to be a blend of a major personality disorder type with one or

more secondary personality disorder types. He identified four adult subtypes of AvPD as outlined below.

SubtypePersonality Traits/Features
Phobic Avoidant (including dependent features)General apprehensiveness displaced with avoidable tangible precipitant; qualms and disquietude symbolised by a repugnant and specific dreadful object or circumstances.
Conflicted Avoidant (including negativistic features)Internal discord and dissension; fears dependence; unsettled; unreconciled within self; hesitating, confused, tormented, paroxysmic, embittered; and unresolvable angst.
Hypersensitive Avoidant (including paranoid features)Intensely wary and suspicious; alternatively panicky, terrified, edgy, and timorous, then thin-skinned, high-strung, petulant, and prickly.
Self-Deserting Avoidant (including depressive features)Blocks or fragments self-awareness; discards painful images and memories; casts away untenable thoughts and impulses; ultimately jettisons self (suicidal).

Others

In 1993, Lynn E. Alden and Martha J. Capreol proposed two other subtypes of avoidant personality disorder, as outlined below.

SubtypePersonality Traits/Features
Cold-AvoidantCharacterised by an inability to experience and express positive emotion towards others.
Exploitable-AvoidantCharacterised by an inability to express anger towards others or to resist coercion from others. May be at risk for abuse by others.

Diagnosis

ICD

The World Health Organisation’s ICD-10 lists avoidant personality disorder as anxious (avoidant) personality disorder (F60.6).

It is characterised by the presence of at least four of the following:

  1. Persistent and pervasive feelings of tension and apprehension.
  2. Belief that one is socially inept, personally unappealing, or inferior to others.
  3. Excessive preoccupation with being criticised or rejected in social situations.
  4. Unwillingness to become involved with people unless certain of being liked.
  5. Restrictions in lifestyle because of need to have physical security.
  6. Avoidance of social or occupational activities that involve significant interpersonal contact because of fear of criticism, disapproval, or rejection.

Associated features may include hypersensitivity to rejection and criticism.

It is a requirement of ICD-10 that all personality disorder diagnoses also satisfy a set of general personality disorder criteria.

DSM

The Diagnostic and Statistical Manual of Mental Disorders (DSM) of the APA also has an avoidant personality disorder diagnosis (301.82). It refers to a widespread pattern of inhibition around people, feeling inadequate and being very sensitive to negative evaluation. Symptoms begin by early adulthood and occur in a range of situations.

Four of the following seven specific symptoms should be present:

  1. Avoids occupational activities that involve significant interpersonal contact, because of fears of criticism, disapproval, or rejection.
  2. Is unwilling to get involved with people unless certain of being liked.
  3. Shows restraint within intimate relationships because of the fear of being shamed or ridiculed.
  4. Is preoccupied with being criticised or rejected in social situations.
  5. Is inhibited in new interpersonal situations because of feelings of inadequacy.
  6. Views self as socially inept, personally unappealing, or inferior to others.
  7. Is unusually reluctant to take personal risk or to engage in any new activities because they may prove embarrassing.

Differential Diagnosis

In contrast to social anxiety disorder, a diagnosis of AvPD also requires that the general criteria for a personality disorder are met.

According to the DSM-5, avoidant personality disorder must be differentiated from similar personality disorders such as dependent, paranoid, schizoid, and schizotypal. But these can also occur together; this is particularly likely for AvPD and dependent personality disorder. Thus, if criteria for more than one personality disorder are met, all can be diagnosed.

There is also an overlap between avoidant and schizoid personality traits and AvPD may have a relationship to the schizophrenia spectrum.

Epidemiology

Data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions indicates a prevalence of 2.36% in the US general population. It appears to occur with equal frequency in males and females. In one study, it was seen in 14.7% of psychiatric outpatients.

Criticism

There is controversy as to whether avoidant personality disorder (AvPD) is distinct from generalised social anxiety disorder. Both have similar diagnostic criteria and may share a similar causation, subjective experience, course, treatment and identical underlying personality features, such as shyness.

It is contended by some that they are merely different conceptualisations of the same disorder, where avoidant personality disorder may represent the more severe form. In particular, those with AvPD experience not only more severe social phobia symptoms, but are also more depressed and more functionally impaired than patients with generalised social phobia alone. But they show no differences in social skills or performance on an impromptu speech. Another difference is that social phobia is the fear of social circumstances whereas AvPD is better described as an aversion to intimacy in relationships.

Treatment

Treatment of avoidant personality disorder can employ various techniques, such as social skills training, psychotherapy, cognitive therapy, and exposure treatment to gradually increase social contacts, group therapy for practicing social skills, and sometimes drug therapy.

A key issue in treatment is gaining and keeping the patient’s trust since people with an avoidant personality disorder will often start to avoid treatment sessions if they distrust the therapist or fear rejection. The primary purpose of both individual therapy and social skills group training is for individuals with an avoidant personality disorder to begin challenging their exaggerated negative beliefs about themselves.

Significant improvement in the symptoms of personality disorders is possible, with the help of treatment and individual effort.

Prognosis

Being a personality disorder, which is usually chronic and has long-lasting mental conditions, an avoidant personality disorder is not expected to improve with time without treatment. Given that it is a poorly studied personality disorder and in light of prevalence rates, societal costs, and the current state of research, AvPD qualifies as a neglected disorder.

PHQ-9 & GAD-7 Data in a National Survey about COVID-19 Restrictions in Australia

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Research paper Title

Patient Health Questionnaire 9 (PHQ-9) and General Anxiety Disorder 7 (GAD-7) data contributed by 13,829 respondents to a national survey about COVID-19 restrictions in Australia.

Background

While the Patient Health Questionnaire 9 (PHQ-9) and General Anxiety Disorder 7 (GAD-7) are frequently used in mental health research, few studies have reported comprehensive data on these measures from population or community samples.

The aim of this study was to describe gender- and age-specific PHQ-9 and GAD-7 item and summary data contributed by those who completed this survey.

Methods

The PHQ-9 and GAD-7 were used as indicators of symptoms of depression and anxiety in a national online anonymous survey to assess the mental health of adults in Australia during the COVID-19 restrictions.

Data were analysed descriptively.

Results

Complete survey responses were contributed by 13,829 people.

For both measures, item-by-item results, summary statistics (mean, standard deviation, minimum, maximum, median and interquartile range) and prevalence of severity categories are reported for the whole sample, and disaggregated by gender and age groups.

Conclusions

These comprehensive data provide a useful point of comparison for future COVID-19-related or other research among population or community samples.

Other researchers are encouraged to report detailed PHQ-9 and GAD-7 data in the future, to enable and promote relevant between-group comparisons.

Reference

Stocker, R., Tran, T., Hammarberg, K., Nguyen, H., Rowe, H. & Fisher, J. (2021) Patient Health Questionnaire 9 (PHQ-9) and General Anxiety Disorder 7 (GAD-7) data contributed by 13,829 respondents to a national survey about COVID-19 restrictions in Australia. Psychiatry Research. doi: 10.1016/j.psychres.2021.113792. Online ahead of print.