Tag: Schizophrenia

An Overview of Thought Disorder

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Introduction

A thought disorder (TD) is a disturbance in cognition which affects language, thought and communication.

Psychiatric and psychological glossaries in 2015 and 2017 identified thought disorders as encompassing poverty of ideas, neologisms, paralogia, word salad, and delusions – all disturbances of thought content and form. Two specific terms have been suggested:

  1. Content thought disorder (CTD); and
  2. Formal thought disorder (FTD).

CTD has been defined as a thought disturbance characterised by multiple fragmented delusions, and the term thought disorder is often used to refer to a FTD: a disruption of the form (or structure) of thought. Also known as disorganised thinking, FTD results in disorganised speech and is recognised as a major feature of schizophrenia and other psychoses (including mood disorders, dementia, mania, and neurological diseases). Disorganised speech leads to an inference of disorganised thought. Thought disorders include derailment, pressured speech, poverty of speech, tangentiality, verbigeration, and thought blocking.

Formal thought disorder affects the form (rather than of the content) of thought. Unlike hallucinations and delusions, it is an observable, objective sign of psychosis. FTD is a common core symptom of a psychotic disorder, and may be seen as a marker of severity and as an indicator of prognosis. It reflects a cluster of cognitive, linguistic, and affective disturbances that have generated research interest in the fields of cognitive neuroscience, neurolinguistics, and psychiatry.

Eugen Bleuler, who named schizophrenia, said that TD was its defining characteristic. Disturbances of thinking and speech, such as clanging or echolalia, may also be present in Tourette syndrome; other symptoms may be found in delirium. A clinical difference exists between these two groups. Patients with psychoses are less likely to show awareness or concern about disordered thinking, and those with other disorders are aware and concerned about not being able to think clearly.

Content Thought Disorder

Content thought disorder (CTD) is a thought disturbance in which a person experiences multiple, fragmented delusions, typically a feature of schizophrenia and some other mental disorders which include obsessive-compulsive disorder and mania. At the core of CTD are abnormal beliefs and convictions (after taking the person’s culture and background into consideration) ranging from overvalued ideas to fixed delusions. These beliefs and delusions are typically non-specific diagnostically, even if some delusions are more prevalent in one disorder than another.

Neurotypical thought—consisting of awareness, concerns, beliefs, preoccupations, wishes, fantasies, imagination, and concepts—can be illogical, and can contain contradictory beliefs and prejudices or biases. Individuals vary considerably, and a person’s thinking may also shift from time to time.

CTD is not limited to delusions. Other possible abnormalities include suicidal, violent, and homicidal ideas and:

  • Preoccupation: centring thought on a particular idea in association with a strong affection
  • Obsession: a persistent thought, idea, or image which is intrusive or inappropriate, and distressing or upsetting
  • Compulsive behaviour: the need to perform an act persistently and repetitively (without it necessarily leading to a reward or pleasure) to reduce distress
  • Magical thinking: belief that one’s thoughts alone can bring about effects in the world, or that thinking something corresponds with doing that thing
  • Overvalued ideas: false or exaggerated belief held with conviction, but without delusional intensity
  • Phobias: irrational fears of objects or circumstances

In psychosis, delusions are the most common CTD. A delusion is a firm, fixed belief based on inadequate grounds, not amenable to rational argument or evidence to the contrary, which is out of sync with a person’s regional, cultural, or educational background. Delusions are common in people with mania, depression, schizoaffective disorder, delirium, dementia, substance use disorders, schizophrenia, and delusional disorders. Common examples in a mental status examination include the following:

  • Erotomania: belief that someone is in love with oneself
  • Grandiose delusions: belief that one is the greatest, strongest, fastest, richest, or the most intelligent person ever
  • Persecutory delusion: belief that the person, or someone to whom the person is close, is being malevolently treated in some way
  • Ideas and delusions of reference: belief that insignificant remarks, coincidental events, or innocuous objects in one’s environment have personal meaning or significance
  • Thought broadcasting: belief that others can hear (or are aware of) one’s thoughts
  • Thought insertion: belief that one’s thoughts are not one’s own, but belong to someone else and have been inserted into one’s mind
  • Thought withdrawal: belief that thoughts have been “taken out” of one’s mind, and one has no power over this
  • Influence: belief that other people (or external agents) are covertly exerting power over oneself
  • Outside control: belief that outside forces are controlling one’s thoughts, feelings, and actions
  • Infidelity: belief that a partner is cheating on oneself
  • Somatic: belief that one has a disease or medical condition
  • Nihilistic: belief that the mind, the body, the world at large, or parts thereof no longer exist

Formal Thought Disorder

Formal thought disorder (FTD) is also known as disorganised speech. Evidence of disorganized thinking, it is a hallmark feature of schizophrenia. FTD, a disorder of the form (rather than content) of thought, encompasses hallucinations and delusions and is an observable sign of psychosis. A common, core symptom of psychosis, it may be seen as a marker of severity and a predictor of prognosis. FTD reflects a cluster of cognitive, linguistic, and affective disturbances which has generated research interest from the fields of cognitive neuroscience, neurolinguistics, and psychiatry.

It can be subdivided into clusters of positive and negative symptoms and objective (rather than subjective) symptoms. On the scale of positive and negative symptoms, they have been grouped into:

  • Positive Formal Thought Disorder (posFTD); and
  • Negative Formal Thought Disorder (negFTD).

Positive subtypes were pressure of speech, tangentiality, derailment, incoherence, and illogicality;[12] negative subtypes were poverty of speech and poverty of content. The two groups were posited to be at either end of a spectrum of normal speech, but later studies showed them to be poorly correlated. A comprehensive measure of FTD is the Thought and Language Disorder (TALD) Scale.

Nancy Andreasen preferred to identify TDs as thought-language-communication disorders (TLC disorders). Up to seven domains of FTD have been described on the Thought, Language, Communication (TLC) Scale, with most of the variance accounted for by two or three domains. Some TLC disorders are more suggestive of severe disorder, and are listed with the first 11 items.

Diagnoses

The DSM V categorises FTD as “a psychotic symptom, manifested as bizarre speech and communication.” FTD may include incoherence, peculiar words, disconnected ideas, or a lack of unprompted content expected from normal speech. Clinical psychologists typically assess FTD by initiating an exploratory conversation with patients and observing the patient’s verbal responses.

FTD is often used to establish a diagnosis of schizophrenia; in cross-sectional studies, 27 to 80 percent of patients with schizophrenia present with FTD. A hallmark feature of schizophrenia, it is also widespread amongst other psychiatric disorders; up to 60 percent of those with schizoaffective disorder and 53 percent of those with clinical depression demonstrate FTD, suggesting that it is not exclusive to schizophrenia. About six percent of healthy subjects exhibit a mild form of FTD.

The characteristics of FTD vary amongst disorders. A number of studies indicate that FTD in mania is marked by irrelevant intrusions and pronounced combinatory thinking, usually with a playfulness and flippancy absent from patients with schizophrenia. The FTD present in patients with schizophrenia was characterized by disorganisation, neologism, and fluid thinking, and confusion with word-finding difficulty.

There is limited data on the longitudinal course of FTD. The most comprehensive longitudinal study of FTD by 2023 found a distinction in the longitudinal course of thought-disorder symptoms between schizophrenia and other psychotic disorders. The study also found an association between pre-index assessments of social, work and educational functioning and the longitudinal course of FTD.

Possible Causes

Several theories have been developed to explain the causes of FTD. It has been proposed that FTD relates to neurocognition via semantic memory. Semantic network impairment in people with schizophrenia – measured by the difference between fluency (e.g. the number of animals’ names produced in 60 seconds) and phonological fluency (e.g. the number of words beginning with “F” produced in 60 seconds) – predicts the severity of FTD, suggesting that verbal information (through semantic priming) is unavailable. Other hypotheses include working memory deficit (being confused about what has already been said in a conversation) and attentional focus.

FTD in schizophrenia has been found to be associated with structural and functional abnormalities in the language network, where structural studies have found bilateral grey matter deficits; deficits in the bilateral inferior frontal gyrus, bilateral inferior parietal lobule and bilateral superior temporal gyrus are FTD correlates. Other studies did not find an association between FTD and structural aberrations of the language network, however, and regions not included in the language network have been associated with FTD. Future research is needed to clarify whether there is an association with FTD in schizophrenia and neural abnormalities in the language network.

Transmitter systems which might cause FTD have also been investigated. Studies have found that glutamate dysfunction, due to a rarefaction of glutamatergic synapses in the superior temporal gyrus in patients with schizophrenia, is a major cause of positive FTD.

The heritability of FTD has been demonstrated in a number of family and twin studies. Imaging genetics studies, using a semantic verbal-fluency task performed by the participants during functional MRI scanning, revealed that alleles linked to glutamatergic transmission contribute to functional aberrations in typical language-related brain areas. FTD is not solely genetically determined, however; environmental influences, such as allusive thinking in parents during childhood, and environmental risk factors for schizophrenia (including childhood abuse, migration, social isolation, and cannabis use) also contribute to the pathophysiology of FTD.

The origins of FTD have been theorised from a social-learning perspective. Singer and Wynne said that familial communication patterns play a key role in shaping the development of FTD; dysfunctional social interactions undermine a child’s development of cohesive, stable mental representations of the world, increasing their risk of developing FTD.

Treatments

Antipsychotic medication is often used to treat FTD. Although the vast majority of studies of the efficacy of antipsychotic treatment do not report effects on syndromes or symptoms, six older studies report the effects of antipsychotic treatment on FTD. These studies and clinical experience indicate that antipsychotics are often an effective treatment for patients with positive or negative FTD, but not all patients respond to them.

Cognitive behavioural therapy (CBT) is another treatment for FTD, but its effectiveness has not been well-studied. Large randomised controlled trials evaluating the effectiveness of CBT for treating psychosis often exclude individuals with severe FTD because it reduces the therapeutic alliance required by the therapy. However, provisional evidence suggests that FTD may not preclude the effectiveness of CBT. Kircher and colleagues have suggested that the following methods should be used in CBT for patients with FTD:

  • Practise structuring, summarising, and feedback methods
  • Repeat and clarify the core issues and main emotions that the patient is trying to communicate
  • Gently encourage patients to clarify what they are trying to communicate
  • Ask patients to clearly state their communication goal
  • Ask patients to slow down and explain how one point leads to another
  • Help patients identify the links between ideas
  • Identify the main affect linked to the thought disorder
  • Normalise problems with thinking

Signs and Symptoms

Language abnormalities exist in the general population, and do not necessarily indicate a condition. They can occur in schizophrenia and other disorders (such as mania or depression), or in anyone who may be tired or stressed. To distinguish thought disorder, patterns of speech, severity of symptoms, their frequency, and any resulting functional impairment can be considered.

Symptoms of TD include derailment, pressured speech, poverty of speech, tangentiality, and thought blocking. FTD is a hallmark feature of schizophrenia, but is also associated with other conditions (including mood disorders, dementia, mania, and neurological diseases). Impaired attention, poor memory, and difficulty formulating abstract concepts may also reflect TD, and can be observed and assessed with mental-status tests such as serial sevens or memory tests.

Types

Thirty symptoms (or features) of TD have been described, including:

  • Alogia: A poverty of speech in amount or content, it is classified as a negative symptom of schizophrenia. When further classifying symptoms, poverty of speech content (little meaningful content with a normal amount of speech) is a disorganisation symptom. Under SANS, thought blocking is considered a part of alogia, and so is increased latency in response.
  • Thought blocking (also known as deprivation of thought and obstructive thought): An abrupt stop in the middle of a train of thought which may not be able to be continued.
  • Circumstantial speech (also known as circumstantial thinking): An inability to answer a question without excessive, unnecessary detail. This differs from tangential thinking in that the person does eventually return to the original point. A patient may answer the question “How have you been sleeping lately?” with “Oh, I go to bed early, so I can get plenty of rest. I like to listen to music or read before bed. Right now I’m reading a good mystery. Maybe I’ll write a mystery someday. But it isn’t helping, reading I mean. I have been getting only 2 or 3 hours of sleep at night.”
  • Clanging: An instance where ideas are related only by similar or rhyming sounds rather than actual meaning. This may be heard as excessive rhyming or alliteration (“Many moldy mushrooms merge out of the mildewy mud on Mondays”, or “I heard the bell. Well, hell, then I fell”). It is most commonly seen in the manic phase of bipolar disorder, although it is also often observed in patients with schizophrenia and schizoaffective disorder.
  • Derailment (also known as loose association and knight’s move thinking): Thought frequently moves from one idea to another which is obliquely related or unrelated, often appearing in speech but also in writing (“The next day when I’d be going out you know, I took control, like uh, I put bleach on my hair in California”),
  • Distractible speech: In mid-speech, the subject is changed in response to a nearby stimulus (“Then I left San Francisco and moved to … Where did you get that tie?”)
  • Echolalia: Echoing of another’s speech, once or in repetition. It may involve repeating only the last few words (or the last word) of another person’s sentences, and is common on the autism spectrum and in Tourette syndrome.
  • Evasion: The next logical idea in a sequence is replaced with another idea closely (but not accurately or appropriately) related to it; also known as paralogia and perverted logic.
  • Flight of ideas: A form of FTD marked by abrupt leaps from one topic to another, possibly with discernible links between successive ideas, perhaps governed by similarities between subjects or by rhyming, puns, wordplay, or innocuous environmental stimuli (such as the sound of birds chirping). It is most characteristic of the manic phase of bipolar disorder.
  • Illogicality: Conclusions are reached which do not follow logically (non sequiturs or faulty inferences). “Do you think this will fit in the box?” is answered with, “Well of course; it’s brown, isn’t it?”
  • Incoherence (word salad): Speech which is unintelligible because the individual words are real, but the manner in which they are strung together results in gibberish. The question “Why do people comb their hair?” elicits a response like “Because it makes a twirl in life, my box is broken help me blue elephant. Isn’t lettuce brave? I like electrons, hello please!”
  • Neologisms: Completely new words (or phrases) whose origins and meanings are usually unrecognisable (“I got so angry I picked up a dish and threw it at the geshinker”). They may also involve elisions of two words which are similar in meaning or sound. Although neologisms may refer to words formed incorrectly whose origins are understandable (such as “headshoe” for “hat”), these can be more clearly referred to as word approximations.
  • Overinclusion: The failure to eliminate ineffective, inappropriate, irrelevant, extraneous details associated with a particular stimulus.
  • Perseveration: Persistent repetition of words or ideas, even when another person tries to change the subject. (“It’s great to be here in Nevada, Nevada, Nevada, Nevada, Nevada.”) It may also involve repeatedly giving the same answer to different questions (“Is your name Mary?” “Yes.” “Are you in the hospital?” “Yes.” “Are you a table?” “Yes”). Perseveration can include palilalia and logoclonia, and may indicate an organic brain disease such as Parkinson’s disease.
  • Phonemic paraphasia: Mispronunciation; syllables out of sequence (“I slipped on the lice and broke my arm”).
  • Pressured speech: Rapid speech without pauses, which is difficult to interrupt.
  • Referential thinking: Viewing innocuous stimuli as having a specific meaning for the self (“What’s the time?” “It’s 7 o’clock. That’s my problem”).
  • Semantic paraphasia: Substitution of inappropriate words (“I slipped on the coat, on the ice I mean, and broke my book”).
  • Stilted speech: Speech characterised by words or phrases which are flowery, excessive, and pompous (“The attorney comported himself indecorously”).
  • Tangential speech: Wandering from the topic and never returning to it, or providing requested information (“Where are you from?” “My dog is from England. They have good fish and chips there. Fish breathe through gills”).
  • Verbigeration: Meaningless, stereotyped repetition of words or phrases which replace understandable speech; seen in schizophrenia.

Terminology

Psychiatric and psychological glossaries in 2015 and 2017 defined thought disorder’ as disturbed thinking or cognition which affects communication, language, or thought content including poverty of ideas, neologisms, paralogia, word salad, and delusions (disturbances of thought content and form), and suggested the more-specific terms content thought disorder (CTD) and formal thought disorder (FTD). CTD was defined as a TD characterised by multiple fragmented delusions, and FTD was defined as a disturbance in the form or structure of thinking. The 2013 DSM-5 only used the term FTD, primarily as a synonym for disorganized thinking and speech. This contrasts with the 1992 ICD-10 (which only used the word “thought disorder”, always accompanied with “delusion” and “hallucination”) and a 2002 medical dictionary which generally defined thought disorders similarly to the psychiatric glossaries and used the word in other entries as the ICD-10 did.

A 2017 psychiatric text describing thought disorder as a “disorganization syndrome” in the context of schizophrenia:

“Thought disorder” here refers to disorganization of the form of thought and not content. An older use of the term “thought disorder” included the phenomena of delusions and sometimes hallucinations, but this is confusing and ignores the clear differences in the relationships between symptoms that have become apparent over the past 30 years. Delusions and hallucinations should be identified as psychotic symptoms, and thought disorder should be taken to mean formal thought disorders or a disorder of verbal cognition. Phenomenology of Schizophrenia (2017), THE SYMPTOMS OF SCHIZOPHRENIA

The text said that some clinicians use the term “formal thought disorder” broadly, referring to abnormalities in thought form with psychotic cognitive signs or symptoms, and studies of cognition and subsyndromes in schizophrenia may refer to FTD as conceptual disorganization or disorganization factor.

Some disagree:

Unfortunately, “thought disorder” is often involved rather loosely to refer to both FTD and delusional content. For the sake of clarity, the unqualified use of the phrase “thought disorder” should be discarded from psychiatric communication. Even the designation “formal thought disorder” covers too wide a territory. It should always be made clear whether one is referring to derailment or loose associations, flight of ideas, or circumstantiality. The Mental Status Examination, The Medical Basis of Psychiatry (2016)

Course, Diagnosis, and Prognosis

It was believed that TD occurred only in schizophrenia, but later findings indicate that it may occur in other psychiatric conditions (including mania) and in people without mental illness. Not all people with schizophrenia have a TD; the condition is not specific to the disease.

When defining thought-disorder subtypes and classifying them as positive or negative symptoms, Nancy Andreasen found that different subtypes of TD occur at different frequencies in those with mania, depression, and schizophrenia. People with mania have pressured speech as the most prominent symptom, and have rates of derailment, tangentiality, and incoherence as prominent as in those with schizophrenia. They are likelier to have pressured speech, distractibility, and circumstantiality.

People with schizophrenia have more negative TD, including poverty of speech and poverty of content of speech, but also have relatively high rates of some positive TD. Derailment, loss of goal, poverty of content of speech, tangentiality and illogicality are particularly characteristic of schizophrenia. People with depression have relatively-fewer TDs; the most prominent are poverty of speech, poverty of content of speech, and circumstantiality. Andreasen noted the diagnostic usefulness of dividing the symptoms into subtypes; negative TDs without full affective symptoms suggest schizophrenia.

She also cited the prognostic value of negative-positive-symptom divisions. In manic patients, most TDs resolve six months after evaluation; this suggests that TDs in mania, although as severe as in schizophrenia, tend to improve. In people with schizophrenia, however, negative TDs remain after six months and sometimes worsen; positive TDs somewhat improve. A negative TD is a good predictor of some outcomes; patients with prominent negative TDs are worse in social functioning six months later. More prominent negative symptoms generally suggest a worse outcome; however, some people may do well, respond to medication, and have normal brain function. Positive symptoms vary similarly.

A prominent TD at illness onset suggests a worse prognosis, including:

  • Illness begins earlier
  • Increased risk of hospitalisation
  • Decreased functional outcomes
  • Increased disability rates
  • Increased inappropriate social behaviours

TD which is unresponsive to treatment predicts a worse illness course. In schizophrenia, TD severity tends to be more stable than hallucinations and delusions. Prominent TDs are more unlikely to diminish in middle age, compared with positive symptoms. Less-severe TD may occur during the prodromal and residual periods of schizophrenia. Treatment for thought disorder may include psychotherapy, such as cognitive behaviour therapy (CBT), and psychotropic medications.

The DSM-5 includes delusions, hallucinations, disorganised thought process (formal thought disorder), and disorganised or abnormal motor behaviour (including catatonia) as key symptoms of psychosis. Schizophrenia-spectrum disorders such as schizoaffective disorder and schizophreniform disorder typically consist of prominent hallucinations, delusions and FTD; the latter presents as severely disorganised, bizarre, and catatonic behaviour. Psychotic disorders due to medical conditions and substance use typically consist of delusions and hallucinations. The rarer delusional disorder and shared psychotic disorder typically present with persistent delusions. FTDs are commonly found in schizophrenia and mood disorders, with poverty of speech content more common in schizophrenia.

Psychoses such as schizophrenia and bipolar mania are distinguishable from malingering, when an individual fakes illness for other gains, by clinical presentations; malingerers feign thought content with no irregularities in form such as derailment or looseness of association. Negative symptoms, including alogia, may be absent, and chronic thought disorder is typically distressing.

Autism spectrum disorders (ASD) whose diagnosis requires the onset of symptoms before three years of age can be distinguished from early-onset schizophrenia; schizophrenia under age 10 is extremely rare, and ASD patients do not display FTDs. However, it has been suggested that individuals with ASD display language disturbances like those found in schizophrenia; a 2008 study found that children and adolescents with ASD showed significantly more illogical thinking and loose associations than control subjects. The illogical thinking was related to cognitive functioning and executive control; the loose associations were related to communication symptoms and parent reports of stress and anxiety.

Rorschach tests have been useful for assessing TD in disturbed patients. A series of inkblots are shown, and patient responses are analysed to determine disturbances of thought. The nature of the assessment offers insight into the cognitive processes of another, and how they respond to equivocal stimuli. Hermann Rorschach developed this test to diagnose schizophrenia after realising that people with schizophrenia gave drastically different interpretations of Klecksographie inkblots from others whose thought processes were considered normal, and it has become one of the most widely-used assessment tools for diagnosing TDs.

The Thought Disorder Index (TDI), also known as the Delta Index, was developed to help further determine the severity of TD in verbal responses. TDI scores are primarily derived from verbally-expressed interpretations of the Rorschach test, but TDI can also be used with other verbal samples (including the Wechsler Adult Intelligence Scale). TDI has a twenty-three-category scoring index; each category scores the level of severity on a scale from 0–1, with .25 being mild and 1.00 being most severe (.25, .50, .75, 1.00).

Criticism

TD has been criticised as being based on circular or incoherent definitions. Symptoms of TD are inferred from disordered speech, based on the assumption that disordered speech arises from disordered thought. Although TD is typically associated with psychosis, similar phenomena can appear in different disorders and leading to misdiagnosis.

A criticism related to the separation of symptoms of schizophrenia into negative or positive symptoms, including TD, is that it oversimplifies the complexity of TD and its relationship to other positive symptoms. Factor analysis has found that negative symptoms tend to correlate with one another, but positive symptoms tend to separate into two groups. The three clusters became known as negative symptoms, psychotic symptoms, and disorganisation symptoms. Alogia, a TD traditionally classified as a negative symptom, can be separated into two types:

  • Poverty of speech content as (a disorganisation symptom); and
  • Poverty of speech, response latency, and thought blocking (negative symptoms).

Positive-negative-symptom diametrics, however, may enable a more accurate characterisation of schizophrenia.

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An Overview of Socioeconomic Status and Mental Health

Published on by Andrew Marshall1 Comment

Introduction

Numerous studies around the world have found a relationship between socioeconomic status and mental health.

There are higher rates of mental illness in groups with lower socioeconomic status (SES), but there is no clear consensus on the exact causative factors. The two principal models that attempt to explain this relationship are the social causation theory, which posits that socioeconomic inequality causes stress that gives rise to mental illness, and the downward drift approach, which assumes that people predisposed to mental illness are reduced in socioeconomic status as a result of the illness. Most literature on these concepts dates back to the mid-1990s and leans heavily towards the social causation model.

Social Causation

The social causation theory is an older theory with more evidence and research behind it. This hypothesis states that one’s socioeconomic status (SES) is the cause of weakening mental functions. As Perry writes in The Journal of Primary Prevention, “members of the lower social classes experience excess psychological stress and relatively few societal rewards, the results of which are manifested in psychological disorder”. The excess stress that people with low SES experience could be inadequate health care, job insecurity, and poverty, which can bring about many other psycho-social and physical stressors like crowding, discrimination, crime, etc. Thus, lower SES predisposes individuals to the development of a mental illness.

Research

The Faris and Dunham (1939), Hollingshead and Redlich (1958), and Midtown Manhattan (1962) studies are three of the most influential in the debate between social causation and downward drift. They lend important evidence to the linear correlation between mental illness and SES, more specifically that a low SES produces a mental illness. The higher rates of mental illness in lower SES are likely due to the greater stress individuals experience. Issues that are not experienced in high SES, such as lack of housing, hunger, unemployment, etc., contribute to the psychological stress levels that can lead to the onset of mental illness. Additionally, while experiencing greater stress levels, there are fewer societal rewards and resources for those at the bottom of the socioeconomic ladder. The moderate economics assets available to those just one level above the lowest socioeconomic group allows them to take preventative action or treatment for psychoses. However, the hypothesis of the social causation model is disputed by the downward drift model.

Faris and Dunham (1939)

Faris and Dunham analysed the prevalence of mental disorders, including schizophrenia, in different areas of Chicago. The researchers plotted the homes of patients preceding their admission to hospitals. They found a remarkable increase of cases from the outskirts of the city moving inwards to the centre. This reflected other rates of distributions, such as unemployment, poverty and family desertion. They also found that cases of schizophrenia were most pervasive in public housing neighbourhoods as well as communities with higher numbers of immigrants. This was one of the first empirical, evidence-based studies supporting social causation theory.

Hollingshead and Redlich (1958)

Hollingshead and Redlich conducted a study in New Haven, Connecticut, that was considered a major breakthrough in this field of research. The authors identified anyone who was hospitalised or in treatment for mental illness by looking at files from clinics, hospitals, and the like. They were able to design a valid and reliable construct to relate these findings to social class using education and occupation as measures for five social class groups. Their results showed high disproportions of schizophrenia among the lowest social group. They also found that the lower people were on the scale of social class, the likelier they were to be admitted to a hospital for psychosis.

Midtown Manhattan Study (1962)

The study by Srole, Langer, Micheal, Opler, and Rennie, known as the Midtown Manhattan Study, has become a quintessential study in mental health. The main focus of the research was to “uncover [the] unknown portion of mental illness which is submerged in the community and thus hidden from sociological and psychiatric investigators alike”. The researchers managed to probe deep into the community to include subjects usually left out of such studies. The experimenters used both parental and personal SES to investigate the correlation between mental illness and social class. When basing their results on parental SES, approximately 33% of Midtown inhabitants in the lowest SES showed some signs of impairments in mental functioning while only 18% of the inhabitants in the highest SES showed these signs. When assessing the relationship based on personal SES, 47% of inhabitants in the lowest SES showed signs of weakening mental functions while only 13% of the highest SES demonstrated these symptoms. These findings remained the same for all ages and genders.

Downward Drift

In contrast to social causation, downward drift (also known as social selection) postulates that there is likely a genetic component that causes the onset of mental illness which may then lead to “a drift down into or fail to rise out of lower SES groups”. This means that a person’s SES level is a consequence rather than a cause of weakening mental functions. The downward drift theory shows promise specifically for individuals with a diagnosis of schizophrenia.

Research

Weich and Lewis (1998)

The Weich and Lewis study was conducted in the United Kingdom where researchers looked at 7,725 adults who had developed mental illnesses. They found that while low SES and unemployment may increase the length of psychiatric episodes they did not increase the likelihood of the initial psychotic break.

Isohanni et al. (2001)

In the Isohanni et al. longitudinal study in Finland, the researchers looked at patients treated in hospitals for mental disorders and who were aged between 16 and 29. The study followed the patients for 31 years and looked at how their illness affected their educational achievement. The study had a total of 80 patients and it compared patients who had been treated in the hospital for diagnoses of schizophrenia, and other psychotic or non-psychotic diagnoses, to those of the same 1966 birth cohort who had received no psychiatric treatment. They found that individuals who were hospitalised at 22 years or younger (early onset) were more likely to only complete a basic level of education and remain stagnant.

Some patients were able to complete secondary education, but none advanced to tertiary education. Those who had not been hospitalised had lower completion rates of basic education but much higher percentages of completing both secondary and tertiary education, 62% and 26%, respectively. This study suggests that mental disorders, especially schizophrenia, impede educational achievement. The inability to complete higher education may be one of the possible contributors to the downward drift in SES by individuals with mental illness.

Wiersma, Giel, De Jong and Slooff (1983)

The researchers in the Wiersma, Giel, De Jong and Slooff study looked at both educational and occupational attainment of patients with psychosis compared to their fathers. Researchers assessed both topic areas in the fathers as well as in the patients. In a two-year follow-up, the downward mobility in both education and occupation was greater than expected in the patients. Only a small percentage of patients were able to keep their job or find a new one after the onset of psychosis. Most of the individuals participating in the study had a lower SES than when they were born. This study also showed that the drift may begin with prodromal symptoms rather than at full onset.

Debate

Many researchers argue against the downward drift model, because unlike its counterpart, “it does not address the psychological stress of being impoverished and fails to validate that persistent economic stress can lead to psychological disturbance”. Mirowsky and Ross discuss in their book, Social Causes of Psychological Distress, that stress frequently stems from lack of control, or the feeling of lack of control, over one’s life. Those in lower SES have a minimal sense of control over the events that occur in their lives.

They argue that lack of control does not only stem from jobs with low income, but that “minority status also lowers the sense of control, partly because of lower education, income, and unemployment, and partly because any given level of achievement requires greater effort and provides fewer opportunities”. The arguments posed in their book support social causation since such high stress levels are involved. Although both models can be existing, they do not need to be mutually exclusive, researchers tend to agree that downward drift has more relevance to someone diagnosed with schizophrenia.

Implications for schizophrenia

Although social causation can explain some forms of mental illnesses, downward drift “has the greatest empirical support and is one of the cardinal features of schizophrenia”. The downward drift theory is more applicable to schizophrenia for a number of reasons. There are varying degrees of the disease, but once a psychotic break is experienced, the person often cannot function at the same level as before. This impairment affects all areas of life—education, occupation, social and family connections, etc. Due to the many challenges, patients will likely drift to a lower SES because they are unable to keep up with previous standards.

Another reason why the downward drift theory is preferred is that, unlike other mental illnesses such as depression, once someone is diagnosed with schizophrenia they have the diagnosis for life. While symptoms may not be constant, “individuals with this diagnosis often experience cycles of remission and relapse throughout their lives”.

This explains the large discrepancy between the incidence of schizophrenia and prevalence of the disease. There is a very low rate of new cases of schizophrenia in comparison to the number of total cases because “it often starts in early adult life and becomes chronic”. Patients will usually function at a lower level once the illness has manifested itself. Even with the help of antipsychotic medication and psycho-social support, most patients will still experience some symptoms making moving up out of a lower SES nearly impossible.

Another possible explanation discussed in literature regarding the relation between the downward drift theory and schizophrenia is the stigma associated with mental illness. Individuals with mental illness are often treated differently, usually negatively, by their community. Although great strides have been made, mental illness is often unfavourably stigmatised. As Livingston explains, “stigma can produce a negative spiraling effect on the life course of people with mental illnesses, which tends to create…a decline in social class”.

Individuals who develop schizophrenia cannot function at the level they are used to, and “are particularly likely to experience the effects of ostracism, being amongst the most stigmatized of all the mental illnesses.” The complete exclusion they experience helps to maintain their new lower status, preventing any upward mobility. The downward drift theory may be mainly applicable to schizophrenia; however, it may also apply to other mental illnesses since each is accompanied by a negative stigma.

While it can be hard to maintain status once the schizophrenia appears, some individuals are able to resist a downward drift, particularly if they start out at a higher SES. For example, if a person is from a high SES, they have the ability to access preventative resources and possible treatment for the disease which can help buffer the drift downwards and help maintain their status. It is also important for those with schizophrenia to have a strong network of friends and family because friends and family may notice signs of the illness before full onset. For example, individuals that are married show less of a drift downwards than those who are not. Individuals who do not have a support system may show early signs of psychotic symptoms that go unnoticed and untreated.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Socioeconomic_status_and_mental_health >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

An Overview of the National Psychosis Unit

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Introduction

The National Psychosis Unit is a national treatment centre for patients with schizophrenia and other psychotic disorders, in the United Kingdom. The unit is a tertiary referral centre in the National Health Service. It is located at the Bethlem Royal Hospital, part of the South London and Maudsley NHS Foundation Trust. It is closely affiliated to the Institute of Psychiatry, King’s College London, and forms part of the Psychosis Clinical Academic Group of King’s Health Partners.

Brief History

The Unit was set up in the early 1990s. It was one of the first units in the UK to offer the antipsychotic drug clozapine, following its reintroduction in the UK in 1990.

Staff

The service has a multidisciplinary team of doctors, nurses, pharmacists and psychologists, many of whom work part of their time as clinical scientists and researchers, investigating the causes of psychotic disorders, and the effectiveness of both existing and new treatments.

Sir Robin Murray, Professor of Psychiatric Research at the Institute of Psychiatry at King’s College London, is a prominent member of staff at National Psychosis Unit.

Treatment

The National Psychosis Unit specialises in evidence-based treatment for people with schizophrenia, bipolar disorder and other similar disorders, particularly where local treatment has been unsuccessful or only partially successful in relieving symptoms. Anyone receiving NHS treatment can access the service free of charge following a referral by the person’s psychiatrist or general practitioner

The service provides second opinions on medication, diagnosis or any other aspect of care. The service has an outpatient clinic and 24-bedded inpatient facility. As well as pharmaceutical treatments, there is a strong focus on psychological treatments, rehabilitation and recovery, and reducing the risk of readmission through exploring what has led to breakdowns in the past and how to avoid this happening in future. The Unit also hosts research into the treatment of psychosis, including clinical trials of new treatments for psychosis. The National Psychosis Carers’ Group, which meets monthly, supports the carers and families of people with psychosis and allows them a forum for discussion.

Links with Other Organisations

The National Psychosis Unit has strong links with the Department of Psychosis Studies at the Institute of Psychiatry, King’s College London. The Unit also has longstanding links with mental health charities, including Rethink and SANE.

Awards

The Unit won the Hospital Doctor Psychiatric Team of the Year Award in 1997.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/National_Psychosis_Unit >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is the Social Support Questionnaire?

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Introduction

The Social Support Questionnaire (SSQ) is a quantitative, psychometrically sound survey questionnaire intended to measure social support and satisfaction with said social support from the perspective of the interviewee.

Degree of social support has been shown to influence the onset and course of certain psychiatric disorders such as clinical depression or schizophrenia. The SSQ was approved for public release in 1981 by Irwin Sarason, Henry Levine, Robert Basham and Barbara Sarason under the University of Washington Department of Psychology and consists of 27 questions. Overall, the SSQ has good test-retest reliability and convergent internal construct validity.

Refer to Peer Support.

Overview

The questionnaire is designed so that each question has a two-part answer. The first part asks the interviewee to list up to nine people available to provide support that meet the criteria stated in the question. These support individuals are specified using their initials in addition to the relationship to the interviewee. Example questions from the first part includes questions such as “Whom could you count on to help if you had just been fired from your job or expelled from school?” and “Whom do you feel would help if a family member very close to you died?”.

The second part asks the interviewee to specify how satisfied they are with each of the people stated in the first part. The SSQ respondents use a 6 -point Likert scale to indicate their degree of satisfaction with the support from the above people ranging from “1 – very dissatisfied” to “6 – very satisfied”.

The Social Support Questionnaire has multiple short forms such as the SSQ3 and the SSQ6.

Brief History

The SSQ is based on 4 original studies. The first study set out to determine whether the SSQ had the desired psychometric properties. The second study tried to relate SSQ and a diversity of personality measures such as anxiety, depression and hostility in connection with the Multiple Affect Adjective Checklist. The third study considered the relationship between social support, the prior year’s negative and positive life events, internal-external locus of control and self- esteem in conjunction with the Life Experiences Survey. The fourth study tested the idea that social support could serve as a buffer when faced with difficult life situations via trying to solve a maze and subsequently completing the Cognitive Interference Questionnaire.

Scoring

The overall support score (SSQN) is calculated by taking an average of the individual scores across the 27 items. A high score on the SSQ indicates more optimism about life than a low score. Respondents with low SSQ scores have a higher prevalence of negative life events and illness. Scoring is as follows:

  1. Add the total number of people for all 27 items (questions). (Max. is 243). Divide by 27 for average item score. This gives you SSQ Number Score, or SSQN.
  2. Add the total satisfaction scores for all 27 items (questions). (Max is 162). Divide by 27 for average item score. This gives you SSQ Satisfaction score or SSQS.
  3. Finally, you can average the above for the total number of people that are family members – this results in the SSQ family score.

Reliability

According to Sarason, the SSQ takes between fifteen and eighteen minutes to properly administer and has “good” test-retest reliability.

Validity

The SSQ was compared with the depression scale and validity tests show significant negative correlation ranging from -0.22 to -0.43. The SSQ and the optimism scale have a correlation of 0.57. The SSQ and the satisfaction score have a correlation of 0.34. The SSQ has high internal consistency among items.

Linkages

The SSQ has been used to show that higher levels of social support correlated with less suicide ideation in Military Medical University Soldiers in Iran in 2015. A low level of social support is an important risk factor in women for dysmenorrhea or menstrual cramps. Low Social Support is the strongest predictor of dysmenorrhea when compared to affect, personality and alexithymia.

Related Surveys

SSQ3

The SSQ3 is a short form of the SSQ and has only three questions. The SSQ3 has acceptable test-test reliability and correlation with personality variables as compared to the long form of the Social Support Questionnaire. The internal reliability was borderline but this low level of internal reliability is as expected since there are only three questions.

SSQ6

The SSQ6 is a short form of the SSQ. The SSQ6 has been shown to have high correlation with: the SSQ, SSQ personality variables and internal reliability. In the development of the SSQ6, the research suggests that professed social support in adults may be a connected to “early attachment experience.” The SSQ6 consists of the below 6 questions:

  1. Whom can you really count on to be dependable when you need help?
  2. Whom can you really count on to help you feel more relaxed when you are under pressure or tense?
  3. Who accepts you totally, including both your worst and your best points?
  4. Whom can you really count on to care about you, regardless of what is happening to you?
  5. Whom can you really count on to help you feel better when you are feeling generally down-in-the-dumps?
  6. Whom can you count on to console you when you are very upset?

Interpersonal Support Evaluation List (ISEL)

The Interpersonal Support Evaluation List includes 40 items (questions) with four sub-scales in the areas of Tangible Support, Belonging Support, Self-Esteem Support and Appraisal Support. The interviewee rates each item based on how true or false they feel the item is for themselves. The four total response options are “Definitely True”, “Probably True”, “Probably False”, and “Definitely False”.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Social_Support_Questionnaire >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

On This Day … 18 December [2022]

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People (Deaths)

  • 1990 – Joseph Zubin, Lithuanian-American psychologist and academic (b. 1900).

Joseph Zubin

Joseph Zubin (09 October 1900 to 18 December 1990) was a Lithuanian-born American educational psychologist and an authority on schizophrenia who is commemorated by the Joseph Zubin Awards.

Zubin was born 09 October 1900 in Raseiniai, Lithuania, but moved to the US in 1908 and grew up in Baltimore. His first degree was in chemistry at Johns Hopkins University in 1921, and he earned a PhD in educational psychology at Columbia University in 1932. In 1934 he married Winifred Anderson (who survived him) and they had three children (2 sons, David and Jonathan, and a daughter, Winfred). At his death on 18 December 1990, he had seven grandchildren.

What is Clozapine?

Published on by Andrew Marshall1 Comment

Introduction

Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson’s disease. Clozapine is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, after resistance to earlier neuroleptic treatment is established.

The role of clozapine in treatment-resistant schizophrenia was established by a 1988 landmark study in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis who had already shown an inadequate response to other antipsychotics. While there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response. The use of clozapine is associated with multiple improved outcomes, including a reduced rate of all-cause mortality, suicide and hospitalisation. In a 2013 network comparative meta-analysis of 15 antipsychotic drugs, clozapine was found to be significantly more effective than all other drugs. In a 2021 UK study, the majority of patients (over 85% of respondents) who took clozapine preferred it to their previous therapies, felt better on it and wanted to keep taking it. In a 2000 Canadian survey of 130 patients, the majority reported better satisfaction, quality of life, compliance with treatment, thinking, mood, and alertness.

Compared to other antipsychotics, clozapine has an increased risk of blood dyscrasias, in particular agranulocytosis, in the first 18 weeks of treatment. After one year, this risk reduces to that associated with most antipsychotics. Clozapine’s use is therefore reserved for people who have not responded to two other antipsychotics and is only done with stringent blood monitoring. Overall, despite the concerns relating to blood and other side effects, clozapine use is associated with a reduced mortality, especially from suicide which is a major cause of premature death in people with schizophrenia. The risk of clozapine related agranulocytosis and neutropenia warranted the mandatory use of stringent risk monitoring and management systems, which have reduced the risk of death from these adverse events to around 1 in 7,700. The association between clozapine use and specific bloods dyscrasias was first noted in the 1970s when eight deaths from agranulocytosis were noted in Finland. At the time it was not clear if this exceeded the established rate of this side effect which is also found in other antipsychotics and although the drug was not completely withdrawn, its use became limited. Clozapine became widely available in the early 1990s and remains the only treatment likely to be effective in treating resistant schizophrenia.

Common adverse effects include drowsiness, constipation, hypersalivation (increased saliva production), tachycardia, low blood pressure, blurred vision, weight gain, and dizziness. Clozapine is not normally associated with tardive dyskinesia (TD) and is recommended as the drug of choice when this is present, although some case reports describe clozapine-induced TD. Other serious risks include seizures, inflammation of the heart, high blood sugar levels, constipation. The use of this drug can rarely result in clozapine-induced gastric hypomotility syndrome which may lead to bowel obstruction and death, and in older people with psychosis, as a result of dementia it may lead to an increased risk of death. The mechanism of action is not entirely clear in the current medical literature. Clozapine is on the World Health Organization’s List of Essential Medicines. It is available as a generic medication.

Brief History

Clozapine was synthesized in 1958 by Wander AG, a Swiss pharmaceutical company, based on the chemical structure of the tricyclic antidepressant imipramine. The first test in humans in 1962 was considered a failure. Trials in Germany in 1965 and 1966 as well as a trial in Vienna in 1966 were successful. In 1967 Wander AG was acquired by Sandoz. Further trials took place in 1972 when clozapine was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany and in Finland in 1975. Early testing was performed in the United States around the same time. In 1975, 16 cases of agranulocytosis leading to 8 deaths in clozapine-treated patients, reported from 6 hospitals mostly in southwestern Finland, led to concern. Analysis of the Finnish cases revealed that all the agranulocytosis cases had occurred within the first 18 weeks of treatment and the authors proposed blood monitoring during this period. The rate of agranulocytosis in Finland appeared to be 20 times higher than in the rest of the world and there was speculation that this may have been due a unique genetic diversity in the region. Whilst the drug continued to be manufactured by Sandoz, and remained available in Europe, development in the US halted.

Interest in clozapine continued in an investigational capacity in the United States because, even in the 1980s, the duration of hospitalisation, especially in State Hospitals for those with treatment resistant schizophrenia might often be measured in years rather than days. The role of clozapine in treatment resistant schizophrenia was established by the landmark Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. This involved both stringent blood monitoring and a double-blind design with the power to demonstrate superiority over standard antipsychotic treatment. The inclusion criteria were patients who had failed to respond to at least three previous antipsychotics and had then not responded to a single blind treatment with haloperidol (mean dose 61 mg +/- 14 mg/d). Two hundred and sixty-eight were randomised were to double blind trials of clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d). 30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses’ Observation Scale for Inpatient Evaluation; this improvement included “negative” as well as positive symptom areas. Following this study, the US Food and Drug Administration (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.

In December 2002, clozapine was approved in the US for reducing the risk of suicide in people with schizophrenia or schizoaffective judged to be at chronic risk for suicidal behaviour. In 2005, the FDA approved criteria to allow reduced blood monitoring frequency. In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared Patient Registry Called The Clozapine REMS Registry. Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardised.

Chemistry

Clozapine is a dibenzodiazepine that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C).[3] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).

Clinical Uses

Schizophrenia

Clozapine is usually used for people diagnosed with schizophrenia who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson’s Disease. It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, supported by systematic reviews and meta-analysis. Whilst all current guidelines reserve clozapine to individuals when two other antipsychotics evidence indicates that clozapine might be used as a second line drug. Clozapine treatment has been demonstrated to produced improved outcomes in multiple domains including; a reduced risk of hospitalisation, a reduced risk of drug discontinuation, a reduction in overall symptoms and has improved efficacy in the treatment of positive psychotic symptoms of schizophrenia. Despite a range of side effects patients report good levels of satisfaction and long term adherence is favourable compared to other antipsychotics. Very long term follow-up studies reveal multiple benefits in terms of reduced mortality, with a particularly strong effect for reduced death by suicide, clozapine is the only antipsychotic known to have an effect reducing the risk of suicide or attempted suicide. Clozapine has a significant anti-aggressive effect. Clozapine is widely used in secure and forensic mental health settings where improvements in aggression, shortened admission and reductions in restrictive practice such as seclusion have been found. In secure hospitals and other settings clozapine has also been used in the treatment of borderline and antisocial personality disorder when this has been associated with violence or self-harm. Although oral treatment is almost universal clozapine has on occasion been enforced using either nasogastric or a short acting injection although in almost 50% of the approximately 100 reported cases patients agreed to take oral medication prior to the use of a coercive intervention. Clozapine has also been used off-label to treat catatonia with success in over 80% of cases.

Bipolar Disorder

On the basis of systematic reviews clozapine is recommended in some treatment guidelines as a third or fourth line treatment for bipolar disorder. Bipolar disorder is an unlicensed indication for clozapine.

Severe Personality Disorders

Clozapine is also used in emotionally unstable personality disorder and a randomised controlled trial is currently underway. The use of clozapine to treat personality disorder is uncommon and unlicensed.

Initiation

Whilst clozapine is usually initiated in hospital setting community initiation is also available. Before clozapine can be initiated multiple assessments and baseline investigations are performed. In the UK and Ireland there must be an assessment that the patient satisfies the criteria for prescription; treatment resistant schizophrenia, intolerance due to extrapyramidal symptoms of other antipsychotics or psychosis in Parkinson’s disease. Establishing a history of treatment resistance may include careful review of the medication history including the durations, doses and compliance of previous antipsychotic therapy and that these did not have an adequate clinical effect. A diagnostic review may also be performed. That could include review of antipsychotic plasma concentrations if available. The prescriber, patient, pharmacy and the laboratory performing blood counts are all registered with a specified clozapine provider who must be advised that there is no history of neutropenia from any cause. The clozapine providers collaborate by sharing information regarding patients who have had clozapine related neutropenia or agranulocytosis so that clozapine cannot be used again on license. Clozapine may only be dispensed after a satisfactory blood result has been received by the risk monitoring agency at which point an individual prescription may be released to an individual patient only.

Baseline tests usually also include; a physical examination including baseline weight, waist circumference and BMI, assessments of renal function and liver function, an ECG and other baseline bloods may also be taken to facilitate monitoring of possible myocarditis, these might include C reactive protein (CRP) and troponin. In Australia and New Zealand pre-clozapine echocardiograms are also commonly performed. A number of service protocols are available and there are variations in the extent of preclozapine work ups. Some might also include fasting lipids, HbA1c and prolactin. At the Maudsley Hospital in the UK the Treat service also routinely performs a wide variety of other investigations including multiple investigations for other causes of psychosis and comorbidities including; MRI brain imaging, thyroid function tests, B12, folate and serum calcium levels, infection screening for blood borne viruses including Hepatitis B and C, HIV and syphilis as well as screening for autoimmune psychosis by anti-NMDA, anti-VGKC and Anti-nuclear Antibody screening. Investigations used to monitor the possibility of clozapine related side effects such as myocarditis are also performed including baseline troponin, CRP and BNP and for neuroleptic malignant syndrome CK.

The dose of clozapine is initially low and gradually increased over a number of weeks. Initial doses may range from 6.5 to 12.5 mg/d increasing stepwise typically to doses in the range of 250-350 mg per day at which point an assessment of response will be performed. In the UK the average clozapine dose is 450 mg/d. But response is highly variable and some patients respond at much lower doses and vice versa.

Monitoring

During the initial dose titration phase the following are typically monitored; usually daily at first; pulse, blood pressure and since orthostatic hypotension can be problematic this should be monitored both sitting and standing. If there is a significant drop then the rate of the dose increase may be slowed, temperature.

Weekly tests include; Mandatory full blood counts are performed weekly for the first 18 weeks. In some services there will also be monitoring of markers that might indicate myocarditis; troponin, CRP and BNP although the exact tests and frequency vary between services. Weight is usually measured weekly.

Thereon other investigations and monitoring will always include full blood counts (fortnightly for 1 year then monthly). Weight, waist circumference, lipids and glucose or HbA1c may also be monitored.

Clozapine Response and Treatment Optimisation

As with other antipsychotics, and in contrast to received wisdom, responses to clozapine are typically seen soon after initiation and often within the first week. That said responses, especially those which are partial, can be delayed. Quite what an adequate trial of clozapine is, is uncertain but a recommendation is that this should be for at least 8 weeks on a plasma trough level above 350-400 micro g/L. There is considerable inter-individual variation. A significant number of patients respond at lower and also much higher plasma concentrations and some patients, especially young male smokers may never achieve these plasma levels even at doses of 900 mg/day. Options then include either increasing the dose above the licensed maximum or the addition of a drug that inhibits clozapine metabolism. Avoiding unnecessary polypharmacy is a general principle in drug treatment.

Optimising Blood Sampling

The neutrophil cut off for clozapine have shown an exceptional ability to mitigate the risk of neutropenia and agranulocytosis. There is a significant margin of safety. Some patients may have marginal neutrophil counts before and after initiation and they are at risk of premature clozapine discontinuation. A knowledge of neutrophil biology allows blood sampling optimisation. Neutrophils show a diurnal variation in response to the natural cycle of G-CSF production, they are increased in the afternoons, they are also mobilised into the circulation after exercise and smoking. Simply shifting blood sampling has been shown to avoid unnecessary discontinuations, especially in black populations. However this is a disruption to usual hospital practice. Other practical steps are to ensure that blood results become available in hours and when senior staff are available.

Underuse of Clozapine

Clozapine is widely recognised as being underused with wide variation in prescribing, especially in patients with African heritage.

Psychiatrists prescribing practices have been found to be the most significant variable regarding variance in its use. Surveys of psychiatrists attitudes to clozapine have found that many had little experience in its use, over estimated the incidence and were fearful of side effects, and did not appreciate that many patients prefer to take clozapine than other antipsychotics, are reluctant to prescribe clozapine, had little experience in its use and believed that patients treated with clozapine were less satisfied than those treated with other antipsychotics. In contrast to many psychiatrists expectations most patients believe that the blood testing and other difficulties are worth the multiple benefits that they perceive. Whilst psychiatrists fear the severe adverse effects such as agranulocytosis, patients are more concerned about hypersalivation. Clozapine is no longer actively marketed and this may also be one of the explanations for its underuse.

Despite the strong evidence and universal endorsement by national and international treatment guidelines and the experiences of patients themselves, most people eligible for clozapine are not treated with it. A large study in England found that approximately 30% of those eligible for clozapine were being treated with it. Those patients that do start clozapine usually face prolonged delay, multiple episodes of psychosis and treatments such as high dose antipsychotics or polypharmacy. Instead of two previous antipsychotics many will have been exposed to ten or more drugs which were not effective. In a study of 120 patients conducted in four hospitals in South-East London, found a mean of 9.2 episodes of antipsychotic prescription before clozapine was initiated and the mean delay in using clozapine was 5 years. Treatments that have no evidence base or are regarded as actively harmful are used instead multiple and or high-dose treatment.

Racial Disparity in the Use of Clozapine

A general finding in healthcare provision is that minority groups receive inferior treatment; this is a particular finding in the US. In the US a general finding is that compared to their white peers African American people are less likely to be prescribed the second generation antipsychotics, which are more expensive than alternatives and this was even apparent and especially so for clozapine when comparison was made in the Veterans Affairs medical system and when differences regarding socioeconomic factors were taken into account. As well as being less likely to start clozapine black patients are more likely to stop clozapine, possibly on account of benign ethnic neutropenia.

Benign Ethnic Neutropenia

Benign reductions in neutrophils are observed in individuals of all ethnic backgrounds ethnic neutropenia (BEN), neutropenia without immune dysfunction or increased liability to infection is not due to abnormal neutrophil production; although, the exact aetiology of the reduction in circulating cells remains unknown. BEN is associated with several ethnic groups, but in particular those with Black African and West African ancestry. A difficulty with the use of clozapine is that neutrophil counts have been standardised on white populations. For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use as the thresholds did not take BEN into account. Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 109/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima. But even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. The Duffy-Null polymorphism, which protects against some types of malaria, is predictive of BEN.

Adverse Effects

Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five black box warnings, including:

  1. Severe neutropenia (low levels of neutrophils);
  2. Orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting;
  3. Seizures;
  4. Myocarditis (inflammation of the heart); and
  5. Risk of death when used in elderly people with dementia-related psychosis.

Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.

Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia, is below that of typical antipsychotics; this may be due to clozapine’s anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine. Sexual problems, like retrograde ejaculation, have been reported while taking clozapine. Despite the risk for numerous side effects, many side effects can be managed while continuing to take clozapine.

Neutropenia and Agranulocytosis

Clozapine Induced Neutropenia (CIN) occurs in approximately 3.8% of cases and Clozapine Induced Agranulocytosis (CIA) in 0.4%. These are potentially serious side effects and agranulocytosis can result in death. To mitigate this risk clozapine is only used with mandatory absolute neutrophil count (ANC) monitoring (neutrophils are the most abundant of the granulocytes); for example, in the United States, the Risk Evaluation and Mitigation Strategy (REMS). The exact schedules and blood count thresholds vary internationally and the thresholds at which clozapine can be used in the US has been lower than those currently used in the UK and Australasia for some time. The effectiveness of the risk management strategies used is such that deaths from these side effects are very rare occurring at approximately 1 in 7,700 patients treated. Almost all the adverse blood reactions occur within the first year of treatment and the majority within the first 18 weeks. After one year of treatment these risks reduce markedly to that seen in other antipsychotic drugs 0.01% or about 1 in 10,000 and the risk of death is markedly lower still. When reductions in neutrophil levels are noted on regular blood monitoring then, depending on the value, monitoring may be increased or, if the neutrophil count is sufficiently low, then clozapine is stopped immediately and can then no longer be used within the medicinal licence. Stopping clozapine almost always results in resolution of the neutrophil reduction. However severe agranulocytosis can result in spontaneous infection and death, is a severe decrease in the amount of a specific kind of white blood cell called granulocytes. Clozapine carries a black box warning for drug-induced agranulocytosis. Rapid point-of-care tests may simplify the monitoring for agranulocytosis.

Clozapine Rechallenge

A clozapine “rechallenge” is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce clozapine but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had clozapine stopped according to the US criteria only 7 would have had clozapine stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use clozapine without difficulty and only 1 had a fall in neutrophils below the US cut off. Other approaches have included the use of other drugs to support neutrophil counts including lithium or granulocyte colony-stimulating factor (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited.

Cardiac Toxicity

Clozapine can rarely cause myocarditis and cardiomyopathy. A large meta-analysis of clozapine exposure to over 250,000 people revealed that these occurred in approximately 7 in 1,000 patients treated and resulted in death in 3 and 4 in 10,000 patients exposed respectively and although myocarditis occurred almost exclusively within the first 8 weeks of treatment, cardiomyopathy can occur much later on. First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness. Signs of heart failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate. A large electronic health register study has revealed that nearly 90% of cases of suspected clozapine related myocarditis are false positives. Rechallenge after clozapine induced myocarditis has been performed and a protocol for this specialist approach has been published. A systematic review of rechallenge after myocarditis has show success in over 60% of reported cases.

Gastrointestinal Hypomotility

Another under-recognised and potentially life-threatening effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, faecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers. Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis. A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication. Monitoring bowel function and the pre-emptive use of laxatives for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae.

Hypersalivation

Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%). The saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day. While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for hypersalivation. Clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication. Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as hyoscine, diphenhydramine and topical anticholinergic medications like ipratropium bromide. Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.

Central Nervous System

CNS side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paraesthesia, status epilepticus, and obsessive compulsive symptoms. Similar to other antipsychotics clozapine rarely has been known to cause neuroleptic malignant syndrome.

Urinary Incontinence

Clozapine is linked to urinary incontinence, though its appearance may be under-recognised.

Withdrawal Effects

Abrupt withdrawal may lead to cholinergic rebound effects, such as indigestion, diarrhoea, nausea/vomiting, overabundance of saliva, profuse sweating, insomnia, and agitation. Abrupt withdrawal can also cause severe movement disorders, catatonia, and psychosis. Doctors have recommended that patients, families, and caregivers be made aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.

Weight Gain and Diabetes

In addition to hyperglycaemia, significant weight gain is frequently experienced by patients treated with clozapine. Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.

Pneumonia

International adverse drug effect databases indicate that clozapine use is associated with a significantly increased incidence of and death from pneumonia and this may be one of the most significant adverse events. The mechanisms for this are unknown although it has been speculated that it may be related to hypersalivation, immune effects of clozapine’s effects on the resolution of inflammation.

Overdose

Symptoms of overdose can be variable, but often include; sedation, confusion, tachycardia, seizures and ataxia. Fatalities have been reported due to clozapine overdose, though overdoses of greater than 5000 mg have been survived.

Drug Interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.

When carbamazepine is concurrently used with clozapine, it has been shown to decrease plasma levels of clozapine significantly thereby decreasing the beneficial effects of clozapine. Patients should be monitored for “decreased therapeutic effects of clozapine if carbamazepine” is started or increased. If carbamazepine is discontinued or the dose of carbamazepine is decreased, therapeutic effects of clozapine should be monitored. The study recommends carbamazepine to not be used concurrently with clozapine due to increased risk of agranulocytosis.

Ciprofloxacin is an inhibitor of CYP1A2 and clozapine is a major CYP1A2 substrate. Randomized study reported elevation in clozapine concentration in subjects concurrently taking ciprofloxacin. Thus, the prescribing information for clozapine recommends “reducing the dose of clozapine by one-third of original dose” when ciprofloxacin and other CYP1A2 inhibitors are added to therapy, but once ciprofloxacin is removed from therapy, it is recommended to return clozapine to original dose.

Pharmacology

Pharmacodynamics

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.

Clozapine is an antagonist at the 5-HT2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.

A direct interaction of clozapine with the GABAB receptor has also been shown. GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.

Pharmacokinetics

The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. However, it was shown that co-administration of food decreases the rate of absorption. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).

Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and faeces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g. cigarette smoke) or inhibit (e.g. theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.

Clozapine and norclozapine (desmethyl-clozapine) plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age. Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimisation.

Society and Culture

Economics

Despite the expense of the risk monitoring and management systems required, clozapine use is highly cost effective; with a number of studies suggesting savings of tens of thousands of dollars per patient per year compared to other antipsychotics as well as advantages regarding improvements in quality of life. Clozapine is available as a generic medication.

Clozapine in the Arts

Carrie Mathison, a fictional CIA operative in the television series Homeland, secretly takes clozapine supplied by her sister for the treatment of bipolar disorder.

In the film Out of Darkness, Diana Ross played the protagonist Paulie Cooper, “a paranoid schizophrenic” who is depicted as having a dramatic improvement on clozapine.

In the television series Last Man On Earth (2015) the character Melissa has a psychotic episode and returns home and starts acting how she did pre-pandemic. Her boyfriend Todd sees her take a medication in the morning and asks her what it is. All she will say is “Santas Penis”. Todd searches medication books and finds clozapine = Clause a peen.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Clozapine >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Aripiprazole?

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Introduction

Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressive disorder (MDD), tic disorders and irritability associated with autism. It is taken by mouth or injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.

Common side effects include vomiting, constipation, sleepiness, dizziness, weight gain and movement disorders. Serious side effects may include neuroleptic malignant syndrome, tardive dyskinesia and anaphylaxis. It is not recommended for older people with dementia-related psychosis due to an increased risk of death. In pregnancy, there is evidence of possible harm to the baby. It is not recommended in women who are breastfeeding. It has not been very well studied in people less than 18 years old. The exact mode of action is not entirely clear but may involve effects on dopamine and serotonin.

Aripiprazole was approved for medical use in the United States in 2002. It is available as a generic medication. In 2019, it was the 101st most commonly prescribed medication in the United States, with more than 6 million prescriptions. Aripiprazole was discovered in 1988 by scientists at the Japanese firm Otsuka Pharmaceutical.

Brief History

Aripiprazole was discovered by scientists at Otsuka Pharmaceutical and was called OPC-14597. It was first published in 1995. Otsuka initially developed the drug, and partnered with Bristol-Myers Squibb (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.

It was approved by the US Food and Drug Administration (FDA) for schizophrenia in November 2002, and the European Medicines Agency in June 2004; for acute manic and mixed episodes associated with bipolar disorder on 01 October 2004; as an adjunct for major depressive disorder on 20 November 2007; and to treat irritability in children with autism on 20 November 2009. Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.

Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years.

In 2006, the FDA required manufacturers to add a black box warning to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.

In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication. That same year, BMS settled a case with the US government in which it paid $515 million; the case covered several drugs but the focus was on BMS’s off-label marketing of aripiprazole for children and older people with dementia.

In 2011 Otsuka and Lundbeck signed a collaboration to develop a depot formulation of apripiprazole.

As of 2013, Abilify had annual sales of US$7 billion. In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug. Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole.

Otsuka’s US patent on aripiprazole expired on 20 October 2014, but due to a paediatric extension, a generic did not become available until 20 April 2015. Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007. On 15 November 2010, this challenge was rejected by the US District Court in New Jersey.

Otsuka’s European patent EP0367141 which would have expired on 26 October 2009, was extended by a Supplementary Protection Certificate (SPC) to 26 October 2014. The UK Intellectual Property Office decided on 04 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015.

From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.

In April 2015, the FDA announced the first generic versions. In October 2015, aripiprazole lauroxil, a prodrug of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA.

In 2016, BMS settled cases with 42 US states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.

In November 2017, the FDA approved Abilify MyCite, a digital pill containing a sensor intended to record when its consumer takes their medication.

Medical Uses

Aripiprazole is primarily used for the treatment of schizophrenia or bipolar disorder.

Schizophrenia

The 2016 NICE guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second line treatment after risperidone for people between 15 and 17 who are having an acute exacerbation or recurrence of psychosis or schizophrenia. A 2014 NICE review of the depot formulation of the drug found that it might have a role in treatment as an alternative to other depot formulations of second generation antipsychotics for people who have trouble taking medication as directed or who prefer it.

A 2014 Cochrane review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor. A 2011 Cochrane review comparing aripiprazole with placebo concluded that high dropout rates in clinical trials, and a lack of outcome data regarding general functioning, behaviour, mortality, economic outcomes, or cognitive functioning make it difficult to definitively conclude that aripiprazole is useful for the prevention of relapse. A Cochrane review found only low quality evidence of effectiveness in treating schizophrenia. Accordingly, part of its methodology on quality of evidence is based on quantity of qualified studies.

A 2013 review found that it is in the middle range of 15 antipsychotics for effectiveness, approximately as effective as haloperidol and quetiapine and slightly more effective than ziprasidone, chlorpromazine, and asenapine, with better tolerability compared to the other antipsychotic drugs (4th best for weight gain, 5th best for extrapyramidal symptoms, best for prolactin elevation, 2nd best for QTc prolongation, and 5th best for sedation). The authors concluded that for acute psychotic episodes aripiprazole results in benefits in some aspects of the condition.

In 2013 the World Federation of Societies for Biological Psychiatry recommended aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A.

The British Association for Psychopharmacology similarly recommends that all persons presenting with psychosis receive treatment with an antipsychotic, and that such treatment should continue for at least 1-2 years, as “There is no doubt that antipsychotic discontinuation is strongly associated with relapse during this period”. The guideline further notes that “Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the recommended range (Evidence level A)”.

The British Association for Psychopharmacology and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on each person’s preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics

Bipolar Disorder

Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents. Used as maintenance therapy, it is useful for the prevention of manic episodes, but is not useful for bipolar depression. Thus, it is often used in combination with an additional mood stabiliser; however, co-administration with a mood stabiliser increases the risk of extrapyramidal side effects.

Major Depression

Aripiprazole is an effective add-on treatment for major depressive disorder; however, there is a greater rate of side effects such as weight gain and movement disorders. The overall benefit is small to moderate and its use appears to neither improve quality of life nor functioning. Aripiprazole may interact with some antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). There are interactions with fluoxetine and paroxetine and lesser interactions with sertraline, escitalopram, citalopram, and fluvoxamine, which inhibit CYP2D6, for which aripiprazole is a substrate. CYP2D6 inhibitors increase aripiprazole concentrations to 2-3 times their normal level.

Autism

Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and stereotypy, but no change in lethargic behaviours. Adverse effects include weight gain, sleepiness, drooling and tremors. It is suggested that children and adolescents need to be monitored regularly while taking this medication, to evaluate if this treatment option is still effective after long-term use and note if side effects are worsening. Further studies are needed to understand if this drug is helpful for children after long term use.

Tic Disorders

Aripiprazole is approved for the treatment of Tourette’s syndrome. It is effective, safe, and well-tolerated for this use per systematic reviews and meta-analyses

Obsessive-Compulsive Disorder

A 2014 systematic review and meta-analysis concluded that add-on therapy with low dose aripiprazole is an effective treatment for obsessive-compulsive disorder (OCD) that does not improve with selective serotonin reuptake inhibitors (SSRIs) alone. The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms. Risperidone, another second-generation antipsychotic, appears to be superior to aripiprazole for this indication, and is recommended by the 2007 American Psychiatric Association guidelines. However, aripiprazole is cautiously recommended by a 2017 review on antipsychotics for OCD. Aripiprazole is not currently approved for the treatment of OCD and is instead used off-label for this indication.

Adverse Effects

In adults, side effects with greater than 10% incidence include weight gain, headache, akathisia, insomnia, and gastro-intestinal effects like nausea and constipation, and lightheadedness. Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose. A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur.

Uncontrolled movement such as restlessness, tremors, and muscle stiffness may occur.

Discontinuation

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.

Overdose

Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these people were elevated by up to 3-4 fold over normal therapeutic levels; as of 2008 no deaths had been recorded.

Interactions

Aripiprazole is a substrate of CYP2D6 and CYP3A4. Coadministration with medications that inhibit (e.g. paroxetine, fluoxetine) or induce (e.g. carbamazepine) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.

Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose.

Antipsychotics like aripiprazole and stimulant medications, such as amphetamine, are traditionally thought to have opposing effects to their effects on dopamine receptors: stimulants are thought to increase dopamine in the synaptic cleft, whereas antipsychotics are thought to decrease dopamine. However, it is an oversimplification to state the interaction as such, due to the differing actions of antipsychotics and stimulants in different parts of the brain, as well as the effects of antipsychotics on non-dopaminergic receptors. This interaction frequently occurs in the setting of comorbid attention-deficit hyperactivity disorder (ADHD) (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has been reported to provide some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.

Pharmacology

Pharmacodynamics

Aripiprazole’s mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). It shows differential engagement at the dopamine receptor (D2). It appears to show predominantly antagonist activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors, D3, and partially D4 and is a partial activator of serotonin (5-HT1A, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7). It also shows lower and likely insignificant effect on histamine (H1), epinephrine/norepinephrine (α), and otherwise dopamine (D4), as well as the serotonin transporter. Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.

As a pharmacologically unique antipsychotic with pronounced functional selectivity, characterization of this dopamine D2 partial agonist (with an intrinsic activity of ~25%) as being similar to a full agonist but at a reduced level of activity presents a misleading oversimplification of its actions; for example, among other effects, aripiprazole has been shown, in vitro, to bind to and/or induce receptor conformations (i.e. facilitate receptor shapes) in such a way as to not only prevent receptor internalisation (and, thus, lower receptor density) but even to lower the rate of receptor internalisation below that of neurons not in the presence of agonists (including dopamine) or antagonists. It is often the nature of partial agonists, including aripiprazole, to display a stabilising effect (such as on mood in this case) with agonistic activity when there are low levels of endogenous neurotransmitters (such as dopamine) and antagonistic activity in the presence of high levels of agonists associated with events such as mania, psychosis, and drug use. In addition to aripiprazole’s partial agonism and functional selectivity characteristics, its effectiveness may be mediated by its very high dopamine D2 receptor occupancy (approximately 32%, 53%, 72%, 80%, and 97% at daily dosages of 0.5 mg, 1 mg, 2 mg, 10 mg, and 40 mg respectively) as well as balanced selectivity for pre- and postsynaptic receptors (as suggested by its equal affinity for both D2S and D2L receptor forms). Aripiprazole has been characterised as possessing predominantly antagonistic activity on postsynaptic D2 receptors and partial agonist activity on presynaptic D2 receptors; however, while this explanation intuitively explains the drug’s efficacy as an antipsychotic, as degree of agonism is a function of more than a drug’s inherent properties as well as in vitro demonstration of aripiprazole’s partial agonism in cells expressing postsynaptic (D2L) receptors, it was noted that “It is unlikely that the differential actions of aripiprazole as an agonist, antagonist, or partial agonist were entirely due to differences in relative D2 receptor expression since aripiprazole was an antagonist in cells with the highest level of expression (4.6 pmol/mg) and a partial agonist in cells with an intermediate level of expression (0.5-1 pmol/mg). Instead, the current data are most parsimoniously explained by the ‘functional selectivity’ hypothesis of Lawler et al (1999)”. Aripiprazole is also a partial agonist of the D3 receptor. In healthy human volunteers, D2 and D3 receptor occupancy levels are high, with average levels ranging between approximately 71% at 2 mg/day to approximately 96% at 40 mg/day. Most atypical antipsychotics bind preferentially to extrastriatal receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.

Aripiprazole is also a partial agonist of the serotonin 5-HT1A receptor (intrinsic activity = 68%). Casting doubt on the significance of aripiprazole’s agonism of 5-HT1A receptors, a PET scan study of 12 patients receiving doses ranging from 10 to 30 mg found 5-HT1A receptor occupancy to be only 16% compared to ~90% for D2. It is a very weak partial agonist of the 5-HT2A receptor (intrinsic activity = 12.7%), and like other atypical antipsychotics, displays a functional antagonist profile at this receptor. The drug differs from other atypical antipsychotics in having higher affinity for the D2 receptor than for the 5-HT2A receptor. At the 5-HT2B receptor, aripiprazole has both great binding affinity and acts as a potent inverse agonist, “Aripiprazole decreased PI hydrolysis from a basal level of 61% down to a low of 30% at 1000 nM, with an EC50 of 11 nM”. Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the 5-HT2C receptor (intrinsic activity = 82%) and with relatively weak affinity; this property may underlie the minimal weight gain seen in the course of therapy. At the 5-HT7 receptor, aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor. Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites, such as the histamine H1, α-adrenergic, and dopamine D4 receptors as well as the serotonin transporter, while it has negligible affinity for the muscarinic acetylcholine receptors.

Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g. at 5-HT6 and D2L), sometimes an inverse agonist (e.g. 5-HT2B), sometimes a partial agonist (e.g. D2L), and sometimes a full agonist (D3, D4). Aripiprazole was frequently found to be a partial agonist, with an intrinsic activity that could be low (D2L, 5-HT2A, 5-HT7), intermediate (5-HT1A), or high (D4, 5-HT2C). This mixture of agonist actions at D2-dopamine receptors is consistent with the hypothesis that aripiprazole has ‘functionally selective’ actions. The ‘functional-selectivity’ hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially ‘sensed’ by the local complement of G proteins to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D2-dopamine receptors are clearly cell-type specific (e.g. agonism, antagonism, partial agonism), and are most parsimoniously explained by the ‘functional selectivity’ hypothesis.

Since 5-HT2C receptors have been implicated in the control of depression, OCD, and appetite, agonism at the 5-HT2C receptor might be associated with therapeutic potential in obsessive compulsive disorder, obesity, and depression. 5-HT2C agonism has been demonstrated to induce anorexia via enhancement of serotonergic neurotransmission via activation of 5-HT2C receptors; it is conceivable that the 5-HT2C agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an anti-obsessional agent, it is worthwhile noting that a variety of 5-HT2A/5-HT2C agonists have shown promise as anti-obsessional agents, yet many of these compounds are hallucinogenic, presumably due to 5-HT2A activation. Aripiprazole has a favourable pharmacological profile in being a 5-HT2A antagonist and a 5-HT2C partial agonist. Based on this profile, one can predict that aripiprazole may have anti-obsessional and anorectic actions in humans.

Wood and Reavill’s (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D2 receptor without significantly affecting the majority of serotonin receptors. A positron emission tomography imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D2 receptor in various brain areas (putamen, caudate, ventral striatum) versus 54 to 60% occupancy of the 5-HT2A receptor and only 16% occupancy of the 5-HT1A receptor. It has been suggested that the low occupancy of the 5-HT1A receptor by aripiprazole may have been an erroneous measurement however.

Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic mesolimbic pathway, which is thought to be a cause of positive schizophrenia symptoms. Due to its agonist activity on D2 receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the mesocortical pathways where it is reduce.

Pharmacokinetics

Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved 3-5 hours after oral dosing. Bioavailability of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes CYP2D6 and CYP3A4. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via faeces and urine.

Chemistry

Aripiprazole is a phenylpiperazine and is chemically related to nefazodone, etoperidone, and trazodone. It is unusual in having twelve known crystalline polymorphs.

Society and Culture

Classification

Aripiprazole has been described as the prototypical third-generation antipsychotic, as opposed to first-generation (typical) antipsychotics like haloperidol and second-generation (atypical) antipsychotics like clozapine. It has received this classification due to its partial agonism of dopamine receptors, and is the first of its kind in this regard among antipsychotics, which before aripiprazole acted only as dopamine receptor antagonists. The introduction of aripiprazole has led to a paradigm shift from a dopamine antagonist-based approach to a dopamine agonist-based approach for antipsychotic drug development.

Research

Attention Deficit Hyperactivity Disorder

Aripiprazole was under development for the treatment of attention-deficit hyperactivity disorder (ADHD), but development for this indication was discontinued. A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD. A 2013 systematic review of aripiprazole for ADHD similarly reported that there is insufficient evidence of effectiveness to support aripiprazole as a treatment for the condition. Although all 6 non-controlled open-label studies in the review reported effectiveness, two small randomised controlled trials found that aripiprazole did not significantly decrease ADHD symptoms. A high rate of adverse effects with aripiprazole such as weight gain, sedation, and headache was noted. Most research on aripiprazole for ADHD is in children and adolescents. Evidence on aripiprazole specifically for adult ADHD appears to be limited to a single case report.

Substance Dependence

Aripiprazole has been studied for the treatment of amphetamine dependence and other substance use disorders, but more research is needed to support aripiprazole for these potential uses. Available evidence of aripiprazole for amphetamine dependence is mixed. Some studies have reported attenuation of the effects of amphetamines by aripiprazole, whereas other studies have reported both enhancement of the effects of amphetamines and increased use of amphetamines by aripiprazole. As such, aripiprazole may not only be ineffective but potentially harmful for treatment of amphetamine dependence, and caution is warranted with regard to its use for such purposes.

Other Uses

Aripiprazole is under development for the treatment of agitation and pervasive child development disorders. As of May 2021, it is in phase 3 clinical trials for these indications.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Aripiprazole >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

On This Day … 19 September [2022]

Published on by Andrew MarshallLeave a comment

People (Births)

  • 1913 – Frances Farmer, American actress (d. 1970).
  • 1954 – Adam Phillips, Welsh psychotherapist and author.

Frances Farmer

Frances Elena Farmer (19 September 1913 to 01 August 1970) was an American actress and television hostess. She appeared in over a dozen feature films over the course of her career, though she garnered notoriety for the various sensationalised accounts of her life, especially her involuntary commitment to psychiatric hospitals and subsequent mental health struggles.

A native of Seattle, Washington, Farmer began acting in stage productions while a student at the University of Washington. After graduating, she began performing in stock theatre before signing a film contract with Paramount Pictures on her 22nd birthday in September 1935. She made her film debut in the B film Too Many Parents (1936), followed by another B picture, Border Flight, before being given the lead role opposite Bing Crosby in the musical Western Rhythm on the Range (1936). Unhappy with the opportunities the studio gave her, Farmer returned to stock theatre in 1937 before being cast in the original Broadway production of Clifford Odets’s Golden Boy, staged by New York City’s Group Theatre. She followed this with two Broadway productions directed by Elia Kazan in 1939, but a battle with depression and binge drinking caused her to drop out of a subsequent Ernest Hemingway stage adaptation.

Farmer returned to Los Angeles, earning supporting roles in the comedy World Premiere (1941) and the film noir Among the Living (1941). In 1942, publicity of her reportedly erratic behaviour began to surface and, after several arrests and committals to psychiatric institutions, Farmer was diagnosed with paranoid schizophrenia. At the request of her family, particularly her mother, she was committed to an institution in her home state of Washington, where she remained a patient until 1950. Farmer attempted an acting comeback, mainly appearing as a television host in Indianapolis on her own series, Frances Farmer Presents. Her final film role was in the 1958 drama The Party Crashers, after which she spent the majority of the 1960s occasionally performing in local theatre productions staged by Purdue University. In the spring of 1970, she was diagnosed with oesophageal cancer, from which she died on 01 August 1970, aged 56.

Farmer has been the subject of various works, including two feature films and several books, many of which focus on her time spent institutionalised, during which she claimed to have been subject to various systemic abuses. Her posthumously released, ghostwritten, and widely discredited autobiography, Will There Really Be a Morning? (1972), details these claims, but has been exposed as a largely fictional work by a friend of Farmer’s to clear debts. Another discredited 1978 biography of her life, Shadowland, alleged that Farmer underwent a transorbital lobotomy during her institutionalisation, but the author has since stated in court that he fabricated this incident and several other aspects of the book. A 1982 biographical film based on this book depicted these events as true, resulting in renewed interest in her life and career.

Adam Phillips

Adam Phillips (born 19 September 1954) is a British psychoanalytic psychotherapist and essayist.

Since 2003 he has been the general editor of the new Penguin Modern Classics translations of Sigmund Freud. He is also a regular contributor to the London Review of Books.

Joan Acocella, writing in The New Yorker, described Phillips as “Britain’s foremost psychoanalytic writer”,[2] an opinion echoed by historian Élisabeth Roudinesco in Le Monde.

What is Paraphrenia?

Published on by Andrew Marshall1 Comment

Introduction

Paraphrenia is a mental disorder characterised by an organised system of paranoid delusions with or without hallucinations (the positive symptoms of schizophrenia) and without deterioration of intellect or personality (its negative symptom).

This disorder is also distinguished from schizophrenia by a lower hereditary occurrence, less premorbid maladjustment, and a slower rate of progression. Onset of symptoms generally occurs later in life, near the age of 60. The prevalence of the disorder among the elderly is between 0.1% and 4%.

Paraphrenia is not included in the DSM-5; psychiatrists often diagnose patients presenting with paraphrenia as having atypical psychosis, delusional disorder, psychosis not otherwise specified, schizoaffective disorders, and persistent persecutory states of older adults. Recently, mental health professionals have also been classifying paraphrenia as very late-onset schizophrenia-like psychosis.

In the Russian psychiatric manuals, paraphrenia (or paraphrenic syndrome) is the last stage of development of paranoid schizophrenia. “Systematised paraphrenia” (with systematised delusions i. e. delusions with complex logical structure) and “expansive-paranoid paraphrenia” (with expansive/grandiose delusions and persecutory delusions) are the variants of paranoid schizophrenia (F20.0). Sometimes systematised paraphrenia can be seen with delusional disorder (F22.0). The word is from Ancient Greek: παρά – beside, near + φρήν – intellect, mind.

Brief History

The term paraphrenia was originally popularised by Karl Ludwig Kahlbaum in 1863 to describe the tendency of certain psychiatric disorders to occur during certain transitional periods in life (describing paraphrenia hebetica as the insanity of the adolescence and paraphrenia senilis as the insanity of the elders.

The term was also used by Sigmund Freud for a short time starting in 1911 as an alternative to the terms schizophrenia and dementia praecox, which in his estimation did not correctly identify the underlying condition, and by Emil Kraepelin in 1912/1913, who changed its meaning to describe paraphrenia as it is understood today, as a small group of individuals that have many of the symptoms of schizophrenia with a lack of deterioration and thought disorder. Kraepelin’s study was discredited by Wilhelm Mayer in 1921 when he conducted a follow-up study using Kraepelin’s data. His study suggested that there was little to no discrimination between schizophrenia and paraphrenia; given enough time, patients presenting with paraphrenia will merge into the schizophrenic pool. However, Meyer’s data are open to various interpretations. In 1952, Roth and Morrissey conducted a large study in which they surveyed the mental hospital admissions of older patients. They characterised patients as having:

“paraphrenic delusions which… occurred in each case in the setting of a well-preserved intellect and personality, were often ‘primary’ in character, and were usually associated with the passivity failings or other volitional disturbances and hallucinations in clear consciousness pathognomonic of schizophrenia”.

In recent medicine, the term paraphrenia has been replaced by the diagnosis of “very late-onset schizophrenia-like psychosis” and has also been called “atypical psychoses, delusional disorder, psychoses not otherwise specified, schizoaffective disorders, and persistent persecutory states of older adults” by psychotherapists.[4] Current studies, however, recognize the condition as “a viable diagnostic entity that is distinct from schizophrenia, with organic factors playing a role in a significant portion of patients.”[4]

Signs and Symptoms

The main symptoms of paraphrenia are paranoid delusions and hallucinations. The delusions often involve the individual being the subject of persecution, although they can also be erotic, hypochondriacal, or grandiose in nature. The majority of hallucinations associated with paraphrenia are auditory, with 75% of patients reporting such an experience; however, visual, tactile, and olfactory hallucinations have also been reported. The paranoia and hallucinations can combine in the form of “threatening or accusatory voices coming from neighbouring houses [and] are frequently reported by the patients as disturbing and undeserved”. Patients also present with a lack of symptoms commonly found in other mental disorders similar to paraphrenia. There is no significant deterioration of intellect, personality, or habits and patients often remain clean and mostly self-sufficient. Patients also remain oriented well in time and space.

Paraphrenia is different from schizophrenia because, while both disorders result in delusions and hallucinations, individuals with schizophrenia exhibit changes and deterioration of personality whereas individuals with paraphrenia maintain a well-preserved personality and affective response.

Causes

Neurological

Paraphrenia is often associated with a physical change in the brain, such as a tumour, stroke, ventricular enlargement, or neurodegenerative process. Research that reviewed the relationship between organic brain lesions and the development of delusions suggested that “brain lesions which lead to subcortical dysfunction could produce delusions when elaborated by an intact cortex”.

Predisposing Factors

Many patients who present with paraphrenia have significant auditory or visual loss, are socially isolated with a lack of social contact, do not have a permanent home, are unmarried and without children, and have maladaptive personality traits. While these factors do not cause paraphrenia, they do make individuals more likely to develop the disorder later in life.

Diagnosis

While the diagnosis of paraphrenia is absent from recent revisions of the DSM and the ICD, many studies have recognised the condition as “a viable diagnostic entity that is distinct from schizophrenia, with organic factors playing a role in a significant portion of patients.” As such, paraphrenia is seen as being distinct from both schizophrenia and progressive dementia in old age. Ravindran (1999) developed a list of criteria for the diagnosis of paraphrenia, which agrees with much of the research done up to the time it was published.

  1. A delusional disorder of at least six months duration characterized by the following:
    1. Preoccupation with one or more semi-systematised delusions, often accompanied by auditory hallucinations.
    2. Affect notably well-preserved and appropriate. Ability to maintain rapport with others.
    3. None of:
      1. Intellectual deterioration.
      2. Visual hallucinations.
      3. Incoherence.
      4. Flat or grossly inappropriate affect.
      5. Grossly disorganised behaviour at times other than during the acute episode.
    4. Disturbance of behaviour understandable in relation to the content of the delusions and hallucinations.
    5. Only partly meets criterion A for schizophrenia. No significant organic brain disorder.

Management

Research suggests that paraphrenics respond well to antipsychotic drug therapy if doctors can successfully achieve sufficient compliance. Herbert found that Stelazine combined with Disipal was an effective treatment. It promoted the discharging of patients and kept discharged patients from being readmitted later. While behaviour therapy may help patients reduce their preoccupation with delusions, psychotherapy is not currently of primary value.

Prognosis

Individuals who develop paraphrenia have a life expectancy similar to the normal population. Recovery from the psychotic symptoms seems to be rare, and in most cases paraphrenia results in in-patient status for the remainder of the life of the patient. Patients experience a slow deterioration of cognitive functions and the disorder can lead to dementia in some cases, but this development is no greater than the normal population.

Epidemiology

Studies suggest that the prevalence of paraphrenia in the elderly population is around 2-4%.

Sex Differences

While paraphrenia can occur in both men and women, it is more common in women, even after the difference has been adjusted for life expectancies. The ratio of women with paraphrenia to men with paraphrenia is anywhere from 3:1 to 45:2.

Age

It is seen mainly in patients over the age of 60, but has been known to occur in patients in their 40s and 50s.

Personality Type and Living Situation

It is suggested that individuals who develop paraphrenia later in life have premorbid personalities, and can be described as “quarrelsome, religious, suspicious or sensitive, unsociable and cold-hearted.” Many patients were also described as being solitary, eccentric, isolated and difficult individuals; these characteristics were also long-standing rather than introduced by the disorder. Most of the traits recognised prior to the onset of paraphrenia in individuals can be grouped as either paranoid or schizoid. Patients presenting with paraphrenia were most often found to be living by themselves (either single, widowed, or divorced). There have also been reports of low marriage rate among paraphrenics and these individuals also have few or no children (possibly because of this premorbid personality).

Physical Factors

The development of paranoia and hallucinations in old age have been related to both auditory and visual impairment, and individuals with paraphrenia often present with one or both of these impairments. Hearing loss in paraphrenics is associated with early age of onset, long duration, and profound auditory loss.

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