Introduction
Mosapramine (Cremin) is an atypical antipsychotic used in Japan for the treatment of schizophrenia.
It is a potent dopamine antagonist with high affinity to the D2, D3, and D4 receptors, and with moderate affinity for the 5-HT2 receptors.
Fluanisone is a typical antipsychotic and sedative of the butyrophenone chemical class.
It is used in the treatment of schizophrenia and mania. It is also a component (along with fentanyl) of the injectable veterinary formulation fentanyl/fluanisone (Hypnorm) where it is used for rodent analgesia during short surgical procedures.
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Blonanserin, sold under the brand name Lonasen, is a relatively new atypical antipsychotic (approved by PMDA in January 2008) commercialised by Dainippon Sumitomo Pharma in Japan and Korea for the treatment of schizophrenia. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension. As with many second-generation (atypical) antipsychotics it is significantly more efficacious in the treatment of the negative symptoms of schizophrenia compared to first-generation (typical) antipsychotics such as haloperidol.
Blonanserin is used to treat schizophrenia in Japan and South Korea but not in the US.
As with many of the atypical antipsychotics, blonanserin can elicit cardio metabolic risks. While the side effects of blonanserin – such as weight gain, cholesterol and triglyceride levels, glucose levels and other blood lipid levels – do not differ greatly from other atypical antipsychotics, the specificity of blonanserin appears to elicit milder side effects, with less weight gain in particular.
Blonanserin acts as a mixed 5-HT2A (Ki = 0.812 nM) and D2 receptor (Ki = 0.142 nM) antagonist and also exerts some blockade of α1-adrenergic receptors (Ki = 26.7 nM). Blonanserin also shows significant affinity for the D3 receptor (Ki = 0.494 nM). It lacks significant affinity for numerous other sites including the 5-HT1A, 5-HT3, D1, α2-adrenergic, β-adrenergic, H1, and mACh receptors and the monoamine transporters, though it does possess low affinity for the sigma receptor (IC50 = 286 nM).
Blonanserin has a relatively high affinity towards the 5-HT6 receptor perhaps underpinning its recently unveiled efficacy in treating the cognitive symptoms of schizophrenia. The efficacy of blonanserin can in part be attributed to its chemical structure, which is unique from those of other atypical antipsychotics. Specifically, the addition of hydroxyl groups to blonanserin’s unique eight membered ring results in the (R) stereoisomer of the compound demonstrating increased affinity for the indicated targets.
Blonanserin has antagonistic action at dopamine-D3 receptors that potentiates phosphorylation levels of Protein kinase A (PKA) and counteracts decreased activity at the dopamine-D1 and/or NMDA receptors, thus potentiating GABA induced Cl- currents. Olanzapine does not appear to affect PKA activity. Many antipsychotics, such as haloperidol, chlorpromazine, risperidone and olanzapine primarily antagonise serotonin 5-HT2A and dopamine-D2 receptors and lack known action at dopamine-D2/3 receptors.
Blonanserin is administered 4 mg orally twice a day or 8 mg once a day, for an adult male with a body mass index between 19–24 kg/m2 and a body weight equal to or greater than 50 kg. The drug is absorbed by a two compartment (central and peripheral) model with first-order absorption and elimination. The half-life of blonanserin is dependent on the dose. A single dose of 4 mg has a half-life of 7.7 ± 4.63 h and a single dose of 8 mg has a half-life of 11.9 ± 4.3 h. The increase of half-life with dose is possibly attributed to there being more individual concentration per time points below the lower limit necessary for quantification in the lower single dose.
Blonanserin is not a charged compound and exhibits very little chemical polarity. The polar surface area of Blonanserin is 19.7 Å It is commonly accepted that a compound needs to have polar surface area less than 90 Å to cross the blood brain barrier so blonanserin is expected to be quite permeable as is demonstrated by a high brain/ plasma ratio of 3.88.
Due to the good permeability of blonanserin, the volume of distribution in the central nervous system is greater than that in the periphery (Vd central = 9500 L, Vd periphery = 8650 L) although it is slower to absorb into the central compartment.
Blonanserin does not meet the criteria in Lipinski’s rule of five.
Food intake slows the absorption of blonanserin and increases the bioavailability peripherally relative to centrally. Single fasting doses are safe and the effects of feeding intake are possibly explained by an interaction between blonanserin and cytochrome P450 3A4 in the gut.
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Psychological inertia is the tendency to maintain the status quo (or default option) unless compelled by a psychological motive to intervene or reject this.
Psychological inertia is similar to the status quo bias but there is an important distinction in that psychological inertia involves inhibiting any action, whereas the status-quo bias involves avoiding any change which would be perceived as a loss.
Research into psychological inertia is limited, particularly into its causes, but it has been seen to affect decision-making by causing individuals to automatically choose or prefer the default option, even if there is a more beneficial option available to them, unless motivated to reject this option. For example, psychological inertia may cause individuals to continue with their investments later than they should, despite information telling them otherwise, causing them to suffer greater losses than they would have if they had disinvested earlier.
Psychological inertia has also seen to be relevant in areas of health, crime and within the workplace.
Refer to Knowledge Inertia and Social Inertia.
David Gal and Derek Rucker both suggest that psychological inertia could be a more suitable explanation for phenomena such as the status-quo bias and the endowment effect than loss aversion.
The psychological inertia account asserts that the reason individuals choose to remain at the status quo is due to a lack of psychological motive to change this behaviour rather than through the weighing up of losses and gains in this decision. Both explanations were tested by David Gal in a study where subjects were asked to imagine that they owned a quarter minted in either Denver or Philadelphia. They were then given the choice of exchanging their coin with one minted in the other city, assuming insignificant time and effort involved in this process. It was found that 85% of participants chose to retain their original coin which can be explained by the inertia account of remaining at the status quo. However, the loss aversion account is unable to explain this decision as it does not provide insight into a propensity towards the status-quo when the option values are equivalent.
The endowment effect, i.e. greater value being placed on objects that are owned than those that are not, has been shown to be caused by loss aversion. This was demonstrated in Daniel Kahneman’s study in 1990 where participants who were given a mug demanded, on average, around seven dollars to part with it. Whereas, individuals who were not given a mug were only willing to spend, on average, around three dollars on the same mug. This therefore demonstrated that losses exert a greater impact than gains. However, it could also be seen as evidence for psychological inertia as the participants were provided with the same objects and therefore, as they were indifferent to them, they chose to maintain the status quo as there was no incentive to trade.
The 1998 article “Psychological Inertia” by James Kowalick refers to a company where the president was displeased that company management had little knowledge of what was going on in the manufacturing department. The management team was not approachable and looked down on employees that were not managers. “Remaining behind the sacred doors of one’s managerial office had become quite a tradition.” To address this issue, the president asked each manager to present a manufacturing procedure in detail at the staff meeting while the other managers asked penetrating questions. As a result, in short time, managers were on the production floor learning the procedures. This form of PI represents “cultural and traditional programming”.
Avolition has been understood as a core symptom in schizophrenia, however, the drives of it are unclear. One possible drive that may underlie avolition is psychological inertia. It has been argued that as individuals with schizophrenia may be less able to convert their preferences into actions, they may display an increased tendency to maintain a current state, even if they attribute greater value to a different option available. Therefore, this causes these individuals to display greater levels of psychological inertia, and since this process inhibits their action, its presence could drive avolition. James Gold found that motivational impairments of schizophrenia may be associated with abnormalities in estimating the “cost” of effortful behaviour leading to increased psychological inertia which, in turn, could lead to increased avolition in these individuals. However, research into links between psychological inertia and schizophrenia is limited as is their relationship to avolition. For example, research is needed to explore whether the differences in levels of psychological inertia in individuals with schizophrenia only occur when there is a need to engage high levels of inertia or when the individual displays a high level of avolition. Research has shown, however, that the differences in levels of psychological inertia among individuals with schizophrenia is not only due to avolition but could be caused by attention deficits or action-readiness deficits.
Psychological inertia is believed to be one explanation factor in crime continuity, that is the persistence of criminal behaviour. Glenn Walter’s psychological inertia theorem states that crime continuity is partly caused by cognitive factors that account for the continuity in behaviour between past and future criminality and derives from his broader ‘lifestyle theory’ model, which explains the overall development of a criminal lifestyle. Walter’s theorem is based upon Newton’s law of inertia which states that a body will remain in motion until acted upon by an outside force, in which here the body in motion is crime. Within this theorem, Walter attributes six slow-changing variables that when combined link past criminality with future criminality. These six cognitive variables are:
The psychological inertia theorem argues that criminal involvement gives rise to these six cognitive variables which then encourage further offending behaviour.
Theories surrounding the expectation of behavioural continuity are a topic of debate in the criminal justice community. But the conventional wisdom that past behaviour is the best predictor of future behaviour has generally led to:
“an expectation that offenders with histories of criminal violence in the community are at increased risk for disruptive conduct in prison [and] has been operationalized as a routine component in prison risk classifications”.
Psychological inertia has been found to be prevalent in change management within the workplace due to the fact it causes individuals to feel anxiety and fear as a result of any type of change away from the status-quo which may bring new responsibilities and roles. There are a variety of different interventions that have been suggested to overcome this psychological inertia which include providing fuller information including explaining the benefits that such a change will bring, causing people to feel less anxious and more motivated to carry out this change.
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Avolition, as a symptom of various forms of psychopathology, is the decrease in the ability to initiate and persist in self-directed purposeful activities. Such activities that appear to be neglected usually include routine activities, including hobbies, going to work or school, and most notably, engaging in social activities. A person experiencing avolition may stay at home for long periods of time, rather than seeking out work or peer relations.
People with avolition often want to complete certain tasks but lack the ability to initiate behaviours necessary to complete them. Avolition is most commonly seen as a symptom of some other disorder, but might be considered a primary clinical disturbance of itself (or as a coexisting second disorder) related to disorders of diminished motivation. In 2006, avolition was identified as a negative symptom of schizophrenia by the National Institute of Mental Health (NIMH), and has been observed in patients with bipolar disorder as well as resulting from trauma.
Avolition is sometimes mistaken for other, similar symptoms also affecting motivation, such as abulia, anhedonia and asociality, or strong general disinterest. For example, abulia is also a restriction in motivation and initiation, but characterised by an inability to set goals or make decisions and considered a disorder of diminished motivation. In order to provide effective treatment, the underlying cause of avolition (if any) has to be identified and it is important to properly differentiate it from other symptoms, even though they might reflect similar aspects of mental illness.
Implications from avolition often result in social deficits. Not being able to initiate and perform purposeful activities can have many implications for a person with avolition. By disrupting interactions with both familiar and unfamiliar people, it jeopardizes the patient’s social relations. When part of a severe mental illness, avolition has been reported, in first person accounts, to lead to physical and mental inability to both initiate and maintain relationships, as well as work, eat, drink or even sleep.
Clinically, it may be difficult to engage an individual experiencing avolition in active participation of psychotherapy. Patients are also faced with the stresses of coping with and accepting a mental illness and the stigma that often accompanies such a diagnosis and its symptoms. Regarding schizophrenia, the American Psychiatric Association reported in 2013 that there currently are “no treatments with proven efficacy for primary negative symptoms” (such as avolition). Together with schizophrenia’s chronic nature, such facts added to the outlook of never getting well, might further implicate feelings of hopelessness and similar in patients as well as their friends and family.
Antipsychotics are less effective in the treatment of negative symptoms of schizophrenia such as avolition than for positive symptoms. Low dose amisulpride has shown to be more effective than placebo for treating the negative symptoms of schizophrenia, which includes avolition. It works by blocking pre-synaptic dopamine receptors, causing a release of dopamine into the synapse.
Compared with social skills training (SST), cognitive behavioural therapy (CBT) shows more promise in treating the negative symptoms of schizophrenia, including avolition.
According to a 2015 article, aripiprazole may be useful for treatment of apathy syndrome (avolition). However, its role and efficacy in treatment of apathy requires further investigation in clinical trials. A comparison to amisulpride published in 2022, found that aripiprazole was effective in treating negative symptoms, while amisulpride was not.
According to a 2020 study, mitragynine contained in kratom may have the ability to reduce avolition.
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Asociality refers to the lack of motivation to engage in social interaction, or a preference for solitary activities. Asociality may be associated with avolition, but it can, moreover, be a manifestation of limited opportunities for social relationships. Developmental psychologists use the synonyms non-social, unsocial, and social uninterest. Asociality is distinct from, but not mutually exclusive to, anti-social behaviour. A degree of asociality is routinely observed in introverts, while extreme asociality is observed in people with a variety of clinical conditions.
Asociality is not necessarily perceived as a totally negative trait by society, since asociality has been used as a way to express dissent from prevailing ideas. It is seen as a desirable trait in several mystical and monastic traditions, notably in Hinduism, Jainism, Roman Catholicism, Eastern Orthodoxy, Buddhism and Sufism.
Introversion is “the state of or tendency toward being wholly or predominantly concerned with and interested in one’s own mental life.” Introverted persons are considered the opposite of extraverts, who seem to thrive in social settings rather than being alone. An introvert may present as an individual preferring being alone or interacting with smaller groups over interaction with larger groups, writing over speaking, having fewer but more fulfilling friendships, and needing time for reflection. While not a measurable personality trait, some popular writers have characterised introverts as people whose energy tends to expand through reflection and dwindle during interaction.
In matters of the brain, researchers have found differences in anatomy between introverted and extraverted persons. Introverted people are found to experience a higher flow of blood to the frontal lobe than extraverts, which is the part of the brain that contributes to problem-solving, memory, and pre-emptive thought.
Social anhedonia is found in both typical and extreme cases of asociality or personality disorders that feature social withdrawal. Social anhedonia is distinct from introversion and is frequently accompanied with alexithymia.
Many cases of social anhedonia are marked by extreme social withdrawal and the complete avoidance of social interaction. One research article studying the individual differences in social anhedonia discusses the negative aspects of this form of extreme or aberrant asociality. Some individuals with social anhedonia are at higher risk of developing schizophrenia and may have mental functioning that becomes poorer than the average
In Human Evolution and Anthropology
Scientific research suggests that asocial traits in human behaviour, personality, and cognition may have several useful evolutionary benefits. Traits of introversion and aloofness can protect an individual from impulsive and dangerous social situations because of reduced impulsivity and reward. Frequent voluntary seclusion stimulates creativity and can give the individual time to think, work, reflect, and see useful patterns more easily.
Research indicates the social and analytical functions of the brain function in a mutually exclusive way. With this in mind, researchers posit that people who devoted less time or interest to socialisation used the analytical part of the brain more frequently and thereby were often responsible for devising hunting strategies, creating tools, and spotting useful patterns in the environment in general for both their own safety and the safety of the group.
Imitation and social learning have been confirmed to be potentially limiting and maladaptive in animal and human populations. When social learning overrides personal experience (asocial learning), negative effects can be observed such as the inability to seek or pick the most efficient way to accomplish a task and a resulting inflexibility to changing environments. Individuals who are less receptible, motivated, and interested in sociability are likely less affected by or sensible to socially imitated information and faster to notice and react to changes in the environment, essentially holding onto their own observations in a rigid manner and, consequently, not imitating a maladaptive behaviour through social learning. These behaviours, including deficits in imitative behaviour, have been observed in individuals with autism spectrum disorders and introverts, and are correlated with the personality traits of neuroticism and disagreeableness.
The benefits of this behaviour for the individual and their kin caused it to be preserved in part of the human population. The usefulness for acute senses, novel discoveries, and critical analytical thought may have culminated in the preservation of the suspected genetic factors of autism and introversion itself due to their increased cognitive, sensorial, and analytical awareness.
In schizophrenia, asociality is one of the main five “negative symptoms”, with the others being avolition, anhedonia, reduced affect, and alogia. Due to a lack of desire to form relationships, social withdrawal is common in people with schizophrenia. People with schizophrenia may experience social deficits or dysfunction as a result of the disorder, leading to asocial behaviour. Frequent or ongoing delusions and hallucinations can deteriorate relationships and other social ties, isolating individuals with schizophrenia from reality and in some cases leading to homelessness. Even when treated with medication for the disorder, they may be unable to engage in social behaviours. These behaviours include things like maintaining conversations, accurately perceiving emotions in others, or functioning in crowded settings. There has been extensive research on the effective use of social skills training (SST) for the treatment of schizophrenia, in outpatient clinics as well as inpatient units. SST can be used to help patients with schizophrenia make better eye contact with other people, increase assertiveness, and improve their general conversational skills.
Asociality is common amongst people with avoidant personality disorder (AvPD). They experience discomfort and feel inhibited in social situations, being overwhelmed by feelings of inadequacy. Such people remain consistently fearful of social rejection, choosing to avoid social engagements as they do not want to give people the opportunity to reject (or possibly, accept) them. Though they inherently crave a sense of belonging, their fear of criticism and rejection leads people with AvPD to actively avoid occasions that require social interaction, leading to extremely asocial tendencies; as a result, these individuals often have difficulty cultivating and preserving close relationships.
People with AvPD may also display social phobia, the difference being that social phobia is the fear of social circumstances whereas AvPD is better described as an aversion to intimacy in relationships.
Schizoid personality disorder (SzPD) is characterised by a lack of interest in social relationships, a tendency towards a solitary lifestyle, secretiveness, emotional coldness, and apathy. Affected individuals may simultaneously demonstrate a rich and elaborate but exclusively internal fantasy world.
It is not the same as schizophrenia, although they share such similar characteristics as detachment and blunted affect. There is, moreover, increased prevalence of the disorder in families with schizophrenia.
Schizotypal personality disorder is characterized by a need for social isolation, anxiety in social situations, odd behaviour and thinking, and often unconventional beliefs. People with this disorder feel extreme discomfort with maintaining close relationships with people, and therefore they often do not. People who have this disorder may display peculiar manners of talking and dressing and often have difficulty in forming relationships. In some cases, they may react oddly in conversations, not respond, or talk to themselves.
Autistic people may display profoundly asocial tendencies, due to differences in how autistic and allistic (non-autistic) people communicate. These different communication styles can cause mutual friction between the two neurotypes, known as the double empathy problem. Autistic people tend to express emotions differently and less intensely than allistic people, and often do not pick up on allistic social cues or linguistic pragmatics (including eye contact, facial expressions, tone of voice, body language, and implicatures) used to convey emotions and hints.
Connecting with others is important to overall health. An increased difficulty in accurately reading social cues by others can affect this desire for people with autism. The risk of adverse social experiences is high for those with autism, and so they may prefer to be avoidant in social situations rather than experience anxiety over social performance. Social deficits in people with autism is directly correlated with the increased prevalence of social anxiety in this community. As they are in a steep minority, there is risk of not having access to like-minded peers in their community, which can lead them to withdrawal and social isolation.
Asociality can be observed in individuals with major depressive disorder or dysthymia, as individuals lose interest in everyday activities and hobbies they used to enjoy, this may include social activities, resulting in social withdrawal and withdrawal tendencies.
SST can be adapted to the treatment of depression with a focus on assertiveness training. Depressed patients often benefit from learning to set limits with others, to obtain satisfaction for their own needs, and to feel more self-confident in social interactions. Research suggests that patients who are depressed because they tend to withdraw from others can benefit from SST by learning to increase positive social interactions with others instead of withdrawing from social interactions.
Asocial behaviour is observed in people with social anxiety disorder (SAD), who experience perpetual and irrational fears of humiliating themselves in social situations. They often have panic attacks and severe anxiety as a result, which can occasionally lead to agoraphobia. The disorder is common in children and young adults, diagnosed on average between the ages of 8 and 15. If left untreated, people with SAD exhibit asocial behaviour into adulthood, avoiding social interactions and career choices that require interpersonal skills. SST can help people with social phobia or shyness to improve their communication and social skills so that they will be able to mingle with others or go to job interviews with greater ease and self-confidence.
Traumatic brain injuries (TBI) can also lead to asociality and social withdrawal.
Social skills training (SST) is an effective technique aimed towards anyone with “difficulty relating to others,” a common symptom of shyness, marital and family conflicts, or developmental disabilities; as well as of many mental and neurological disorders including adjustment disorders, anxiety disorders, attention-deficit/hyperactivity disorder, social phobia, alcohol dependence, depression, bipolar disorder, schizophrenia, avoidant personality disorder, paranoid personality disorder, obsessive-compulsive disorder, and schizotypal personality disorder.
Fortunately for people who display difficulty relating to others, social skills can be learned, as they are not simply inherent to an individual’s personality or disposition. Therefore, there is hope for anyone who wishes to improve their social skills, including those with psychosocial or neurological disorders. Nonetheless, it is important to note that asociality may still be considered neither a character flaw nor an inherently negative trait.
SST includes improving eye contact, speech duration, frequency of requests, and the use of gestures, as well as decreasing automatic compliance to the requests of others. SST has been shown to improve levels of assertiveness (positive and negative) in both men and women.
Additionally, SST can focus on receiving skills (e.g. accurately perceiving problem situations), processing skills (e.g. considering several response alternatives), and sending skills (delivering appropriate verbal and non-verbal responses).
Metacognitive interpersonal therapy is a method of treating and improving the social skills of people with personality disorders that are associated with asociality. Through metacognitive interpersonal therapy, clinicians seek to improve their patients’ metacognition, meaning the ability to recognise and read the mental states of themselves. The therapy differs from SST in that the patient is trained to identify their own thoughts and feelings as a means of recognising similar emotions in others. Metacognitive interpersonal therapy has been shown to improve interpersonal and decision-making skills by encouraging awareness of suppressed inner states, which enables patients to better relate to other people in social environments.
The therapy is often used to treat patients with two or more co-occurring personality disorders, commonly including obsessive-compulsive and avoidant behaviours.
In order to cope with asocial behaviour, many individuals, especially those with avoidant personality disorder, develop an inner world of fantasy and imagination to entertain themselves when feeling rejected by peers. Asocial people may frequently imagine themselves in situations where they are accepted by others or have succeeded at an activity. Additionally, they may have fantasies relating to memories of early childhood and close family members.
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Lurasidone, sold under the trade name Latuda among others, is an antipsychotic medication used to treat schizophrenia and bipolar disorder. It is taken by mouth.
Common side effects include sleepiness, movement disorders, nausea, and diarrhoea. Serious side effects are valid for all atypical antipsychotics and may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, angioedema, and high blood sugar levels, although lurasidone is less likely to cause high blood sugar levels in most patients, hyperosmolar hyperglycaemic syndrome may occur. In older people with psychosis as a result of dementia, it may increase the risk of dying. Use during pregnancy is of unclear safety.
Lurasidone was first approved for medical use in the United States in 2010. In 2013, it was approved in Canada, and by the United States Food and Drug Administration, to treat bipolar depression, either as monotherapy or adjunctively with lithium or valproate. Generic versions were approved in the United States in 2019, and became available in 2023. In 2020, it was the 259th most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Lurasidone was first synthesised circa 2003.
Lurasidone is a structural analogue of ziprasidone. Lurasidone shows a very close pharmacological profile and has been synthesized similarly to ziprasidone.
Lurasidone is chemically similar to perospirone (also a chemical analogue of ziprasidone), as well as risperidone, paliperidone and iloperidone.
It has approval from the US Food and Drug Administration (FDA) for treating schizophrenia since 2010, and for treating depressive episodes in adults with bipolar I disorder since 2013.
Lurasidone is used to treat schizophrenia and bipolar disorder. In bipolar disorder, It has been studied both as a monotherapy and adjunctive treatment to lithium or valproate.
The European Medicines Agency approved lurasidone for the treatment of schizophrenia for people aged 13 years and older, but not for bipolar disorder. In the United States, it is used to treat schizophrenia for people aged 13 years and older, as well as depressive episodes of bipolar disorder age 10 and over as a monotherapy, and in conjunction with lithium or valproate in adults.
In July 2013, lurasidone received approval for bipolar I depression.
In June 2020, lurasidone was approved in Japan, eight years after its first approval in the United States. In Japan it is approved for bipolar depression and schizophrenia.
Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine, olanzapine and possibly asenapine) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity, which is yet to be clearly demonstrated for lurasidone.
In the early post approval period lurasidone-treated patients with bipolar disorder were retrospectively found to have more complex clinical profiles, comorbidities, and prior treatment history compared to patients initiated with other atypical antipsychotics. The study authors suggest this may be due to:
“the overall clinical profile of lurasidone, the role perceived for lurasidone in the therapeutic armamentarium by practitioners, and the recent introduction of lurasidone into clinical practice during the study period.”
Lurasidone is not approved by the FDA for the treatment of behaviour disorders in older adults with dementia.
Lurasidone is contraindicated in individuals who are taking strong inhibitors of the liver enzyme CYP3A4 (ketoconazole, clarithromycin, ritonavir, levodropropizine, etc.) or inducers (carbamazepine, St. John’s wort, phenytoin, rifampicin etc.). The use of lurasidone in pregnant women has not been studied and is not recommended; in animal studies, no risks have been found. Excretion in breast milk is also unknown; lurasidone is not recommended for breastfeeding women. In the United States it is not indicated for use in children. The enzyme CYP3A4 is involved in the digestion of drugs. Inhibitors such as grapefruit juice block its function resulting in too much drug in the body.
Side effects are generally similar to other antipsychotics. The drug has a relatively well tolerated side effect profile, with low propensity for QTc interval changes, weight gain and lipid-related adverse effects. In a 2013 meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to produce the second least (after haloperidol) weight gain, the least QT interval prolongation, the fourth most extrapyramidal side effects (after haloperidol, zotepine and chlorpromazine) and the sixth least sedation (after paliperidone, sertindole, amisulpride, iloperidone, and aripiprazole).
As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack; however, these risks are not likely to be greater than those associated with antipsychotics of other classes. Similarly, lurasidone should not be used to treat dementia-related psychosis, as evidence has shown increased mortality with antipsychotic use.
Weight gain is reported in up to 15% and 16% of users. Other possible side effects include vomiting, akathisia, dystonia, parkinsonism, somnolence, dizziness, sedation and nausea.
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Blood plasma concentrations may be increased when combined with CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir, and voriconazole) possibly leading to more side effects. This has been clinically verified for ketoconazole, which increases lurasidone exposure by a factor of 9, and is also expected for other 3A4 inhibitors such as grapefruit juice. Co-administration of CYP3A4 inducers like rifampicin, carbamazepine or St. John’s wort can reduce plasma levels of lurasidone and its active metabolite, and consequently decrease the effects of the drug. For rifampicin, the reduction was sixfold in a study.
Lurasidone [(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl) piperazin-1-ylmethyl]-cyclohexylmethyl}-hexahydro-4,7-methano-2Hisoindole-1,3-dione hydrochloride]] is an azapirone derivative and acts as an antagonist of the dopamine D2 and D3 receptors, and the serotonin 5-HT2A and 5-HT7 receptors, and the α2C-adrenergic receptor, and as a partial agonist of the serotonin 5-HT1A receptor. It has moderate-affinity antagonism at α2C-adrenergic receptors; low to very low-affinity antagonism at α1A-adrenergic α2A-adrenergic receptors.
It has only low and likely clinically unimportant affinity for the serotonin 5-HT2C receptor, which may underlie its low propensity for appetite stimulation and weight gain. The drug also has negligible affinity for the histamine H1 receptor and the muscarinic acetylcholine receptors, and hence has no antihistamine or anticholinergic effects. Drowsiness (somnolence) side effect is not explained by its antagonist activity to histamine.
The relationship between dose and D2 receptor occupancy levels were 41–43% for 10 mg, 51–55% for 20 mg, 63–67% for 40 mg, 77–84% for 60 mg, and 73–79% for 80 mg.
Lurasidone is taken by mouth and has an estimated absorption rate of 9 to 19%. Studies have shown that when lurasidone is taken with food, absorption increases about twofold. Peak blood plasma concentrations are reached after one to three hours. About 99% of the circulating substance are bound to plasma proteins. Efficacy data for lurasidone have been evaluated for doses of 20 mg to 120 mg daily
Lurasidone is extensively metabolised by CYP3A4 leading to contraindication of both strong inhibitors as well as strong inducers of this enzyme, but has negligible affinity to other cytochrome P450 enzymes. It is transported by P-glycoprotein and ABCG2 and also inhibits these carrier proteins in vitro. It also inhibits the solute carrier protein SLC22A1, but no other relevant transporters.
Main metabolism pathways are oxidative N-dealkylation between the piperazine and cyclohexane rings, hydroxylation of the norbornane ring, and S-oxidation. Other pathways are hydroxylation of the cyclohexane ring and reductive cleavage of the isothiazole ring followed by S-methylation. The two relevant active metabolites are the norbornane hydroxylation products called ID-14283 and ID-14326, the former reaching pharmacologically relevant blood plasma concentrations. The two major inactive metabolites are the N-dealkylation products (the carboxylic acid ID-20219 and the piperazine ID-11614), and a norbornane hydroxylated derivative of ID-20219 (ID-20220). Of lurasidone and its metabolites circulating in the blood, the native drug makes up 11%, the main active metabolite 4%, and the inactive carboxylic acids 24% and 11%, respectively. Several dozen metabolites have been identified altogether.
Biological half-life is given as 18 hours or 20 to 40 hours in different sources. 80% or 67% of a radiolabelled dose was recovered from the faeces, and 9% or 19% from the urine.
In Canada, as of 2014, lurasidone is generally more expensive than risperidone and quetiapine but less expensive than aripiprazole.
In the US, because a number of doses have the same price per tablet, pill splitting has been used to decrease costs. In 2019, generic versions were approved in the United States; however, they only became available in 2023 due to drug patents.
In India, this drug is available under the brand names of Atlura, Lurace, Lurafic, Luramax (Sun Pharma), Lurasid, Lurastar, Latuda, Lurata and additionally as Alsiva, Emsidon, Lurakem, Luratrend, Tablura, and Unison.
Lurasidone was approved in the United States for the treatment of schizophrenia in October 2010 and for the treatment of depressive episodes associated with bipolar I disorder in June 2013. It received regulatory approval in the United Kingdom in September 2014. In October 2014, NHS Scotland advised use of lurasidone for schizophrenic adults who have not seen improvements with previous antipsychotics due to problems that arise from weight gain or changes in metabolic pathways when taking other medications. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion for it in January 2014, and it was approved for medical use by the EMA in March 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on 15 October 2012. European Commission has granted a marketing authorization for once-daily oral lurasidone for the treatment of schizophrenia in adults. It is approved for use in the EU.
Generic versions of lurasidone were approved for use in the United States in January 2019 and became available in 2023.
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Brexpiprazole, sold under the brand name Rexulti among others, is a medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer’s disease. It is an atypical antipsychotic.
The most common side effects include akathisia (a constant urge to move) and weight gain. The most common side effects among people with agitation associated with dementia due to Alzheimer’s disease include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances (both somnolence and insomnia).
Brexpiprazole was developed by Otsuka and Lundbeck, and is considered to be a successor to aripiprazole (Abilify). It was approved for medical use in the United States in July 2015. A generic version was approved in August 2022. Brexpiprazole is the first treatment approved by the US Food and Drug Administration (FDA) for agitation associated with dementia due to Alzheimer’s disease.
In the United States and Canada, brexpiprazole is indicated as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia. In May 2023, the indication for brexpiprazole was expanded in the US to include the treatment of agitation associated with dementia due to Alzheimer’s disease.
In Australia and the European Union, brexpiprazole is indicated for the treatment of schizophrenia.
In 2020, it was approved in Brazil only as an adjunctive to the treatment of major depressive disorder.
The most common adverse events associated with brexpiprazole (all doses of brexpiprazole cumulatively greater than or equal to 5% vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%). Brexpiprazole can cause impulse control disorders.
Brexpiprazole acts as a partial agonist of the serotonin 5-HT1A receptor and the dopamine D2 and D3 receptors. Partial agonists have both blocking properties and stimulating properties at the receptor they bind to. The ratio of blocking activity to stimulating activity determines a portion of its clinical effects. Brexpiprazole has more blocking and less stimulating activity at the dopamine receptors than its predecessor, aripiprazole, which may decrease its risk for agitation and restlessness. Specifically, where aripiprazole has an intrinsic activity or agonist effect at the D2 receptor of 60%+, brexpiprazole has an intrinsic activity at the same receptor of about 45%. For aripiprazole, this means more dopamine receptor activation at lower doses, with blockade being reached at higher doses, while brexpiprazole has the inverse effect because a partial agonist competes with dopamine. Brexpiprazole has a high affinity for the 5-HT1A receptor, acting as a potent antagonist at 5-HT2A receptors, and a potent partial agonist at dopamine D2 receptors with lower intrinsic activity compared to aripiprazole. In vivo characterisation of brexpiprazole shows that it may act as a near-full agonist of the 5-HT1A receptor. This may further underlie a lower potential than aripiprazole to cause treatment-emergent, movement-related disorders such as akathisia due to the downstream dopamine release that is triggered by 5-HT1A receptor agonism. It is also an antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT7 receptors, which may contribute to antidepressant effect. It also binds to and blocks the α1A-, α1B-, α1D-, and α2C-adrenergic receptors. The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects. Although brexpiprazole has less affinity for H1 compared to aripiprazole, weight gain can occur.
Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and agitation associated with dementia due to Alzheimer’s disease.
The phase II multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three approved antidepressant treatments (ADTs) in the current episode. The study was designed to assess the efficacy and safety of brexpiprazole as an adjunctive treatment to standard antidepressant treatment. The antidepressants included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.
A phase III study was in the recruiting stage: “Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)”. Its goal is “to compare the effect of brexpiprazole to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with major depressive disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT”. Estimated enrolment was 1,250 volunteers.
The effectiveness of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer’s disease was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies. In these studies, participants were required to have a probable diagnosis of Alzheimer’s dementia; have a score between 5 and 22 on the Mini-Mental State Examination, a test that detects whether a person is experiencing cognitive impairment; and exhibit the type, frequency, and severity of agitation behaviours that require medication. Trial participants ranged between 51 and 90 years of age.
In January 2018, it was approved for the treatment of schizophrenia in Japan.
In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance. Lundbeck gave Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion. Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.
Brexpiprazole was under development for the treatment of attention deficit hyperactivity disorder (ADHD) as an adjunct to stimulants, but was discontinued for this indication. It reached phase II clinical trials for this use prior to discontinuation.
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Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder as well as the medium to long-term management of bipolar disorder.
It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.
It was initially approved in the United States in 2009 and approved as a generic medication in 2020.
Asenapine has been approved by the FDA (US Food and Drug Administration) for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. In Australia asenapine’s approved (and also listed on the PBS (Pharmaceutical Benefits Scheme)) indications include the following.
In the European Union and the United Kingdom, asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.
Asenapine is absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed. A transdermal formulation of asenapine was approved in the United States in October 2019 under the brand name Secuado.
A Cochrane systematic review found that while Asenapine has some preliminary evidence that it improves positive, negative, and depressive symptoms, it does not have enough research to merit a certain recommendation of asenapine for the treatment of schizophrenia.
For the medium-term and long-term management and control of both depressive and manic features of bipolar disorder asenapine was found be equally effective as olanzapine, but with a substantially superior side effect profile.
In acute mania, asenapine was found to be significantly superior to placebo. As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs such as risperidone and olanzapine (with the exception of ziprasidone). Drop-out rates (in clinical trials) were also unusually high with asenapine. According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes.
Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and a 2013 meta-analysis found significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22).
Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis. This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic. The same meta-analysis suggested that asenapine had a relatively high risk of extrapyramidal symptoms compared to other atypical antipsychotics but a lower risk than first-generation or typical antipsychotics.
For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a transient withdrawal symptom. It may also result in recurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors. At all other targets asenapine is an antagonist.
Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors.
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The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signalling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signalling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.
Like the dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, NMDA antagonists mimic some positive and negative symptoms with less brain harm, when combined with a GABAA activating drug. Likely, both dopaminergic and glutaminergic abnormalities are implicated in schizophrenia, from a profound alteration in the function of the chemical synapses, as well as electrical synaptic irregularities. These form a portion of the complex constellation of factors, neurochemically, psychologically, psychosocially, and structurally, which result in schizophrenia.
Refer to Dopamine Hypothesis of Schizophrenia.
Alteration in the expression, distribution, autoregulation, and prevalence of specific glutamate heterodimers alters relative levels of paired G proteins to the heterodimer-forming glutamate receptor in question.
Namely: 5HT2A and mGlu2 form a dimer which mediates psychotomimetic and entheogenic effects of psychedelics; as such this receptor is of interest in schizophrenia. Agonists at either constituent receptor may modulate the other receptor allosterically; e.g. glutamate-dependent signalling via mGlu2 may modulate 5HT2A-ergic activity. Equilibrium between mGlu2/5HT2A is altered against tendency towards of psychosis by neuroleptic-pattern 5HT2A antagonists and mGlu2 agonists; both display antipsychotic activity. AMPA, the most widely distributed receptor in the brain, is a tetrameric ionotropic receptor; alterations in equilibrium between constituent subunits are seen in mGlu2/5HT2A antagonist (antipsychotic) administration- GluR2 is seen to be upregulated in the PFC while GluR1 downregulates in response to antipsychotic administration.
Reelin abnormalities may also be involved in the pathogenesis of schizophrenia via a glutamate-dependent mechanism. Reelin expression deficits are seen in schizophrenia, and reelin enhances expression of AMPA and NMDA alike. As such deficits in these two ionotropic glutamate receptors may be partially explained by altered reelin cascades. Neuregulin 1 deficits may also be involved in glutaminergic hypofunction as NRG1 hypofunction leads to schizophrenia-pattern behaviour in mice; likely due in part to reduced NMDA signalling via Src suppression.
Various neurotrophic factors dysregulate in schizophrenia and other mental illnesses, namely BDNF; expression of which is lowered in schizophrenia as well as in major depression and bipolar disorder. BDNF regulates in an AMPA-dependent mechanism – AMPA and BDNF alike are critical mediators of growth cone survival. NGF, another neurotrophin involved in maintenance of synaptic plasticity is similarly seen in deficit.
Dopaminergic excess, classically understood to result in schizophrenia, puts oxidative load on neurons; leading to inflammatory response and microglia activation. Similarly, toxoplasmosis infection in the CNS (positively correlated to schizophrenia) activates inflammatory cascades, also leading to microglion activation. The lipoxygenase-5 inhibitor minocycline has been seen to be marginally effective in halting schizophrenia progression. One of such inflammatory cascades’ downstream transcriptional target, NF-κB, is observed to have altered expression in schizophrenia.
In addition, CB2 is one of the most widely distributed glial cell-expressed receptors, downregulation of this inhibitory receptor may increase global synaptic pruning activity. While difference in expression or distribution is observed, when the CB2 receptor is knocked out in mice, schizophreniform behaviours manifest. This may deregulate synaptic pruning processes in a tachyphlaxis mechanism wherein immediate excess CB2 activity leads to phosphorylation of the receptor via GIRK, resultant in b-arrestin-dependent internalisation and subsequent trafficking to the proteasome for degradation.
Alterations in production of endogenous NMDA antagonists such as agmatine and kynurenic acid have been shown in schizophrenia. Deficit in NMDA activity produces psychotomimetic effects, though it remains to be seen if the blockade of NMDA via these agents is causative or actually mimetic of patterns resultant from monoaminergic disruption.
AMPA, the most widely distributed receptor in the brain, mediates long term potentiation via activity-dependent modulation of AMPA density. GluR1 subunit-containing AMPA receptors are Ca2+ permeable while GluR2/3 subunit-positive receptors are nearly impermeable to calcium ions. In the regulated pathway, GluR1 dimers populate the synapse at a rate proportional to NMDA-ergic Ca2+ influx. In the constitutative pathway, GluR2/3 dimers populate the synapse at a steady state.
This forms a positive feedback loop, where a small trigger impulse degating NMDA from Mg2+ pore blockade results in calcium influx, this calcium influx then triggers trafficking of GluR1-containing(Ca2+ permeable) subunits to the PSD, such trafficking of GluR1-positive AMPA to the postsynaptic neuron allows for upmodulation of the postsynaptic neuron’s calcium influx in response to presynaptic calcium influx. Robust negative feedback at NMDA from kynurenic acid, magnesium, zinc, and agmatine prevents runaway feedback.
Misregulation of this pathway would sympathetically dysregulate LTP via disruption of NMDA. Such alteration in LTP may play a role, specifically in negative symptoms of schizophrenia, in creation of more broad disruptions such as loss of brain volume; an effect of the disease which antidopaminergics actually worsen, rather than treat.
Anandamide, an endocannabinoid, is an a7 nicotinic antagonist. Cigarettes, consumed far out of proportion by schizophrenics, contain nornitrosonicotine; a potent a7 antagonist. This may indicate a7 pentameter excess as a causative factor, or possibly as a method of self-medication to combat antipsychotic side effects. Cannabidiol, a FAAH inhibitor, increases levels in anandamide and may have antipsychotic effect; though results are mixed here as anandamide also is a cannabinoid and as such displays some psychotomimetic effect. However, a7 nicotinic agonists have been indicated as potential treatments for schizophrenia, though evidence is somewhat contradictory there is indication a7 nAChR is somehow involved in the pathogenesis of schizophrenia.
This deficit in activation also results in a decrease in activity of 5-HT1A receptors in the raphe nucleus. This serves to increase global serotonin levels, as 5-HT1A serves as an autoreceptor. The 5-HT1B receptor, also acting as an autoreceptor, specifically within the striatum, but also parts of basal ganglia then will inhibit serotonin release. This disinhibits frontal dopamine release. The local deficit of 5-HT within the striatum, basal ganglia, and prefrontal cortex causes a deficit of excitatory 5-HT6 signalling. This could possibly be the reason antipsychotics sometimes are reported to aggravate negative symptoms as antipsychotics are 5HT6 antagonists This receptor is primarily GABAergic, as such, it causes an excess of glutamatergic, noradrenergic, dopaminergic, and cholinergic activity within the prefrontal cortex and the striatum. An excess of 5-HT7 signaling within the thalamus also creates too much excitatory transmission to the prefrontal cortex. Combined with another critical abnormality observed in those with schizophrenia: 5-HT2A dysfunction, this altered signalling cascade creates cortical, thus cognitive abnormalities. 5-HT2A allows a link between cortical, thus conscious, and the basal ganglia, unconscious. Axons from 5-HT2A neurons in layer V of the cerebral cortex reach the basal ganglia, forming a feedback loop. Signalling from layer V of the cerebral cortex to the basal ganglia alters 5-HT2C signalling. This feedback loop with 5-HT2A/5-HT2C is how the outer cortex layers can exert some control over our neuropeptides, specifically opioid peptides, oxytocin and vasopressin. This alteration in this limbic-layer V axis may create the profound change in social cognition (and sometimes cognition as a whole) that is observed in schizophrenia. However, genesis of the actual alterations is a much more complex phenomena.
The cortico-basal ganglia-thalamo-cortical loop is the source of the ordered input necessary for a higher level upper cortical loop. Feedback is controlled by the inhibitory potential of the cortices via the striatum. Through 5-HT2A efferents from layer V of the cortex transmission proceeds through the striatum into the globulus pallidus internal and substantia nigra pars compacta. This core input to the basal ganglia is combined with input from the subthalamic nucleus. The only primarily dopaminergic pathway in this loop is a reciprocal connection from the substantia nigra pars reticulata to the striatum.
Dopaminergic drugs such as dopamine releasing agents and direct dopamine receptor agonists create alterations in this primarily GABAergic pathway via increased dopaminergic feedback from the substantia nigra pars compacta to the striatum. However, dopamine also modulates other cortical areas, namely the VTA; with efferents to the amygdala and locus coeruleus, likely modulating anxiety and paranoid aspects of psychotic experience. As such, the glutamate hypothesis is probably not an explanation of primary causative factors in positive psychosis, but rather might possibly be an explanation for negative symptoms.
Dopamine hypothesis of schizophrenia elaborates upon the nature of abnormal lateral structures found in someone with a high risk for psychosis.
Again, thalamic input from layer V is a crucial factor in the functionality of the human brain. It allows the two sides to receive similar inputs, thus be able to perceive the same world. In psychosis, thalamic input loses much of its integrated character: hyperactive core feedback loops overwhelm the ordered output. This is due to excessive D2 and 5-HT2A activity. This alteration in input to the top and bottom of the cortex. The altered 5-HT signal cascade enhances the strength of excitatory thalamic input from layer V. This abnormality, enhancing the thalamic-cortical transmission cascade versus the corticostriatal control, creates a feedback loop, resulting in abnormally strong basal ganglia output.
The root of psychosis (experiences that cannot be explained, even within their own mind) is when basal ganglia input to layer V overwhelms the inhibitory potential of the higher cortexies resulting from striatal transmission. When combined with the excess prefrontal, specifically orbitofrontal transmission, from the hippocampus, this creates a brain prone to falling into self reinforcing belief.
However, given a specific environment, a person with this kind of brain (a human) can create a self-reinforcing pattern of maladaptive behaviour, from the altered the layer II/III and III/I axises, from the disinhibited thalamic output. Rationality is impaired, primarily as response to the deficit of oxytocin and excess of vasopressin from the abnormal 5HT2C activity.
Frontal cortex activity will be impaired, when combined with excess DA activity: the basis for the advancement of schizophrenia, but it is also the neurologic mechanism behind many other psychotic diseases as well. Heredation of schizophrenia may even be a result of conspecific “refrigerator parenting” techniques passed on though generations. However, the genetic component is the primary source of the neurological abnormalities which leave one prone to psychological disorders. Specifically, there is much overlap between bipolar disorder and schizophrenia, and other psychotic disorders.
Psychotic disorder is linked to excessive drug use, specifically dissociatives, psychedelics, stimulants, and marijuana.
Alterations in serine racemase indicate that the endogenous NMDA agonist D-serine may be produced abnormally in schizophrenia and that d-serine may be an effective treatment for schizophrenia.
Schizophrenia is now treated by medications known as antipsychotics (or neuroleptics) that typically reduce dopaminergic activity because too much activity has been most strongly linked to positive symptoms, specifically persecutory delusions. Dopaminergic drugs do not induce the characteristic auditory hallucinations of schizophrenia. Dopaminergic drug abuse such as abuse of methamphetamine may result in a short lasting psychosis or provocation of a longer psychotic episode that may include symptoms of auditory hallucinations. The typical antipsychotics are known to have significant risks of side effects that can increase over time, and only show clinical effectiveness in reducing positive symptoms. Additionally, although newer atypical antipsychotics can have less affinity for dopamine receptors and still reduce positive symptoms, do not significantly reduce negative symptoms.
Ketamine and PCP were observed to produce significant similarities to schizophrenia. Ketamine produces more similar symptoms (hallucinations, withdrawal) without observed permanent effects (other than ketamine tolerance). Both arylcyclohexamines have some(uM) affinity to D2 and as triple reuptake inhibitors. PCP is representative symptomatically, but does appear to cause brain structure changes seen in schizophrenia. Although unconfirmed, Dizocilpine discovered by a team at Merck seems to model both the positive and negative effects in a manner very similar to schizophreniform disorders.
An early clinical trial by Eli Lilly of the drug LY2140023 has shown potential for treating schizophrenia without the weight gain and other side-effects associated with conventional antipsychotics. A trial in 2009 failed to prove superiority over placebo or Olanzapine, but Lilly explained this as being due to an exceptionally high placebo response. However, Eli Lilly terminated further development of the compound in 2012 after it failed in phase III clinical trials. This drug acts as a selective agonist at metabotropic mGluR2 and mGluR3 glutamate receptors (the mGluR3 gene has previously been associated with schizophrenia).
Studies of glycine (and related co-agonists at the NMDA receptor) added to conventional antipsychotics have also found some evidence that these may improve symptoms in schizophrenia.
Research done on mice in early 2009 has shown that when the neuregulin-1\ErbB post-synaptic receptor genes are deleted, the dendritic spines of glutamate neurons initially grow, but break down during later development. This led to symptoms (such as disturbed social function, inability to adapt to predictable future stressors) that overlap with schizophrenia. This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood.
Disrupted in schizophrenia 1 is a gene that is disrupted in schizophrenia.
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