What is a Typical Antipsychotic?

Introduction

Typical antipsychotics (also known as major tranquilisers, or first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia).

Advertisement for Thorazine (chlorpromazine) from the 1950s, reflecting the perceptions of psychosis, including the now-discredited perception of a tendency towards violence, from the time when antipsychotics were discovered.

Typical antipsychotics may also be used for the treatment of acute mania, agitation, and other conditions. The first typical antipsychotics to come into medical use were the phenothiazines, namely chlorpromazine which was discovered serendipitously. Another prominent grouping of antipsychotics are the butyrophenones, an example of which is haloperidol. The newer, second-generation antipsychotics, also known as atypical antipsychotics, have largely supplanted the use of typical antipsychotics as first-line agents due to the higher risk of movement disorders in the latter.

Both generations of medication tend to block receptors in the brain’s dopamine pathways, but atypicals at the time of marketing were claimed to differ from typical antipsychotics in that they are less likely to cause extrapyramidal symptoms (EPS), which include unsteady Parkinson’s disease-type movements, internal restlessness, and other involuntary movements (e.g. tardive dyskinesia, which can persist after stopping the medication). More recent research has demonstrated the side effect profile of these drugs is similar to older drugs, causing the leading medical journal The Lancet to write in its editorial “the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.” While typical antipsychotics are more likely to cause EPS, atypicals are more likely to cause adverse metabolic effects, such as weight gain and increase the risk for type II diabetes.

Brief History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anaesthetic after an initial report in 1952. It was first used in psychiatric institutions because of its powerful tranquilising effect; at the time it was regarded as a non-permanent “pharmacological lobotomy” (Note that “tranquilizing” here only refers to changes in external behaviour, while the experience a person has internally may be one of increased agitation but inability to express it).

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was “neuroleptic”, followed by “major tranquilizer” and then “ataraxic”. The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the Greek: “νεῦρον” (neuron, originally meaning “sinew” but today referring to the nerves) and “λαμβάνω” (lambanō, meaning “take hold of”). Thus, the word means taking hold of one’s nerves. It was often taken to refer also to common effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and harmful, they were, along with akathisia, considered a reliable sign that the drug was working. These terms have been largely replaced by the term “antipsychotic” in medical and advertising literature, which refers to the medication’s more-marketable effects.

Clinical Uses

Typical antipsychotics block the dopamine 2 receptor (D2) receptor, causing a tranquilising effect. It is thought that 60-80% of D2 receptors need to be occupied for antipsychotic effect. For reference, the typical antipsychotic haloperidol tends to block about 80% of D2 receptors at doses ranging from 2 to 5 mg per day. On the aggregate level, no typical antipsychotic is more effective than any other, though people will vary in which antipsychotic they prefer to take (based on individual differences in tolerability and effectiveness). Typical antipsychotics can be used to treat, e.g. schizophrenia or severe agitation. Haloperidol, due to the availability of a rapid-acting injectable formulation and decades of use, remains the most commonly used tranquilizer for chemical restraint in the emergency department setting (in the interests of hospital staff, not to meet a medical need of the patient).

Adverse Effects

Adverse effects vary among the various agents in this class of medications, but common effects include: dry mouth, muscle stiffness, muscle cramping, tremors, EPS and weight gain. EPS refers to a cluster of symptoms consisting of akathisia, parkinsonism, and dystonia. Anticholinergics such as benztropine and diphenhydramine are commonly prescribed to treat the EPS. 4% of users develop rabbit syndrome while on typical antipsychotics.

There is a risk of developing a serious condition called tardive dyskinesia as a side effect of antipsychotics, including typical antipsychotics. The risk of developing tardive dyskinesia after chronic typical antipsychotic usage varies on several factors, such as age and gender, as well as the specific antipsychotic used. The commonly reported incidence of TD among younger patients is about 5% per year. Among older patients incidence rates as high as 20% per year have been reported. The average prevalence is approximately 30%. There are few treatments that have consistently been shown to be effective for the treatment of tardive dyskinesia, though an VMAT2 inhibitor like valbenazine may help. The atypical antipsychotic clozapine has also been suggested as an alternative antipsychotic for patients experiencing tardive dyskinesia. Tardive dyskinesia may reverse upon discontinuation of the offending agent or it may be irreversible, withdrawal may also make tardive dyskinesia more severe.

Neuroleptic malignant syndrome, or NMS, is a rare, but potentially fatal side effect of antipsychotic treatment. NMS is characterized by fever, muscle rigidity, autonomic dysfunction, and altered mental status. Treatment includes discontinuation of the offending agent and supportive care.

The role of typical antipsychotics has come into question recently as studies have suggested that typical antipsychotics may increase the risk of death in elderly patients. A retrospective cohort study from the New England Journal of Medicine on 01 December 2005 showed an increase in risk of death with the use of typical antipsychotics that was on par with the increase shown with atypical antipsychotics. This has led some to question the common use of antipsychotics for the treatment of agitation in the elderly, particularly with the availability of alternatives such as mood stabilising and antiepileptic drugs.

Potency

Traditional antipsychotics are classified as high-potency, mid-potency, or low-potency based on their potency for the D2 receptor as noted in the table below.

PotencyExamplesAdverse Effect Profile
HighFluphenazine and HaloperidolMore extrapyramidal side effects (EPS) and less antihistaminic effects (e.g. sedation), alpha adrenergic antagonism (e.g. orthostatic hypotension), and anticholinergic effects (e.g. dry mouth).
MediumPerphenazine and LoxapineIntermediate D2 affinity, with more off-target effects than high-potency agents.
LowChlorpromazineLess risk of EPS but more antihistaminic effects, alpha adrenergic antagonism, and anticholinergic effects.

Prochlorperazine (Compazine, Buccastem, Stemetil) and Pimozide (Orap) are less commonly used to treat psychotic states, and so are sometimes excluded from this classification.

A related concept to D2 potency is the concept of “chlorpromazine equivalence”, which provides a measure of the relative effectiveness of antipsychotics. The measure specifies the amount (mass) in milligrams of a given drug that must be administered in order to achieve desired effects equivalent to those of 100 milligrams of chlorpromazine. Another method is “defined daily dose” (DDD), which is the assumed average dose of an antipsychotic that an adult would receive during long-term treatment. DDD is primarily used for comparing the utilization of antipsychotics (e.g. in an insurance claim database), rather than comparing therapeutic effects between antipsychotics. Maximum dose methods are sometimes used to compare between antipsychotics as well. It is important to note that these methods do not generally account for differences between the tolerability (i.e. the risk of side effects) or the safety between medications.

Below is list of typical antipsychotics organised by potency.

  • Low potency:
    • Chlorpromazine.
    • Chlorprothixene.
    • Levomepromazine.
    • Mesoridazine.
    • Periciazine.
    • Promazine.
    • Thioridazine (withdrawn by brand-name manufacturer and most countries, and since discontinued).
  • Medium potency:
    • Loxapine.
    • Molindone.
    • Perphenazine.
    • Thiothixene.
  • High potency:
    • Droperidol.
    • Flupentixol.
    • Fluphenazine.
    • Haloperidol.
    • Pimozide.
    • Prochlorperazine.
    • Thioproperazine.
    • Trifluoperazine.
    • Zuclopenthixol.

Long-Acting Injectables

Some typical antipsychotics have been formulated as a long-acting injectable (LAI), or “depot”, formulation. Depot injections are also used on persons under involuntary commitment to force compliance with a court treatment order when the person would refuse to take daily oral medication. This has the effect of dosing a person who doesn’t consent to take the drug. The United Nations Special Rapporteur On Torture has classified this as a human rights violation and cruel or inhuman treatment.

The first LAI antipsychotics (often referred to as simply “LAIs”) were the typical antipsychotics fluphenazine and haloperidol. Both fluphenazile and haloperidol are formulated as decanoates, referring to the attachment of a decanoic acid group to the antipsychotic molecule. These are then dissolved in an organic oil. Together, these modifications prevent the active medications from being released immediately upon injection, attaining a slow release of the active medications (note, though, that the fluphenazine decanoate product is unique for reaching peak fluphenazine blood levels within 24 hours after administration). Fluphenazine decanoate can be administered every 7 to 21 days (usually every 14 to 28 days), while haloperidol decanoate can be administered every 28 days, though some people receive more or less frequent injections. If a scheduled injection of either haloperidol decanoate or fluphenazine decanoate is missed, recommendations for administering make-up injectable dose(s) or providing antipsychotics to be taken by mouth vary by, e.g. how long ago the last injection was and how many previous injections the person has received (i.e. if steady state levels of the medication have been reached or not).

Both of the typical antipsychotic LAIs are inexpensive in comparison to the atypical LAIs. Doctors usually prefer atypical LAIs over typical LAIs due to the differences in adverse effects between typical and atypical antipsychotics in general.

What is Thioridazine?

Introduction

Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis.

The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.

Brief History

The manufacturer Novartis/Sandoz/Wander of the brands of thioridazine, Mellaril in the US and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.

Indications

Thioridazine was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias.

Its primary use in medicine was the treatment of schizophrenia. It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia, but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.

Side Effects

Thioridazine prolongs the QTc interval in a dose-dependent manner. It produces significantly less extrapyramidal side effects than most first-generation antipsychotics. Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies. It has a higher propensity for causing anticholinergic side effects coupled with a lower propensity for causing extrapyramidal side effects and sedation than chlorpromazine, but also has a higher incidence of hypotension and cardiotoxicity. It is also known to possess a relatively high liability for causing orthostatic hypotension compared to other antipsychotics. Similarly to other first-generation antipsychotics it has a relatively high liability for causing prolactin elevation. It is moderate risk for causing weight gain. As with all antipsychotics thioridazine has been linked to cases of tardive dyskinesia (an often permanent neurological disorder characterised by slow, repetitive, purposeless and involuntary movements, most often of the facial muscles, that is usually brought on by years of continued treatment with antipsychotics, especially the first-generation (or typical) antipsychotics such as thioridazine) and neuroleptic malignant syndrome (a potentially fatal complication of antipsychotic treatment). Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment. Thioridazine is also associated with abnormal retinal pigmentation after many years of use. Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury.

Metabolism

Thioridazine is a racemic compound with two enantiomers, both of which are metabolised, according to Eap et al., by CYP2D6 into (S)- and (R)-thioridazine-2-sulfoxide, better known as mesoridazine, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine. Thioridazine is an inhibitor of CYP1A2 and CYP3A4.

Antibiotic Activity

Thioridazine is known to kill extensively drug-resistant tuberculosis and to make methicillin-resistant Staphylococcus aureus sensitive to β-lactam antibiotics. A possible mechanism of action for the drug’s antibiotic activity is via the inhibition of bacterial secretion pumps. The β-lactam antibiotic resistance is due to the secretion β-lactamase a protein that destroys antibiotics. If the bacteria cannot secrete the β-lactamase, then the antibiotic will be effective.

What is an Antipsychotic?

Introduction

Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of other psychotic disorders.

They are also the mainstay together with mood stabilisers in the treatment of bipolar disorder.

Recent research has shown that use of any antipsychotic results in smaller brain tissue volumes and that this brain shrinkage is dose dependent and time dependent. A review of the research has also reinforced this effect.

The use of antipsychotics may result in many unwanted side effects such as involuntary movement disorders, gynecomastia, impotence, weight gain and metabolic syndrome. Long-term use can produce adverse effects such as tardive dyskinesia.

First-generation antipsychotics, known as typical antipsychotics, were first introduced in the 1950s, and others were developed until the early 1970s. Second-generation drugs, known as atypical antipsychotics, were introduced firstly with clozapine in the early 1970s followed by others. Both generations of medication block receptors in the brain for dopamine, but atypicals tend to act on serotonin receptors as well. Neuroleptic, originating from Greek: νεῦρον (neuron) and λαμβάνω (take hold of) – thus meaning “which takes the nerve” – refers to both common neurological effects and side effects.

Brief History

The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anaesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a non-permanent “pharmacological lobotomy”. Lobotomy at the time was used to treat many behavioural disorders, including psychosis, although its effect was to markedly reduce behaviour and mental functioning of all types. However, chlorpromazine proved to reduce the effects of psychosis in a more effective and specific manner than lobotomy, even though it was known to be capable of causing severe sedation. The underlying neurochemistry involved has since been studied in detail, and subsequent antipsychotic drugs have been discovered by an approach that incorporates this sort of information.

The discovery of chlorpromazine’s psychoactive effects in 1952 led to further research that resulted in the development of antidepressants, anxiolytics, and the majority of other drugs now used in the management of psychiatric conditions. In 1952, Henri Laborit described chlorpromazine only as inducing indifference towards what was happening around them in nonpsychotic, non-manic patients, and Jean Delay and Pierre Deniker described it as controlling manic or psychotic agitation. The former claimed to have discovered a treatment for agitation in anyone, and the latter team claimed to have discovered a treatment for psychotic illness.

Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs. In the late 1950s the most widely used term was “neuroleptic”, followed by “major tranquilizer” and then “ataraxic”. The first recorded use of the term tranquilizer dates from the early nineteenth century. In 1953 Frederik F. Yonkman, a chemist at the Swiss-based Cibapharmaceutical company, first used the term tranquiliser to differentiate reserpine from the older sedatives. The word neuroleptic was coined in 1955 by Delay and Deniker after their discovery (1952) of the antipsychotic effects of chlorpromazine. It is derived from the Greek: “νεῦρον” (neuron, originally meaning “sinew” but today referring to the nerves) and “λαμβάνω” (lambanō, meaning “take hold of”). Thus, the word means taking hold of one’s nerves. It was often taken to refer also to common side effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time, along with akathisia, considered a reliable sign that the drug was working. The term “ataraxy” was coined by the neurologist Howard Fabing and the classicist Alister Cameron to describe the observed effect of psychic indifference and detachment in patients treated with chlorpromazine. This term derived from the Greek adjective “ἀτάρακτος” (ataraktos), which means “not disturbed, not excited, without confusion, steady, calm”. In the use of the terms “tranquiliser” and “ataractic”, medical practitioners distinguished between the “major tranquilizers” or “major ataractics”, which referred to drugs used to treat psychoses, and the “minor tranquilizers” or “minor ataractics”, which referred to drugs used to treat neuroses. While popular during the 1950s, these terms are infrequently used today. They are being abandoned in favour of “antipsychotic”, which refers to the drug’s desired effects. Today, “minor tranquiliser” can refer to anxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines, which have some antipsychotic properties and are recommended for concurrent use with antipsychotics, and are useful for insomnia or drug-induced psychosis. They are potentially addictive sedatives.

Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics. The difference between first- and second-generation antipsychotics is a subject of debate. The second-generation antipsychotics are generally distinguishable by the presence of 5HT2A receptor antagonism and a corresponding lower propensity for extrapyramidal side effects compared to first-generation antipsychotics.

Medical Uses

Antipsychotics are most frequently used for the following conditions:

  • Schizophrenia.
  • Schizoaffective disorder most commonly in conjunction with either an antidepressant (in the case of the depressive subtype) or a mood stabiliser (in the case of the bipolar subtype).
  • Bipolar disorder (acute mania and mixed episodes) may be treated with either typical or atypical antipsychotics, although atypical antipsychotics are usually preferred because they tend to have more favourable adverse effect profiles and, according to a recent meta-analysis, they tend to have a lower liability for causing conversion from mania to depression.
  • Psychotic depression. In this indication it is a common practice for the psychiatrist to prescribe a combination of an atypical antipsychotic and an antidepressant as this practice is best supported by the evidence.
  • Treatment resistant depression as an adjunct to standard antidepressant therapy.

Antipsychotics are generally not recommended for treating behavioural problems associated with dementia, given that the risk of use tends to be greater than the potential benefit. The same can be said for insomnia, in which they are not recommended as first-line therapy. There are evidence-based indications for using antipsychotics in children (e.g. tic disorder, bipolar disorder, psychosis), but the use of antipsychotics outside of those contexts (e.g. to treat behavioural problems) warrants significant caution.

Schizophrenia

Antipsychotic drug treatment is a key component of schizophrenia treatment recommendations by the National Institute of Health and Care Excellence (NICE), the American Psychiatric Association, and the British Society for Psychopharmacology. The main aim of treatment with antipsychotics is to reduce the positive symptoms of psychosis that include delusions and hallucinations. There is mixed evidence to support a significant impact of antipsychotic use on negative symptoms (such as apathy, lack of emotional affect, and lack of interest in social interactions) or on the cognitive symptoms (memory impairments, reduced ability to plan and execute tasks). In general, the efficacy of antipsychotic treatment in reducing both positive and negative symptoms appears to increase with increasing severity of baseline symptoms. All antipsychotic medications work relatively the same way, by antagonising D2 dopamine receptors. However, there are some differences when it comes to typical and atypical antipsychotics. For example, atypical antipsychotic medications have been seen to lower the neurocognitive impairment associated with schizophrenia more so than conventional antipsychotics, although the reasoning and mechanics of this are still unclear to researchers.

Applications of antipsychotic drugs in the treatment of schizophrenia include prophylaxis in those showing symptoms that suggest that they are at high risk of developing psychosis, treatment of first episode psychosis, maintenance therapy (a form of prophylaxis, maintenance therapy aims to maintain therapeutic benefit and prevent symptom relapse), and treatment of recurrent episodes of acute psychosis.

Prevention of Psychosis and Symptom Improvement

Test batteries such as the PACE (Personal Assessment and Crisis Evaluation Clinic) and COPS (Criteria of Prodromal Syndromes), which measure low-level psychotic symptoms and cognitive disturbances, are used to evaluate people with early, low-level symptoms of psychosis. Test results are combined with family history information to identify patients in the “high-risk” group; they are considered to have a 20-40% risk of progression to frank psychosis within two years. These patients are often treated with low doses of antipsychotic drugs with the goal of reducing their symptoms and preventing progression to frank psychosis. While generally useful for reducing symptoms, clinical trials to date show little evidence that early use of antipsychotics improves long-term outcomes in those with prodromal symptoms, either alone or in combination with cognitive behavioural therapy (CBT).

First Episode Psychosis

First episode psychosis (FEP), is the first time that psychotic symptoms are presented. NICE recommends that all persons presenting with first episode psychosis be treated with both an antipsychotic drug, and CBT. NICE further recommends that those expressing a preference for CBT alone are informed that combination treatment is more effective. A diagnosis of schizophrenia is not made at this time as it takes longer to determine by both DSM-5 and ICD-11, and only around 60% of those presenting with a first episode psychosis will later be diagnosed with schizophrenia.

The conversion rate for a first episode drug induced psychosis to bipolar disorder or schizophrenia are lower, with 30% of people converting to either bipolar disorder or schizophrenia. NICE makes no distinction between a substance-induced psychosis, and any other form of psychosis. The rate of conversion differs for different classes of drug.

Pharmacological options for the specific treatment of FEP have been discussed in recent reviews. The goals of treatment for FEP include reducing symptoms and potentially improving long-term treatment outcomes. Randomised clinical trials have provided evidence for the efficacy of antipsychotic drugs in achieving the former goal, with first-generation and second generation antipsychotics showing about equal efficacy. Evidence that early treatment has a favourable effect on long term outcomes is equivocal.

Recurrent Psychotic Episodes

Placebo controlled trials of both first and second generation antipsychotic drugs consistently demonstrate the superiority of active drug to placebo in suppressing psychotic symptoms. A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia acute psychotic episodes showed an effect size of about 0.5. There is little or no difference in efficacy among approved antipsychotic drugs, including both first- and second-generation agents. The efficacy of such drugs is suboptimal. Few patients achieve complete resolution of symptoms. Response rates, calculated using various cutoff values for symptom reduction, are low and their interpretation is complicated by high placebo response rates and selective publication of clinical trial results.

Maintenance Therapy

The majority of patients treated with an antipsychotic drug will experience a response within four weeks. The goals of continuing treatment are to maintain suppression of symptoms, prevent relapse, improve quality of life, and support engagement in psychosocial therapy.

Maintenance therapy with antipsychotic drugs is clearly superior to placebo in preventing relapse but is associated with weight gain, movement disorders, and high dropout rates. A 3-year trial following persons receiving maintenance therapy after an acute psychotic episode found that 33% obtained long-lasting symptom reduction, 13% achieved remission, and only 27% experienced satisfactory quality of life. The effect of relapse prevention on long term outcomes is uncertain, as historical studies show little difference in long term outcomes before and after the introduction of antipsychotic drugs.

While maintenance therapy clearly reduces the rate of relapses requiring hospitalization, a large observational study in Finland found that, in people that eventually discontinued antipsychotics, the risk of being hospitalized again for a mental health problem or dying increased the longer they were dispensed (and presumably took) antipsychotics prior to stopping therapy. If people did not stop taking antipsychotics, they remained at low risk for relapse and hospitalisation compared to those that stopped taking antipsychotics. The authors speculated that the difference may be because the people that discontinued treatment after a longer time had more severe mental illness than those that discontinued antipsychotic therapy sooner.

A significant challenge in the use of antipsychotic drugs for the prevention of relapse is the poor rate of adherence. In spite of the relatively high rates of adverse effects associated with these drugs, some evidence, including higher dropout rates in placebo arms compared to treatment arms in randomised clinical trials, suggest that most patients who discontinue treatment do so because of suboptimal efficacy. If someone experiences psychotic symptoms due to nonadherence, they may be compelled to treatment through a process called involuntary commitment, in which they can be forced to accept treatment (including antipsychotics). A person can also be committed to treatment outside of a hospital, called outpatient commitment.

Antipsychotics in long-acting injectable (LAI), or “depot”, form have been suggested as a method of decreasing medication nonadherence (sometimes also called non-compliance). NICE advises LAIs be offered to patients when preventing covert, intentional nonadherence is a clinical priority. LAIs are used to ensure adherence in outpatient commitment. A meta-analysis found that LAIs resulted in lower rates of rehospitalisation with a hazard ratio of 0.83, however these results were not statistically significant (the 95% confidence interval was 0.62 to 1.11).

Bipolar Disorder

Antipsychotics are routinely used, often in conjunction with mood stabilisers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder. The reason for this combination is the therapeutic delay of the aforementioned mood stabilisers (for valproate therapeutic effects are usually seen around five days after treatment is commenced whereas lithium usually takes at least a week before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs. The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.

Three atypical antipsychotics (lurasidone, olanzapine and quetiapine) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy, whereas only olanzapine and quetiapine have been proven to be effective broad-spectrum (i.e. against all three types of relapse – manic, mixed and depressive) prophylactic (or maintenance) treatments in patients with bipolar disorder. A recent Cochrane review also found that olanzapine had a less favourable risk/benefit ratio than lithium as a maintenance treatment for bipolar disorder.

The American Psychiatric Association and the UK National Institute for Health and Care Excellence recommend antipsychotics for managing acute psychotic episodes in schizophrenia or bipolar disorder, and as a longer-term maintenance treatment for reducing the likelihood of further episodes. They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible. A number of studies have looked at levels of “compliance” or “adherence” with antipsychotic regimes and found that discontinuation (stopping taking them) by patients is associated with higher rates of relapse, including hospitalisation.

Dementia

Psychosis and agitation develop in as many as 80 percent of people living in nursing homes. Despite a lack of Federal Drug Administration (FDA) approval and black-box warnings, atypical antipsychotics are often prescribed to people with dementia. An assessment for an underlying cause of behaviour is needed before prescribing antipsychotic medication for symptoms of dementia. Antipsychotics in old age dementia showed a modest benefit compared to placebo in managing aggression or psychosis, but this is combined with a fairly large increase in serious adverse events. Thus, antipsychotics should not be used routinely to treat dementia with aggression or psychosis, but may be an option in a few cases where there is severe distress or risk of physical harm to others. Psychosocial interventions may reduce the need for antipsychotics. In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%.

Major Depressive Disorder

A number of atypical antipsychotics have some benefits when used in addition to other treatments in major depressive disorder. Aripiprazole, quetiapine extended-release, and olanzapine (when used in conjunction with fluoxetine) have received FDA labelling for this indication. There is, however, a greater risk of side effects with their use compared to using traditional antidepressants. The greater risk of serious side effects with antipsychotics is why, e.g. quetiapine was denied approval as monotherapy for major depressive disorder or generalised anxiety disorder, and instead was only approved as an adjunctive treatment in combination with traditional antidepressants.

Other

Besides the above uses antipsychotics may be used for obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), personality disorders, Tourette syndrome, autism and agitation in those with dementia. Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder. The atypical antipsychotic risperidone may be useful for OCD. The use of low doses of antipsychotics for insomnia, while common, is not recommended as there is little evidence of benefit and concerns regarding adverse effects. Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.

In children they may be used in those with disruptive behaviour disorders, mood disorders and pervasive developmental disorders or intellectual disability. Antipsychotics are only weakly recommended for Tourette syndrome, because although they are effective, side effects are common. The situation is similar for those on the autism spectrum. Much of the evidence for the off-label use of antipsychotics (for example, for dementia, OCD, PTSD, personality disorders, Tourette’s) was of insufficient scientific quality to support such use, especially as there was strong evidence of increased risks of stroke, tremors, significant weight gain, sedation, and gastrointestinal problems. A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns. A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Both risperidone and aripiprazole have been approved by the FDA for the treatment of irritability in autistic children and adolescents.

Aggressive challenging behaviour in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomised controlled trial, however, found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.

Antipsychotics may be an option, together with stimulants, in people with ADHD and aggressive behaviour when other treatments have not worked. They have not been found to be useful for the prevention of delirium among those admitted to hospital.

Typicals vs Atypicals

It is unclear whether the atypical (second-generation) antipsychotics offer advantages over older, first generation antipsychotics. Amisulpride, olanzapine, risperidone and clozapine may be more effective but are associated with greater side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.

Clozapine is an effective treatment for those who respond poorly to other drugs (“treatment-resistant” or “refractory” schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.

Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.

In 2005, a US government body, the National Institute of Mental Health published the results of a major independent study (the CATIE project). No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine, although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%).

Atypical antipsychotics do not appear to lead to improved rates of medication adherence compared to typical antipsychotics.

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes. In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and other extrapyramidal symptoms with the typicals and for this reason alone recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter. NICE recently revised its recommendation favouring atypicals, to advise that the choice should be an individual one based on the particular profiles of the individual drug and on the patient’s preferences.

The re-evaluation of the evidence has not necessarily slowed the bias toward prescribing the atypical

Adverse Effects

Generally, more than one antipsychotic drug should not be used at a time because of increased adverse effects.

Very rarely antipsychotics may cause tardive psychosis.

By Rate

Common (≥ 1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:

  • Sedation (particularly common with asenapine, clozapine, olanzapine, quetiapine, chlorpromazine and zotepine).
  • Headaches.
  • Dizziness.
  • Diarrhoea.
  • Anxiety.
  • Extrapyramidal side effects (particularly common with first-generation antipsychotics), which include:
    • Akathisia, an often distressing sense of inner restlessness.
    • Dystonia, an abnormal muscle contraction.
    • Pseudoparkinsonism, symptoms that are similar to what people with Parkinson’s disease experience, including tremulousness and drooling.
  • Hyperprolactinaemia (rare for those treated with clozapine, quetiapine and aripiprazole), which can cause:
    • Galactorrhoea, the unusual secretion of breast milk.
    • Gynaecomastia, abnormal growth of breast tissue.
    • Sexual dysfunction (in both sexes).
    • Osteoporosis.
  • Orthostatic hypotension.
  • Weight gain (particularly prominent with clozapine, olanzapine, quetiapine and zotepine).
  • Anticholinergic side-effects (common for olanzapine, clozapine; less likely on risperidone) such as:
    • Blurred vision.
    • Constipation.
    • Dry mouth (although hypersalivation may also occur).
    • Reduced perspiration.
  • Tardive dyskinesia appears to be more frequent with high-potency first-generation antipsychotics, such as haloperidol, and tends to appear after chronic and not acute treatment. It is characterised by slow (hence the tardive) repetitive, involuntary and purposeless movements, most often of the face, lips, legs, or torso, which tend to resist treatment and are frequently irreversible. The rate of appearance of TD is about 5% per year of use of antipsychotic drug (whatever the drug used).

Rare/Uncommon (<1% incidence for most antipsychotic drugs) adverse effects of antipsychotics include:

  • Blood dyscrasias (e.g., agranulocytosis, leukopenia, and neutropoenia), which is more common in patients on clozapine.
  • Metabolic syndrome and other metabolic problems such as type II diabetes mellitus – particularly common with clozapine, olanzapine and zotepine. In American studies African Americans appeared to be at a heightened risk for developing type II diabetes mellitus. Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males. Metabolic adverse effects appear to be mediated by the following mechanisms:
    • Causing weight gain by antagonising the histamine H1 and serotonin 5-HT2Creceptors] and perhaps by interacting with other neurochemical pathways in the central nervous system.
  • Neuroleptic malignant syndrome, a potentially fatal condition characterised by:
    • Autonomic instability, which can manifest with tachycardia, nausea, vomiting, diaphoresis, etc.
    • Hyperthermia – elevated body temperature.
    • Mental status change (confusion, hallucinations, coma, etc.).
    • Muscle rigidity.
    • Laboratory abnormalities (e.g. elevated creatine kinase, reduced iron plasma levels, electrolyte abnormalities, etc.).
  • Pancreatitis.
  • QT interval prolongation – more prominent in those treated with amisulpride, pimozide, sertindole, thioridazine and ziprasidone.
  • Torsades de pointes.
  • Seizures, particularly in people treated with chlorpromazine and clozapine.
  • Thromboembolism.
  • Myocardial infarction.
  • Stroke.

Long-Term Effects

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed. Antipsychotics may also increase the risk of early death in individuals with dementia. Antipsychotics typically worsen symptoms in people who suffer from depersonalisation disorder. Antipsychotic polypharmacy (prescribing two or more antipsychotics at the same time for an individual) is a common practice but not evidence-based or recommended, and there are initiatives to curtail it. Similarly, the use of excessively high doses (often the result of polypharmacy) continues despite clinical guidelines and evidence indicating that it is usually no more effective but is usually more harmful.

Loss of grey matter and other brain structural changes over time are observed amongst people diagnosed with schizophrenia. Meta-analyses of the effects of antipsychotic treatment on grey matter volume and the brain’s structure have reached conflicting conclusions. A 2012 meta-analysis concluded that grey matter loss is greater in patients treated with first generation antipsychotics relative to those treated with atypicals, and hypothesized a protective effect of atypicals as one possible explanation. A second meta-analysis suggested that treatment with antipsychotics was associated with increased grey matter loss. Animal studies found that monkeys exposed to both first- and second-generation antipsychotics experience significant reduction in brain volume, resulting in an 8-11% reduction in brain volume over a 17-27 month period.

Subtle, long-lasting forms of akathisia are often overlooked or confused with post-psychotic depression, in particular when they lack the extrapyramidal aspect that psychiatrists have been taught to expect when looking for signs of akathisia.

Adverse effect on cognitive function and increased risk of death in people with dementia along with worsening of symptoms has been describe in the literature.

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 recurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Unexpected psychotic episodes have been observed in patients withdrawing from clozapine. This is referred to as supersensitivity psychosis, not to be equated with tardive dyskinesia.

Tardive dyskinesia may abate during withdrawal from the antipsychotic agent, or it may persist.

Withdrawal effects may also occur when switching a person from one antipsychotic to another, (it is presumed due to variations of potency and receptor activity). Such withdrawal effects can include cholinergic rebound, an activation syndrome, and motor syndromes including dyskinesias. These adverse effects are more likely during rapid changes between antipsychotic agents, so making a gradual change between antipsychotics minimises these withdrawal effects. The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse. The process of cross-titration involves gradually increasing the dose of the new medication while gradually decreasing the dose of the old medication.

City and Hackney Clinical Commissioning Group found more than 1,000 patients in their area in July 2019 who had not had regular medication reviews or health checks because they were not registered as having serious mental illness. On average they had been taking these drugs for six years. If this is typical of practice in England more than 100,000 patients are probably in the same position.

List of Agents

Clinically used antipsychotic medications are listed below by drug group. Trade names appear in parentheses. A 2013 review has stated that the division of antipsychotics into first and second generation is perhaps not accurate.

Notes:

  • † indicates drugs that are no longer (or were never) marketed in English-speaking countries.
  • ‡ denotes drugs that are no longer (or were never to begin with) marketed in the United States. Some antipsychotics are not firmly placed in either first-generation or second-generation classes.
  • # denotes drugs that have been withdrawn worldwide.

First-Generation (Typical)

  • Butyrophenones:
    • Benperidol‡
    • Bromperidol†
    • Droperidol‡
    • Haloperidol
    • Moperone (discontinued)†
    • Pipamperone (discontinued)†
    • Timiperone †
  • Diphenylbutylpiperidines:
    • Fluspirilene ‡
    • Penfluridol ‡
    • Pimozide
  • Phenothiazines:
    • Acepromazine † – although it is mostly used in veterinary medicine.
    • Chlorpromazine
    • Cyamemazine †
    • Dixyrazine †
    • Fluphenazine
    • Levomepromazine‡
    • Mesoridazine (discontinued)†
    • Perazine
    • Pericyazine‡
    • Perphenazine
    • Pipotiazine ‡
    • Prochlorperazine
    • Promazine (discontinued)
    • Promethazine
    • Prothipendyl †
    • Thioproperazine‡ (only English-speaking country it is available in is Canada)
    • Thioridazine (discontinued)
    • Trifluoperazine
    • Triflupromazine (discontinued)†
  • Thioxanthenes:
    • Chlorprothixene †
    • Clopenthixol
    • Flupentixol ‡
    • Thiothixene
    • Zuclopenthixol ‡

Disputed/Unknown

This category is for drugs that have been called both first and second-generation, depending on the literature being used.

  • Benzamides:
    • Sulpiride ‡
    • Sultopride †
    • Veralipride †
  • Tricyclics:
    • Carpipramine †
    • Clocapramine †
    • Clorotepine †
    • Clotiapine ‡
    • Loxapine
    • Mosapramine †
  • Others:
    • Molindone #

Second-Generation (Atypical)

  • Benzamides:
    • Amisulpride ‡ – Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias.
    • Nemonapride † – Used in Japan.
    • Remoxipride # – Has a risk of causing aplastic anaemia and, hence, has been withdrawn from the market worldwide. It has also been found to possess relatively low (virtually absent) potential to induce hyperprolactinaemia and extrapyramidal symptoms, likely attributable to its comparatively weak binding to (and, hence, rapid dissociation from) the D2 receptor.
    • Sultopride – An atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2 and D3 receptor antagonist.
  • Benzisoxazoles/benzisothiazoles:
    • Iloperidone – Approved by the FDA in 2009, it is fairly well tolerated, although hypotension, dizziness, and somnolence were very common side effects. Has not received regulatory approval in other countries, however.
    • Lurasidone – Approved by the FDA for schizophrenia and bipolar depression, and for use as schizophrenia treatment in Canada.
    • Paliperidone – Primary, active metabolite of risperidone that was approved in 2006.
    • Paliperidone palmitate – Long-acting version of paliperidone for once-monthly injection.
    • Perospirone † – Has a higher incidence of extrapyramidal side effects than other atypical antipsychotics.
    • Risperidone – Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder.
    • Ziprasidone – Approved in 2004 to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval.
  • Butyrophenones:
    • Melperone † – Only used in a few European countries. No English-speaking country has licensed it to date.
    • Lumateperone.
  • Phenylpiperazines/quinolinones:
    • Aripiprazole – Partial agonist at the D2 receptor unlike almost all other clinically-utilized antipsychotics.
    • Aripiprazole lauroxil – Long-acting version of aripiprazole for injection.
    • Brexpiprazole – Partial agonist of the D2 receptor. Successor of aripiprazole.
    • Cariprazine – A D3-preferring D2/D3 partial agonist.
  • Tricyclics:
    • Asenapine – Used for the treatment of schizophrenia and acute mania associated with bipolar disorder.
    • Clozapine – Requires routine laboratory monitoring of complete blood counts every one to four weeks due to the risk of agranulocytosis. It has unparalleled efficacy in the treatment of treatment-resistant schizophrenia.
    • Olanzapine – Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Used as an adjunct to antidepressant therapy, either alone or in combination with fluoxetine as Symbyax.
    • Quetiapine – Used primarily to treat bipolar disorder and schizophrenia. Also used and licensed in a few countries (including Australia, the United Kingdom and the United States) as an adjunct to antidepressant therapy in patients with major depressive disorder. It is the only antipsychotic that has demonstrated efficacy as a monotherapy for the treatment of major depressive disorder. It indirectly serves as a norepinephrine reuptake inhibitor by means of its active metabolite, norquetiapine.
    • Zotepine – An atypical antipsychotic indicated for acute and chronic schizophrenia. It is still used in Japan and was once used in Germany but it was discontinued.†
  • Others:
    • Blonanserin – Approved by the PMDA in 2008. Used in Japan and South Korea.
    • Pimavanserin – A selective 5-HT2A receptor antagonist approved for the treatment of Parkinson’s disease psychosis in 2016.
    • Sertindole ‡ – Developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it is believed to have antagonist activity at dopamine and serotonin receptors in the brain.

Mechanism of Action

Antipsychotic drugs such as haloperidol and chlorpromazine tend to block dopamine D2 receptors in the dopaminergic pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. Decreased dopamine release in the prefrontal cortex, and excess dopamine release in other pathways, are associated with psychotic episodes in schizophrenia and bipolar disorder. In addition to the antagonistic effects of dopamine, antipsychotics (in particular atypical neuroleptics) also antagonise 5-HT2A receptors. Different alleles of the 5-HT2A receptor have been associated with schizophrenia and other psychoses, including depression. Higher concentrations of 5-HT2A receptors in cortical and subcortical areas, in particular in the right caudate nucleus have been historically recorded.

Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some unwanted side effects that the typical antipsychotics can produce (see above). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side-effects.

Atypical antipsychotic drugs have a similar blocking effect on D2 receptors; however, most also act on serotonin receptors, especially 5-HT2A and 5-HT2C receptors. Both clozapine and quetiapine appear to bind just long enough to elicit antipsychotic effects but not long enough to induce extrapyramidal side effects and prolactin hypersecretion. 5-HT2A antagonism increases dopaminergic activity in the nigrostriatal pathway, leading to a lowered extrapyramidal side effect liability among the atypical antipsychotics.

Society and Culture

Terminology

The term major tranquiliser was used for older antipsychotic drugs. The term neuroleptic is often used as a synonym for antipsychotic, even though – strictly speaking – the two terms are not interchangeable. Antipsychotic drugs are a subgroup of neuroleptic drugs, because the latter have a wider range of effects.

Antipsychotics are a type of psychoactive or psychotropic medication.

Sales

Antipsychotics were once among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008. By 2003 in the US, an estimated 3.21 million patients received antipsychotics, worth an estimated $2.82 billion. Over 2/3 of prescriptions were for the newer, more expensive atypicals, each costing on average $164 per year, compared to $40 for the older types. By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.

Overprescription

Antipsychotics in the nursing home population are often overprescribed, often for the purposes of making it easier to handle dementia patients. Federal efforts to reduce the use of antipsychotics in US nursing homes has led to a nationwide decrease in their usage in 2012.

Legal

Antipsychotics are sometimes administered as part of compulsory psychiatric treatment via inpatient (hospital) commitment or outpatient commitment.

Formulations

They may be administered orally or, in some cases, through long-acting (depot) injections administered in the dorsgluteal, ventrogluteal or deltoid muscle. Short-acting parenteral formulations also exist, which are generally reserved for emergencies or when oral administration is otherwise impossible. The oral formulations include immediate release, extended release, and orally disintegrating products (which are not sublingual, and can help ensure that medications are swallowed instead of “cheeked”). Sublingual products (e.g. asenapine) also exist, which must be held under the tongue for absorption. The first transdermal formulation of an antipsychotic (transdermal asenapine, marketed as Secuado), was FDA-approved in 2019.

Recreational Use

Certain second-generation antipsychotics are misused or abused for their sedative, tranquilising, and (paradoxically) “hallucinogenic” effects. The most commonly second-generation antipsychotic implicated is quetiapine. In case reports, quetiapine has been abused in doses taken by mouth (which is how the drug is available from the manufacturer), but also crushed and insufflated or mixed with water for injection into a vein. Olanzapine, another sedating second-generation antipsychotic, has also been misused for similar reasons. There is no standard treatment for antipsychotic abuse, though switching to a second-generation antipsychotic with less abuse potential (e.g. aripiprazole) has been used.

Controversy

Joanna Moncrieff has argued that antipsychotic drug treatment is often undertaken as a means of control rather than to treat specific symptoms experienced by the patient.

Use of this class of drugs has a history of criticism in residential care. As the drugs used can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff. In an official review commissioned by UK government ministers it was reported that the needless use of antipsychotic medication in dementia care was widespread and was linked to 1800 deaths per year. In the US, the government has initiated legal action against the pharmaceutical company Johnson & Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic risperidone (Risperdal) in nursing homes.

There has also been controversy about the role of pharmaceutical companies in marketing and promoting antipsychotics, including allegations of downplaying or covering up adverse effects, expanding the number of conditions or illegally promoting off-label usage; influencing drug trials (or their publication) to try to show that the expensive and profitable newer atypicals were superior to the older cheaper typicals that were out of patent. Following charges of illegal marketing, settlements by two large pharmaceutical companies in the US set records for the largest criminal fines ever imposed on corporations. One case involved Eli Lilly and Company’s antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic, Geodon. In addition, Astrazeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal investigations of its marketing practices. By expanding the conditions for which they were indicated, Astrazeneca’s Seroquel and Eli Lilly’s Zyprexa had become the biggest selling antipsychotics in 2008 with global sales of $5.5 billion and $5.4 billion respectively.

Harvard medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate investigation found that Biederman also received $1.6 million in speaking and consulting fees between 2000 and 2007 – some of them undisclosed to Harvard – from companies including makers of antipsychotic drugs prescribed for children with bipolar disorder. Johnson & Johnson gave more than $700,000 to a research centre that was headed by Biederman from 2002 to 2005, where research was conducted, in part, on Risperdal, the company’s antipsychotic drug. Biederman has responded saying that the money did not influence him and that he did not promote a specific diagnosis or treatment.

Pharmaceutical companies have also been accused of attempting to set the mental health agenda through activities such as funding consumer advocacy groups.

Special Populations

It is recommended that persons with dementia who exhibit behavioural and psychological symptoms should not be given antipsychotics before trying other treatments. When taking antipsychotics this population has increased risk of cerebrovascular effects, parkinsonism or extrapyramidal symptoms, sedation, confusion and other cognitive adverse effects, weight gain, and increased mortality. Physicians and caretakers of persons with dementia should try to address symptoms including agitation, aggression, apathy, anxiety, depression, irritability, and psychosis with alternative treatments whenever antipsychotic use can be replaced or reduced. Elderly persons often have their dementia treated first with antipsychotics and this is not the best management strategy.

What is Neurosis?

Introduction

Neurosis is a class of functional mental disorders involving chronic distress, but neither delusions nor hallucinations. The term is no longer used by the professional psychiatric community in the United States, having been eliminated from the Diagnostic and Statistical Manual of Mental Disorders (DSM) in 1980 with the publication of DSM III. However, it is still used in the ICD-10 Chapter V F40-48.

Neurosis should not be mistaken for psychosis, which refers to a loss of touch with reality. Nor should it be mistaken for neuroticism, a fundamental personality trait proposed in the Big Five personality traits theory.

Etymology

The term is derived from the Greek word neuron (νεῦρον, ‘nerve’) and the suffix -osis (-ωσις, ‘diseased’ or ‘abnormal condition’).

The term neurosis was coined by Scottish doctor William Cullen in 1769 to refer to “disorders of sense and motion” caused by a “general affection of the nervous system.” Cullen used the term to describe various nervous disorders and symptoms that could not be explained physiologically. Physical features, however, were almost inevitably present, and physical diagnostic tests, such as exaggerated knee-jerks, loss of the gag reflex and dermatographia, were used into the 20th century. The meaning of the term was redefined by Carl Jung and Sigmund Freud over the early and middle 20th century, and has continued to be used in psychology and philosophy.

The DSM eliminated the neurosis category in 1980, because of a decision by its editors to provide descriptions of behaviour rather than descriptions of hidden psychological mechanisms. This change has been controversial. Likewise, according to the American Heritage Medical Dictionary, neurosis is “no longer used in psychiatric diagnosis.”

Symptoms and Causes

Neurosis may be defined simply as a “poor ability to adapt to one’s environment, an inability to change one’s life patterns, and the inability to develop a richer, more complex, more satisfying personality.” There are many different neuroses, including:

According to C. George Boeree, professor emeritus at Shippensburg University, the symptoms of neurosis may involve:

… anxiety, sadness or depression, anger, irritability, mental confusion, low sense of self-worth, etc., behavioral symptoms such as phobic avoidance, vigilance, impulsive and compulsive acts, lethargy, etc., cognitive problems such as unpleasant or disturbing thoughts, repetition of thoughts and obsession, habitual fantasizing, negativity and cynicism, etc. Interpersonally, neurosis involves dependency, aggressiveness, perfectionism, schizoid isolation, socio-culturally inappropriate behaviors, etc.

Jungian Theory

Carl Jung found his approach particularly effective for patients who are well adjusted by social standards but are troubled by existential questions. Jung claims to have “frequently seen people become neurotic when they content themselves with inadequate or wrong answers to the questions of life”. Accordingly, the majority of his patients “consisted not of believers but of those who had lost their faith”. Contemporary man, according to Jung,

…is blind to the fact that, with all his rationality and efficiency, he is possessed by ‘powers’ that are beyond his control. His gods and demons have not disappeared at all; they have merely got new names. They keep him on the run with restlessness, vague apprehensions, psychological complications, an insatiable need for pills, alcohol, tobacco, food — and, above all, a large array of neuroses.

Jung found that the unconscious finds expression primarily through an individual’s inferior psychological function, whether it is thinking, feeling, sensation, or intuition. The characteristic effects of a neurosis on the dominant and inferior functions are discussed in his Psychological Types. Jung also found collective neuroses in politics: “Our world is, so to speak, dissociated like a neurotic.”

Psychoanalytic Theory

According to psychoanalytic theory, neuroses may be rooted in ego defence mechanisms, though the two concepts are not synonymous. Defence mechanisms are a normal way of developing and maintaining a consistent sense of self (i.e. an ego). However, only those thoughts and behaviours that produce difficulties in one’s life should be called neuroses.

A neurotic person experiences emotional distress and unconscious conflict, which are manifested in various physical or mental illnesses; the definitive symptom being anxiety. Neurotic tendencies are common and may manifest themselves as acute or chronic anxiety, depression, an obsessive compulsive disorder, a phobia, or a personality disorder.

Horney’s Theory

In her final book, Neurosis and Human Growth, Karen Horney lays out a complete theory of the origin and dynamics of neurosis. In her theory, neurosis is a distorted way of looking at the world and at oneself, which is determined by compulsive needs rather than by a genuine interest in the world as it is. Horney proposes that neurosis is transmitted to a child from his or her early environment and that there are many ways in which this can occur:

When summarized, they all boil down to the fact that the people in the environment are too wrapped up in their own neuroses to be able to love the child, or even to conceive of him as the particular individual he is; their attitudes toward him are determined by their own neurotic needs and responses.

The child’s initial reality is then distorted by his or her parents’ needs and pretences. Growing up with neurotic caretakers, the child quickly becomes insecure and develops basic anxiety. To deal with this anxiety, the child’s imagination creates an idealised self-image:

Each person builds up his personal idealized image from the materials of his own special experiences, his earlier fantasies, his particular needs, and also his given faculties. If it were not for the personal character of the image, he would not attain a feeling of identity and unity. He idealizes, to begin with, his particular “solution” of his basic conflict: compliance becomes goodness, love, saintliness; aggressiveness becomes strength, leadership, heroism, omnipotence; aloofness becomes wisdom, self-sufficiency, independence. What—according to his particular solution—appear as shortcomings or flaws are always dimmed out or retouched.

Once he identifies himself with his idealised image, a number of effects follow. He will make claims on others and on life based on the prestige he feels entitled to because of his idealised self-image. He will impose a rigorous set of standards upon himself in order to try to measure up to that image. He will cultivate pride, and with that will come the vulnerabilities associated with pride that lacks any foundation. Finally, he will despise himself for all his limitations. Vicious circles will operate to strengthen all of these effects.

Eventually, as he grows to adulthood, a particular “solution” to all the inner conflicts and vulnerabilities will solidify. He will be either:

  • Expansive, displaying symptoms of narcissism, perfectionism, or vindictiveness;
  • Self-effacing and compulsively compliant, displaying symptoms of neediness or codependence; or
  • Resigned, displaying schizoid tendencies.

In Horney’s view, mild anxiety disorders and full-blown personality disorders all fall under her basic scheme of neurosis as variations in the degree of severity and in the individual dynamics. The opposite of neurosis is a condition Horney calls self-realisation, a state of being in which the person responds to the world with the full depth of his or her spontaneous feelings, rather than with anxiety-driven compulsion. Thus the person grows to actualize his or her inborn potentialities. Horney compares this process to an acorn that grows and becomes a tree: the acorn has had the potential for a tree inside it all along.

What is Substance-Induced Psychosis?

Introduction

Substance-induced psychosis (commonly known as toxic psychosis or drug-induced psychosis) is a form of psychosis that is attributed to substance use.

It is a psychosis that results from the effects of chemicals or drugs, including those produced by the body itself. Various psychoactive substances have been implicated in causing or worsening psychosis in users.

Signs and Symptoms

Psychosis manifests as disorientation, visual hallucinations and/or haptic hallucinations. It is a state in which a person’s mental capacity to recognise reality, communicate, and relate to others is impaired, thus interfering with the capacity to deal with life demands. While there are many types of psychosis, substance-induced psychosis can be pinpointed to specific chemicals.

Transition to schizophrenia

A 2019 systematic review and meta-analysis by Murrie and colleagues found that the pooled proportion of transition from substance-induced psychosis to schizophrenia was 25% (95% CI 18%-35%), compared with 36% (95% CI 30%-43%) for brief, atypical and not otherwise specified psychoses.

Type of substance was the primary predictor of transition from drug-induced psychosis to schizophrenia, with highest rates associated with cannabis (6 studies, 34%, CI 25%-46%), hallucinogens (3 studies, 26%, CI 14%-43%) and amphetamines (5 studies, 22%, CI 14%-34%). Lower rates were reported for opioid (12%), alcohol (10%) and sedative (9%) induced psychoses.

Transition rates were slightly lower in older cohorts but were not affected by sex, country of the study, hospital or community location, urban or rural setting, diagnostic methods, or duration of follow-up.

Substances

Psychotic states may occur after using a variety of legal and illegal substances. Usually such states are temporary and reversible, with fluoroquinolone-induced psychosis being a notable exception. Substances whose use or withdrawal are implicated in psychosis include the following:

International Classification of Diseases

Psychoactive substance-induced psychotic disorders outlined within the ICD-10 codes F10.5-F19.5:

  • F10.5 alcohol:
    • Alcohol is a common cause of psychotic disorders or episodes, which may occur through acute intoxication, chronic alcoholism, withdrawal, exacerbation of existing disorders, or acute idiosyncratic reactions.
    • Research has shown that excessive alcohol use causes an 8-fold increased risk of psychotic disorders in men and a 3 fold increased risk of psychotic disorders in women.
    • While the vast majority of cases are acute and resolve fairly quickly upon treatment and/or abstinence, they can occasionally become chronic and persistent.
    • Alcoholic psychosis is sometimes misdiagnosed as another mental illness such as schizophrenia.
  • F11.5 opioid:
    • Studies show stronger opioids such as Fentanyl are more likely to cause psychosis and hallucinations.
  • F12.5 cannabinoid:
    • Some studies indicate that cannabis may trigger full-blown psychosis.
    • Recent studies have found an increase in risk for psychosis in cannabis users.
  • F13.5 sedatives/hypnotics (barbiturates; benzodiazepines):
    • It is also important to this topic to understand the paradoxical effects of some sedative drugs.
    • Serious complications can occur in conjunction with the use of sedatives creating the opposite effect as to that intended.
    • Malcolm Lader at the Institute of Psychiatry in London estimates the incidence of these adverse reactions at about 5%, even in short-term use of the drugs.
    • The paradoxical reactions may consist of depression, with or without suicidal tendencies, phobias, aggressiveness, violent behaviour and symptoms sometimes misdiagnosed as psychosis.
    • However, psychosis is more commonly related to the benzodiazepine withdrawal syndrome.
  • F14.5 cocaine.
  • F15.5 other stimulants:
    • Amphetamines; methamphetamine; and methylphenidate.
    • Refer to stimulant psychosis.
  • F16.5 hallucinogens (LSD and others).
  • F18.5 volatile solvents (volatile inhalants):
    • Toluene, found in glue, paint, thinner, etc. See also toluene toxicity.
    • Butane.
    • Gasoline (petrol).

F17.5 is reserved for tobacco-induced psychosis, but is traditionally not associated with the induction of psychosis.

The code F15.5 also includes caffeine-induced psychosis, despite not being specifically listed in the DSM-IV. However, there is evidence that caffeine, in extreme acute doses or when taken in excess for long periods of time, may induce psychosis.

Medication

  • Fluoroquinolone drugs, fluoroquinolone use has been linked to serious cases of toxic psychosis that have been reported to be irreversible and permanent, see adverse effects of fluoroquinolones. The related quinoline derivative mefloquine (Lariam) has also been associated with psychosis.
  • Some over-the-counter drugs, including:
    • Dextromethorphan (DXM) at high doses.
    • Certain antihistamines at high doses.
    • Cold Medications (i.e. containing Phenylpropanolamine, or PPA)
  • Prescription drugs:
    • Prednisone and other corticosteroids.
    • Isotretinoin
    • Anticholinergic drugs.
      • Atropine.
      • Scopolamine.
    • Antidepressants.
    • L-dopa.
    • Antiepileptics.
  • Antipsychotics, in an idiosyncratic reaction.
  • Antimalarials.
  • Mepacrine.

Other drugs illicit in America

Other drugs illegal in America (not listed above), including:

  • MDMA (ecstasy).
  • Phencyclidine (PCP).
  • Ketamine.
  • Synthetic research chemicals used recreationally, including:
    • JWH-018 and some other synthetic cannabinoids, or mixtures containing them (e.g. “Spice”, “Kronic”, “MNG” or “Mr. Nice Guy”, “Relaxinol”, etc.).
    • Various “JWH-XXX” compounds in “Spice” or “Incense” have also been found and have been found to cause psychosis in some people.
  • Mephedrone and related amphetamine-like drugs sold as “bath salts” or “plant food”.

Plants

  • Hawaiian baby woodrose (contains ergine).
  • Morning glory seeds (contains ergine).
  • Jimson weed (Datura, angel’s trumpet, thorn apple).
  • Belladonna (deadly nightshade).
  • Salvia divinorum.

Nonmedicinal Substances

Substances chiefly nonmedicinal as to source:

  • Carbon monoxide, carbon dioxide, and carbon disulfide.
  • Heavy metals.
  • Organophosphate insecticides.
  • Sarin and other nerve gases.
  • Tetraethyllead.
  • Aniline.
  • Acetone and other ketones.
  • Antifreeze – a mixture of ethylene glycol and other glycols.
  • Arsenic and its compounds.

Reference

Murrie, B., Lappin, J., Large, M. & Sara, G. (2019) Transition of Substance-Induced, Brief, and Atypical Psychoses to Schizophrenia: A Systematic Review and Meta-analysis. Schizophrenia Bulletin. 46(3), pp.505-516. doi:10.1093/schbul/sbz102.

What is Open Dialogue?

Introduction

Open Dialogue is an alternative approach for treating psychosis as well as other mental health disorders developed in the 1980s in Finland by Yrjö Alanen and his collaborators.

Background

Open dialogue interventions are currently being trialed in several other countries including Australia, Austria, Denmark, Germany, Italy, Norway, Poland, the United Kingdom, and the United States.

Key principles of the open dialogue method include: the participation of friends and family, responding to the client’s utterances (which may seem nonsensical in the case of pyschosis), trying to make meaning of what a client has to say, and “tolerating uncertainty”.

Theoretical Basis

In a paper illustrating the Open dialogue method Seikkula, Alakar and Aaltonen postulate that “from the social constructionist point of view, psychosis can be seen as one way of dealing with terrifying experience in one’s life that do not have language other than the one of hallucinations and delusions” and that “psychotic reactions should be seen [as] attempts to make sense of one’s experiences that are so heavy that they have made it impossible to construct a rational spoken narrative” arguing that people may talk about such experiences in metaphor.

They offer a model that “psychotic reactions greatly resemble traumatic experiences” with experiences of victimisation “not being stored in the part of the memory system that promotes sense-making”. Postulating that “an open dialogue, without any pre-planned themes or forms seems to be important in enabling the construction of a new language in which to express difficult events in one’s life.”

This understanding differs radically from common psychiatric models of psychosis that view it as being caused by a biological process in the brain, such as the dopamine hypothesis of schizophrenia.

Effectiveness

A systematic review of academic publications on the topic in 2018 concluded that: “most studies were highly biased and of low quality” and that “further studies are needed in a real-world setting to explore how and why [open dialogue] works.”

Linking Age, COVID-19 & First Episodes Psychosis

Research Paper Title

Impact of the first Covid-19 pandemic wave on first episode psychosis in Milan, Italy.

Background

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic appears to increase risk for mental illness, either directly due to inflammation caused by the virus or indirectly due to related psychosocial stress, resulting in the development of both anxious-depressive and psychotic symptoms.

The purpose of the present study was to assess the frequency and characteristics of all patients with First Episodes Psychosis (FEP) without COVID-19 infection hospitalised in the first four months since lockdown in Milan.

Methods

The researchers recruited sixty-two patients hospitalised between 08 March to 08 July 2020 versus those first hospitalised in the same period in 2019.

The two subgroups were compared for sociodemographic variables and clinical characteristics of the episodes.

Results

Patients with FEP in 2020 were significantly older than patients with FEP in 2021, and presented with significantly less substances abuse.

Interestingly, patients presenting with FEP in 2020 were significantly older than patients with FEP in 2019.

Conclusions

These data are compatible with the greater vulnerability to stressful factors during the pandemic, as well as with the greater concern regarding a possible COVID-19 infection producing brain damage causing the FEP.

Reference

Esposito, C.M., D’Agostino, A., Osso, B.D., Fiorentini, A., Prunas, C., Callari, A., Oldani, L., Fontana, E., Gargano, G., Viscardi, B., Giordano, B., D’Angelo, S., Widenmann, F., Macellaro, M., Giorgetti, F., Turtulici, N., Gambini, O. & Brambilla, P. (2021) Impact of the first Covid-19 pandemic wave on first episode psychosis in Milan, Italy. Psychiatry Research. doi: 10.1016/j.psychres.2021.113802. Online ahead of print.

What is Psychosis?

Introduction

Psychosis is an abnormal condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations. Other symptoms may include incoherent speech and behaviour that is inappropriate for the situation. There may also be sleep problems, social withdrawal, lack of motivation, and difficulties carrying out daily activities. Psychosis can have serious outcomes.

Psychosis has many different causes. These include mental illness, such as schizophrenia or bipolar disorder, sleep deprivation, some medical conditions, certain medications, and drugs such as alcohol or cannabis. One type, known as postpartum psychosis, can occur after giving birth. The neurotransmitter dopamine is believed to play a role. Acute psychosis is considered primary if it results from a psychiatric condition and secondary if it is caused by a medical condition. The diagnosis of a mental illness requires excluding other potential causes. Testing may be done to check for central nervous system diseases, toxins, or other health problems as a cause.

Treatment may include antipsychotic medication, counselling, and social support. Early treatment appears to improve outcomes. Medications appear to have a moderate effect. Outcomes depend on the underlying cause. In the United States about 3% of people develop psychosis at some point in their lives. The condition has been described since at least the 4th century BC by Hippocrates and possibly as early as 1500 BC in the Egyptian Ebers Papyrus.

Signs and Symptoms

Hallucinations

A hallucination is defined as sensory perception in the absence of external stimuli. Hallucinations are different from illusions and perceptual distortions, which are the misperception of external stimuli. Hallucinations may occur in any of the senses and take on almost any form. They may consist of simple sensations (such as lights, colours, sounds, tastes, or smells) or more detailed experiences (such as seeing and interacting with animals and people, hearing voices, and having complex tactile sensations). Hallucinations are generally characterised as being vivid and uncontrollable. Auditory hallucinations, particularly experiences of hearing voices, are the most common and often prominent feature of psychosis.

Up to 15% of the general population may experience auditory hallucinations (though not all are due to psychosis). The prevalence of auditory hallucinations in patients with schizophrenia is generally put around 70%, but may go as high as 98%. Reported prevalence in bipolar disorder ranges between 11% and 68%. During the early 20th century, auditory hallucinations were second to visual hallucinations in frequency, but they are now the most common manifestation of schizophrenia, although rates vary between cultures and regions. Auditory hallucinations are most commonly intelligible voices. When voices are present, the average number has been estimated at three. Content, like frequency, differs significantly, especially across cultures and demographics. People who experience auditory hallucinations can frequently identify the loudness, location of origin, and may settle on identities for voices. Western cultures are associated with auditory experiences concerning religious content, frequently related to sin. Hallucinations may command a person to do something potentially dangerous when combined with delusions.

Extracampine hallucinations are perceptions outside the sensory apparatus for example a sound is perceived through the knee, or a visual extracampine hallucination is seeing by sensing that somebody is near to you, that is not there.

Visual hallucinations occur in roughly a third of people with schizophrenia, although rates as high as 55% are reported. The prevalence in bipolar disorder is around 15%. Content frequently involves animate objects, although perceptual abnormalities such as changes in lighting, shading, streaks, or lines may be seen. Visual abnormalities may conflict with proprioceptive information, and visions may include experiences such as the ground tilting. Lilliputian hallucinations are less common in schizophrenia, and occur more frequently in various types of encephalopathy such as peduncular hallucinosis.

A visceral hallucination, also called a cenesthetic hallucination, is characterised by visceral sensations in the absence of stimuli. Cenesthetic hallucinations may include sensations of burning, or re-arrangement of internal organs.

Delusions

Psychosis may involve delusional beliefs. A delusion is commonly defined as an unrelenting sense of certainty maintained despite strong contradictory evidence. Delusions are context- and culture-dependent: a belief which inhibits critical functioning and is widely considered delusional in one population may be common (and even adaptive) in another, or in the same population at a later time. Since normative views may themselves contradict available evidence, a belief need not contravene cultural standards in order to be considered delusional.

Prevalence in schizophrenia is generally considered at least 90%, and around 50% in bipolar disorder.

The DSM-5 characterises certain delusions as “bizarre” if they are clearly implausible, or are incompatible with the surrounding cultural context. The concept of bizarre delusions has many criticisms, the most prominent being judging its presence is not highly reliable even among trained individuals.

A delusion may involve diverse thematic content. The most common type is a persecutory delusion, in which a person believes that some entity is attempting to harm them. Others include delusions of reference (the belief that some element of one’s experience represents a deliberate and specific act by or message from some other entity), delusions of grandeur (the belief that one possesses special power or influence beyond one’s actual limits), thought broadcasting (the belief that one’s thoughts are audible) and thought insertion (the belief that one’s thoughts are not one’s own).

The subject matter of delusions seems to reflect the current culture in a particular time and location. For example in the US, during the early 1900s syphilis was a common topic, during the second world war Germany, during the cold war communists, and in recent years technology has been a focus. Some psychologists, such as those who practice the Open Dialogue method believe that the content of psychosis represent an underlying thought process that may, in part, be responsible for psychosis, though the accepted medical position is that psychosis is due to a brain disorder.

Historically, Karl Jaspers classified psychotic delusions into primary and secondary types. Primary delusions are defined as arising suddenly and not being comprehensible in terms of normal mental processes, whereas secondary delusions are typically understood as being influenced by the person’s background or current situation (e.g. ethnicity; also religious, superstitious, or political beliefs).

Disorganisation

Disorganisation is split into disorganised speech or thinking, and grossly disorganised motor behaviour. Disorganised speech or thinking, also called formal thought disorder, is disorganisation of thinking that is inferred from speech. Characteristics of disorganised speech include rapidly switching topics, called derailment or loose association; switching to topics that are unrelated, called tangential thinking; incomprehensible speech, called word salad or incoherence. Disorganised motor behaviour includes repetitive, odd, or sometimes purposeless movement. Disorganised motor behaviour rarely includes catatonia, and although it was a historically prominent symptom, it is rarely seen today. Whether this is due to historically used treatments or the lack thereof is unknown.

Catatonia describes a profoundly agitated state in which the experience of reality is generally considered impaired. There are two primary manifestations of catatonic behaviour. The classic presentation is a person who does not move or interact with the world in any way while awake. This type of catatonia presents with waxy flexibility. Waxy flexibility is when someone physically moves part of a catatonic person’s body and the person stays in the position even if it is bizarre and otherwise non-functional (such as moving a person’s arm straight up in the air and the arm staying there).

The other type of catatonia is more of an outward presentation of the profoundly agitated state described above. It involves excessive and purposeless motor behaviour, as well as extreme mental preoccupation that prevents an intact experience of reality. An example is someone walking very fast in circles to the exclusion of anything else with a level of mental preoccupation (meaning not focused on anything relevant to the situation) that was not typical of the person prior to the symptom onset. In both types of catatonia there is generally no reaction to anything that happens outside of them. It is important to distinguish catatonic agitation from severe bipolar mania, although someone could have both.

Negative Symptoms

Negative symptoms include reduced emotional expression, decreased motivation, and reduced spontaneous speech. Afflicted individuals lack interest and spontaneity, and have the inability to feel pleasure.

Psychosis in Adolescents

Psychosis is rare in adolescents. Young people who have psychosis may have trouble connecting with the world around them and may experience hallucinations and/or delusions. Adolescents with psychosis may also have cognitive deficits that may make it harder for the youth to socialise and work. Potential impairments include the speed of mental processing, ability to focus without getting distracted (attention span), and problems with their verbal memory.

Causes

The symptoms of psychosis may be caused by serious psychiatric disorders such as schizophrenia, a number of medical illnesses, and trauma. Psychosis may also be temporary or transient, and be caused by medications or substance abuse (substance-induced psychosis).

Normal States

Brief hallucinations are not uncommon in those without any psychiatric disease. Causes or triggers include:

  • Falling asleep and waking: hypnagogic and hypnopompic hallucinations, which are entirely normal.
  • Bereavement, in which hallucinations of a deceased loved one are common.
  • Severe sleep deprivation.
  • Stress.

Trauma

Traumatic life events have been linked with an elevated risk in developing psychotic symptoms. Childhood trauma has specifically been shown to be a predictor of adolescent and adult psychosis. Approximately 65% of individuals with psychotic symptoms have experienced childhood trauma (e.g. physical or sexual abuse, physical or emotional neglect). Increased individual vulnerability toward psychosis may interact with traumatic experiences promoting an onset of future psychotic symptoms, particularly during sensitive developmental periods. Importantly, the relationship between traumatic life events and psychotic symptoms appears to be dose-dependent in which multiple traumatic life events accumulate, compounding symptom expression and severity. This suggests trauma prevention and early intervention may be an important target for decreasing the incidence of psychotic disorders and ameliorating its effects.

Psychiatric Disorder

From a diagnostic standpoint, organic disorders were believed to be caused by physical illness affecting the brain (that is, psychiatric disorders secondary to other conditions) while functional disorders were considered disorders of the functioning of the mind in the absence of physical disorders (that is, primary psychological or psychiatric disorders). Subtle physical abnormalities have been found in illnesses traditionally considered functional, such as schizophrenia. The DSM-IV-TR avoids the functional/organic distinction, and instead lists traditional psychotic illnesses, psychosis due to general medical conditions, and substance-induced psychosis.

Primary psychiatric causes of psychosis include the following:

  • Schizophrenia and schizophreniform disorder.
  • Affective (mood) disorders, including major depression, and severe depression or mania in bipolar disorder (manic depression).
    • People experiencing a psychotic episode in the context of depression may experience persecutory or self-blaming delusions or hallucinations, while people experiencing a psychotic episode in the context of mania may form grandiose delusions.
  • Schizoaffective disorder, involving symptoms of both schizophrenia and mood disorders.
  • Brief psychotic disorder, or acute/transient psychotic disorder.
  • Delusional disorder (persistent delusional disorder).
  • Chronic hallucinatory psychosis.

Psychotic symptoms may also be seen in:

  • Schizotypal personality disorder.
  • Certain personality disorders at times of stress (including paranoid personality disorder, schizoid personality disorder, and borderline personality disorder).
  • Major depressive disorder in its severe form, although it is possible and more likely to have severe depression without psychosis.
  • Bipolar disorder in the manic and mixed episodes of bipolar I disorder and depressive episodes of both bipolar I and bipolar II; however, it is possible to experience such states without psychotic symptoms.
  • Posttraumatic stress disorder.
  • Induced delusional disorder.
  • Sometimes in obsessive compulsive disorder.
  • Juvenile‐onset affective disorder.
  • Dissociative disorders, due to many overlapping symptoms, careful differential diagnosis includes especially dissociative identity disorder.

Stress is known to contribute to and trigger psychotic states. A history of psychologically traumatic events, and the recent experience of a stressful event, can both contribute to the development of psychosis. Short-lived psychosis triggered by stress is known as brief reactive psychosis, and patients may spontaneously recover normal functioning within two weeks. In some rare cases, individuals may remain in a state of full-blown psychosis for many years, or perhaps have attenuated psychotic symptoms (such as low intensity hallucinations) present at most times.

Neuroticism is an independent predictor of the development of psychosis.

Subtypes

Subtypes of psychosis include:

  • Menstrual psychosis, including circa-mensual (approximately monthly) periodicity, in rhythm with the menstrual cycle.
  • Postpartum psychosis, occurring shortly after giving birth.
  • Monothematic delusions.
  • Myxedematous psychosis.
  • Stimulant psychosis.
  • Tardive psychosis.
  • Shared psychosis.

Cycloid Psychosis

Cycloid psychosis is a psychosis that progresses from normal to full-blown, usually between a few hours to days, not related to drug intake or brain injury. The cycloid psychosis has a long history in European psychiatry diagnosis. The term “cycloid psychosis” was first used by Karl Kleist in 1926. Despite the significant clinical relevance, this diagnosis is neglected both in literature and in nosology. The cycloid psychosis has attracted much interest in the international literature of the past 50 years, but the number of scientific studies have greatly decreased over the past 15 years, possibly partly explained by the misconception that the diagnosis has been incorporated in current diagnostic classification systems. The cycloid psychosis is therefore only partially described in the diagnostic classification systems used. Cycloid psychosis is nevertheless its own specific disease that is distinct from both the manic-depressive disorder, and from schizophrenia, and this despite the fact that the cycloid psychosis can include both bipolar (basic mood shifts) as well as schizophrenic symptoms. The disease is an acute, usually self-limiting, functionally psychotic state, with a very diverse clinical picture that almost consistently is characterized by the existence of some degree of confusion or distressing perplexity, but above all, of the multifaceted and diverse expressions the disease takes. The main features of the disease is thus that the onset is acute, contains the multifaceted picture of symptoms and typically reverses to a normal state and that the long-term prognosis is good. In addition, diagnostic criteria include at least four of the following symptoms:

  • Confusion.
  • Mood-incongruent delusions.
  • Hallucinations.
  • Pan-anxiety, a severe anxiety not bound to particular situations or circumstances.
  • Happiness or ecstasy of high degree.
  • Motility disturbances of akinetic or hyperkinetic type.
  • Concern with death.
  • Mood swings to some degree, but less than what is needed for diagnosis of an affective disorder.

Cycloid psychosis occurs in people of generally 15-50 years of age.

Medical Conditions

A very large number of medical conditions can cause psychosis, sometimes called secondary psychosis. Examples include:

  • Disorders causing delirium (toxic psychosis), in which consciousness is disturbed.
  • Neurodevelopmental disorders and chromosomal abnormalities, including velocardiofacial syndrome.
  • Neurodegenerative disorders, such as Alzheimer’s disease, dementia with Lewy bodies, and Parkinson’s disease.
  • Focal neurological disease, such as stroke, brain tumours, multiple sclerosis, and some forms of epilepsy.
  • Malignancy (typically via masses in the brain, paraneoplastic syndromes).
  • Infectious and post-infectious syndromes, including infections causing delirium, viral encephalitis, HIV/AIDS, malaria, syphilis.
  • Endocrine disease, such as hypothyroidism, hyperthyroidism, Cushing’s syndrome, hypoparathyroidism and hyperparathyroidism; sex hormones also affect psychotic symptoms and sometimes giving birth can provoke psychosis, termed postpartum psychosis.
  • Inborn errors of metabolism, such as Succinic semialdehyde dehydrogenase deficiency, porphyria and metachromatic leukodystrophy.
  • Nutritional deficiency, such as vitamin B12 deficiency.
  • Other acquired metabolic disorders, including electrolyte disturbances such as hypocalcaemia, hypernatremia, hyponatremia, hypokalaemia, hypomagnesemia, hypermagnesemia, hypercalcemia, and hypophosphatemia, but also hypoglycaemia, hypoxia, and failure of the liver or kidneys.
  • Autoimmune and related disorders, such as systemic lupus erythematosus (lupus, SLE), sarcoidosis, Hashimoto’s encephalopathy, anti-NMDA-receptor encephalitis, and non-celiac gluten sensitivity.
  • Poisoning, by therapeutic drugs (see below), recreational drugs (see below), and a range of plants, fungi, metals, organic compounds, and a few animal toxins.
  • Sleep disorders, such as in narcolepsy (in which REM sleep intrudes into wakefulness).
  • Parasitic diseases, such as neurocysticercosis.

Psychoactive Drugs

Various psychoactive substances (both legal and illegal) have been implicated in causing, exacerbating, or precipitating psychotic states or disorders in users, with varying levels of evidence. This may be upon intoxication for a more prolonged period after use, or upon withdrawal. Individuals who have a substance induced psychosis tend to have a greater awareness of their psychosis and tend to have higher levels of suicidal thinking compared to individuals who have a primary psychotic illness. Drugs commonly alleged to induce psychotic symptoms include alcohol, cannabis, cocaine, amphetamines, cathinones, psychedelic drugs (such as LSD and psilocybin), κ-opioid receptor agonists (such as enadoline and salvinorin A) and NMDA receptor antagonists (such as phencyclidine and ketamine). Caffeine may worsen symptoms in those with schizophrenia and cause psychosis at very high doses in people without the condition. Cannabis and other illicit recreational drugs are often associated with psychosis in adolescents and cannabis use before 15 years old may increase the risk of psychosis later in life as an adult.

Alcohol

Approximately three percent of people who are suffering from alcoholism experience psychosis during acute intoxication or withdrawal. Alcohol related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related psychosis is due to the long-term effects of alcohol consumption resulting in distortions to neuronal membranes, gene expression, as well as thiamine deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance induced psychotic disorder, i.e. schizophrenia. The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as causing psychosocial impairments.

Cannabis

According to some studies, the more often cannabis is used the more likely a person is to develop a psychotic illness, with frequent use being correlated with twice the risk of psychosis and schizophrenia. While cannabis use is accepted as a contributory cause of schizophrenia by some, it remains controversial, with pre-existing vulnerability to psychosis emerging as the key factor that influences the link between cannabis use and psychosis. Some studies indicate that the effects of two active compounds in cannabis, tetrahydrocannabinol (THC) and cannabidiol (CBD), have opposite effects with respect to psychosis. While THC can induce psychotic symptoms in healthy individuals, CBD may reduce the symptoms caused by cannabis.

Cannabis use has increased dramatically over the past few decades whereas the rate of psychosis has not increased. Together, these findings suggest that cannabis use may hasten the onset of psychosis in those who may already be predisposed to psychosis. High-potency cannabis use indeed seems to accelerate the onset of psychosis in predisposed patients. A 2012 study concluded that cannabis plays an important role in the development of psychosis in vulnerable individuals, and that cannabis use in early adolescence should be discouraged.

Methamphetamine

Methamphetamine induces a psychosis in 26-46% of heavy users. Some of these people develop a long-lasting psychosis that can persist for longer than six months. Those who have had a short-lived psychosis from methamphetamine can have a relapse of the methamphetamine psychosis years later after a stressful event such as severe insomnia or a period of heavy alcohol abuse despite not relapsing back to methamphetamine. Individuals who have a long history of methamphetamine abuse and who have experienced psychosis in the past from methamphetamine abuse are highly likely to re-experience methamphetamine psychosis if drug use is recommenced. Methamphetamine-induced psychosis is likely gated by genetic vulnerability, which can produce long-term changes in brain neurochemistry following repetitive use.

Medication

Administration, or sometimes withdrawal, of a large number of medications may provoke psychotic symptoms. Drugs that can induce psychosis experimentally or in a significant proportion of people include amphetamine and other sympathomimetics, dopamine agonists, ketamine, corticosteroids (often with mood changes in addition), and some anticonvulsants such as vigabatrin. Stimulants that may cause this include lisdexamfetamine.

Medication may induce psychological side effects, including depersonalisation, derealisation and psychotic symptoms like hallucinations as well as mood disturbances.

Pathophysiology

Neuroimaging

The first brain image of an individual with psychosis was completed as far back as 1935 using a technique called pneumoencephalography (a painful and now obsolete procedure where cerebrospinal fluid is drained from around the brain and replaced with air to allow the structure of the brain to show up more clearly on an X-ray picture).

Both first episode psychosis, and high risk status is associated with reductions in grey matter volume (GMV). First episode psychotic and high risk populations are associated with similar but distinct abnormalities in GMV. Reductions in the right middle temporal gyrus, right superior temporal gyrus (STG), right parahippocampus, right hippocampus, right middle frontal gyrus, and left anterior cingulate cortex (ACC) are observed in high risk populations. Reductions in first episode psychosis span a region from the right STG to the right insula, left insula, and cerebellum, and are more severe in the right ACC, right STG, insula and cerebellum.

Another meta analysis reported bilateral reductions in insula, operculum, STG, medial frontal cortex, and ACC, but also reported increased GMV in the right lingual gyrus and left precentral gyrus. The Kraepelinian dichotomy is made questionable by grey matter abnormalities in bipolar and schizophrenia; schizophrenia is distinguishable from bipolar in that regions of grey matter reduction are generally larger in magnitude, although adjusting for gender differences reduces the difference to the left dorsomedial prefrontal cortex, and right dorsolateral prefrontal cortex.

During attentional tasks, first episode psychosis is associated with hypoactivation in the right middle frontal gyrus, a region generally described as encompassing the dorsolateral prefrontal cortex (dlPFC). In congruence with studies on grey matter volume, hypoactivity in the right insula, and right inferior parietal lobe is also reported. During cognitive tasks, hypoactivities in the right insula, dACC, and the left precuneus, as well as reduced deactivations in the right basal ganglia, right thalamus, right inferior frontal and left precentral gyri are observed. These results are highly consistent and replicable possibly except the abnormalities of the right inferior frontal gyrus. Decreased grey matter volume in conjunction with bilateral hypoactivity is observed in anterior insula, dorsal medial frontal cortex, and dorsal ACC. Decreased grey matter volume and bilateral hyperactivity is reported in posterior insula, ventral medial frontal cortex, and ventral ACC.

Hallucinations

Studies during acute experiences of hallucinations demonstrate increased activity in primary or secondary sensory cortices. As auditory hallucinations are most common in psychosis, most robust evidence exists for increased activity in the left middle temporal gyrus, left superior temporal gyrus, and left inferior frontal gyrus (i.e. Broca’s area). Activity in the ventral striatum, hippocampus, and ACC are related to the lucidity of hallucinations, and indicate that activation or involvement of emotional circuitry are key to the impact of abnormal activity in sensory cortices. Together, these findings indicate abnormal processing of internally generated sensory experiences, coupled with abnormal emotional processing, results in hallucinations. One proposed model involves a failure of feedforward networks from sensory cortices to the inferior frontal cortex, which normally cancel out sensory cortex activity during internally generated speech. The resulting disruption in expected and perceived speech is thought to produce lucid hallucinatory experiences.

Delusions

The two-factor model of delusions posits that dysfunction in both belief formation systems and belief evaluation systems are necessary for delusions. Dysfunction in evaluations systems localised to the right lateral prefrontal cortex, regardless of delusion content, is supported by neuroimaging studies and is congruent with its role in conflict monitoring in healthy persons. Abnormal activation and reduced volume is seen in people with delusions, as well as in disorders associated with delusions such as frontotemporal dementia, psychosis and Lewy body dementia. Furthermore, lesions to this region are associated with “jumping to conclusions”, damage to this region is associated with post-stroke delusions, and hypometabolism this region associated with caudate strokes presenting with delusions.

The aberrant salience model suggests that delusions are a result of people assigning excessive importance to irrelevant stimuli. In support of this hypothesis, regions normally associated with the salience network demonstrate reduced grey matter in people with delusions, and the neurotransmitter dopamine, which is widely implicated in salience processing, is also widely implicated in psychotic disorders.

Specific regions have been associated with specific types of delusions. The volume of the hippocampus and parahippocampus is related to paranoid delusions in Alzheimer’s disease, and has been reported to be abnormal post mortem in one person with delusions. Capgras delusions have been associated with occipito-temporal damage, and may be related to failure to elicit normal emotions or memories in response to faces.

Negative Symptoms

Psychosis is associated with ventral striatal hypoactivity during reward anticipation and feedback. Hypoactivity in the left ventral striatum is correlated with the severity of negative symptoms. While anhedonia is a commonly reported symptom in psychosis, hedonic experiences are actually intact in most people with schizophrenia. The impairment that may present itself as anhedonia probably actually lies in the inability to identify goals, and to identify and engage in the behaviours necessary to achieve goals. Studies support a deficiency in the neural representation of goals and goal directed behaviour by demonstrating that receipt (not anticipation) of reward is associated with a robust response in the ventral striatum; reinforcement learning is intact when contingencies about stimulus-reward are implicit, but not when they require explicit neural processing; reward prediction errors (during functional neuroimaging studies), particularly positive PEs are abnormal. A positive prediction error response occurs when there is an increased activation in a brain region, typically the striatum, in response to unexpected rewards. A negative prediction error response occurs when there is a decreased activation in a region when predicted rewards do not occur. ACC response, taken as an indicator of effort allocation, does not increase with reward or reward probability increase, and is associated with negative symptoms; deficits in dlPFC activity and failure to improve performance on cognitive tasks when offered monetary incentives are present; and dopamine mediated functions are abnormal.

Neurobiology

Psychosis has been traditionally linked to the overactivity of the neurotransmitter dopamine. In particular to its effect in the mesolimbic pathway. The two major sources of evidence given to support this theory are that dopamine receptor D2 blocking drugs (i.e., antipsychotics) tend to reduce the intensity of psychotic symptoms, and that drugs that accentuate dopamine release, or inhibit its reuptake (such as amphetamines and cocaine) can trigger psychosis in some people (see stimulant psychosis).

NMDA receptor dysfunction has been proposed as a mechanism in psychosis. This theory is reinforced by the fact that dissociative NMDA receptor antagonists such as ketamine, PCP and dextromethorphan (at large overdoses) induce a psychotic state. The symptoms of dissociative intoxication are also considered to mirror the symptoms of schizophrenia, including negative symptoms. NMDA receptor antagonism, in addition to producing symptoms reminiscent of psychosis, mimics the neurophysiological aspects, such as reduction in the amplitude of P50, P300, and MMN evoked potentials. Hierarchical Bayesian neurocomputational models of sensory feedback, in agreement with neuroimaging literature, link NMDA receptor hypofunction to delusional or hallucinatory symptoms via proposing a failure of NMDA mediated top down predictions to adequately cancel out enhanced bottom up AMPA mediated predictions errors. Excessive prediction errors in response to stimuli that would normally not produce such a response is thought to root from conferring excessive salience to otherwise mundane events. Dysfunction higher up in the hierarchy, where representation is more abstract, could result in delusions. The common finding of reduced GAD67 expression in psychotic disorders may explain enhanced AMPA mediated signalling, caused by reduced GABAergic inhibition.

The connection between dopamine and psychosis is generally believed to be complex. While dopamine receptor D2 suppresses adenylate cyclase activity, the D1 receptor increases it. If D2-blocking drugs are administered, the blocked dopamine spills over to the D1 receptors. The increased adenylate cyclase activity affects genetic expression in the nerve cell, which takes time. Hence antipsychotic drugs take a week or two to reduce the symptoms of psychosis. Moreover, newer and equally effective antipsychotic drugs actually block slightly less dopamine in the brain than older drugs whilst also blocking 5-HT2A receptors, suggesting the ‘dopamine hypothesis’ may be oversimplified. Soyka and colleagues found no evidence of dopaminergic dysfunction in people with alcohol-induced psychosis and Zoldan et al. reported moderately successful use of ondansetron, a 5-HT3 receptor antagonist, in the treatment of levodopa psychosis in Parkinson’s disease patients.

A review found an association between a first-episode of psychosis and prediabetes.

Prolonged or high dose use of psychostimulants can alter normal functioning, making it similar to the manic phase of bipolar disorder. NMDA antagonists replicate some of the so-called “negative” symptoms like thought disorder in subanesthetic doses (doses insufficient to induce anesthesia), and catatonia in high doses). Psychostimulants, especially in one already prone to psychotic thinking, can cause some “positive” symptoms, such as delusional beliefs, particularly those persecutory in nature.

Diagnosis

To make a diagnosis of a mental illness in someone with psychosis other potential causes must be excluded. An initial assessment includes a comprehensive history and physical examination by a health care provider. Tests may be done to exclude substance use, medication, toxins, surgical complications, or other medical illnesses. A person with psychosis is referred to as psychotic.

Delirium should be ruled out, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, indicating other underlying factors, including medical illnesses. Excluding medical illnesses associated with psychosis is performed by using blood tests to measure:

  • Thyroid-stimulating hormone to exclude hypo- or hyperthyroidism.
  • Basic electrolytes and serum calcium to rule out a metabolic disturbance.
  • Full blood count including ESR to rule out a systemic infection or chronic disease.
  • Serology to exclude syphilis or HIV infection.
  • Other investigations include:
    • EEG to exclude epilepsy; and
    • MRI or CT scan of the head to exclude brain lesions.

Because psychosis may be precipitated or exacerbated by common classes of medications, medication-induced psychosis should be ruled out, particularly for first-episode psychosis. Both substance- and medication-induced psychosis can be excluded to a high level of certainty, using toxicology screening.

Because some dietary supplements may also induce psychosis or mania, but cannot be ruled out with laboratory tests, a psychotic individual’s family, partner, or friends should be asked whether the patient is currently taking any dietary supplements.

Common mistakes made when diagnosing people who are psychotic include:

  • Not properly excluding delirium.
  • Not appreciating medical abnormalities (e.g., vital signs).
  • Not obtaining a medical history and family history.
  • Indiscriminate screening without an organizing framework.
  • Missing a toxic psychosis by not screening for substances and medications.
  • Not asking their family or others about dietary supplements.
  • Premature diagnostic closure.
  • Not revisiting or questioning the initial diagnostic impression of primary psychiatric disorder.

Only after relevant and known causes of psychosis are excluded, a mental health clinician may make a psychiatric differential diagnosis using a person’s family history, incorporating information from the person with psychosis, and information from family, friends, or significant others.

Types of psychosis in psychiatric disorders may be established by formal rating scales. The Brief Psychiatric Rating Scale (BPRS) assesses the level of 18 symptom constructs of psychosis such as hostility, suspicion, hallucination, and grandiosity. It is based on the clinician’s interview with the patient and observations of the patient’s behaviour over the previous 2-3 days. The patient’s family can also answer questions on the behaviour report. During the initial assessment and the follow-up, both positive and negative symptoms of psychosis can be assessed using the 30 item Positive and Negative Symptom Scale (PANSS).

The DSM-5 characterizes disorders as psychotic or on the schizophrenia spectrum if they involve hallucinations, delusions, disorganised thinking, grossly disorganised motor behaviour, or negative symptoms. The DSM-5 does not include psychosis as a definition in the glossary, although it defines “psychotic features”, as well as “psychoticism” with respect to personality disorder. The ICD-10 has no specific definition of psychosis.

Factor analysis of symptoms generally regarded as psychosis frequently yields a five factor solution, albeit five factors that are distinct from the five domains defined by the DSM-5 to encompass psychotic or schizophrenia spectrum disorders. The five factors are frequently labelled as hallucinations, delusions, disorganisation, excitement, and emotional distress. The DSM-5 emphasizes a psychotic spectrum, wherein the low end is characterised by schizoid personality disorder, and the high end is characterised by schizophrenia.

Prevention

The evidence for the effectiveness of early interventions to prevent psychosis appeared inconclusive. But psychosis caused by drugs can be prevented. Whilst early intervention in those with a psychotic episode might improve short-term outcomes, little benefit was seen from these measures after five years. However, there is evidence that cognitive behavioural therapy (CBT) may reduce the risk of becoming psychotic in those at high risk, and in 2014 the UK National Institute for Health and Care Excellence (NICE) recommended preventive CBT for people at risk of psychosis.

Treatment

The treatment of psychosis depends on the specific diagnosis (such as schizophrenia, bipolar disorder or substance intoxication). The first-line treatment for many psychotic disorders is antipsychotic medication, which can reduce the positive symptoms of psychosis in about 7 to 14 days. For youth or adolescents, treatment options include medications, psychological interventions, and social interventions.

Medication

The choice of which antipsychotic to use is based on benefits, risks, and costs. It is debatable whether, as a class, typical or atypical antipsychotics are better. Tentative evidence supports that amisulpride, olanzapine, risperidone and clozapine may be more effective for positive symptoms but result in more side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages. There is a good response in 40-50%, a partial response in 30-40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two or three different antipsychotics) in 20% of people. Clozapine is an effective treatment for those who respond poorly to other drugs (“treatment-resistant” or “refractory” schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.

Most people on antipsychotics get side effects. People on typical antipsychotics tend to have a higher rate of extrapyramidal side effects while some atypicals are associated with considerable weight gain, diabetes and risk of metabolic syndrome; this is most pronounced with olanzapine, while risperidone and quetiapine are also associated with weight gain. Risperidone has a similar rate of extrapyramidal symptoms to haloperidol.

Counselling

Psychological treatments such as acceptance and commitment therapy (ACT) are possibly useful in the treatment of psychosis, helping people to focus more on what they can do in terms of valued life directions despite challenging symptomology.

There are psychological interventions that seek to treat the symptoms of psychosis. In a 2019 review, nine classes of psychosocial interventions were identified: need adapted treatment, open dialogue, psychoanalysis/psychodynamic psychotherapy, major role therapy, soteria, psychosocial outpatient and inpatient treatment, milieu therapy, and CBT. This paper concluded that when on minimal or no medication “the overall evidence supporting the effectiveness of these interventions is generally weak”.

Early Intervention

Refer to early intervention in psychosis.

Early intervention in psychosis is based on the observation that identifying and treating someone in the early stages of a psychosis can improve their longer term outcome. This approach advocates the use of an intensive multi-disciplinary approach during what is known as the critical period, where intervention is the most effective, and prevents the long-term morbidity associated with chronic psychotic illness.

Brief History

Etymology

The word psychosis was introduced to the psychiatric literature in 1841 by Karl Friedrich Canstatt in his work Handbuch der Medizinischen Klinik. He used it as a shorthand for ‘psychic neurosis’. At that time neurosis meant any disease of the nervous system, and Canstatt was thus referring to what was considered a psychological manifestation of brain disease. Ernst von Feuchtersleben is also widely credited as introducing the term in 1845, as an alternative to insanity and mania.

The term stems from Modern Latin psychosis, “a giving soul or life to, animating, quickening” and that from Ancient Greek ψυχή (psyche), “soul” and the suffix -ωσις (-osis), in this case “abnormal condition”.

In its adjective form “psychotic”, references to psychosis can be found in both clinical and non-clinical discussions. However, in a non-clinical context, “psychotic” is generally used as a synonym for “insane”.

Classification

The word was also used to distinguish a condition considered a disorder of the mind, as opposed to neurosis, which was considered a disorder of the nervous system. The psychoses thus became the modern equivalent of the old notion of madness, and hence there was much debate on whether there was only one (unitary) or many forms of the new disease. One type of broad usage would later be narrowed down by Koch in 1891 to the ‘psychopathic inferiorities’ – later renamed abnormal personalities by Schneider.

The division of the major psychoses into manic depressive illness (now called bipolar disorder) and dementia praecox (now called schizophrenia) was made by Emil Kraepelin, who attempted to create a synthesis of the various mental disorders identified by 19th-century psychiatrists, by grouping diseases together based on classification of common symptoms. Kraepelin used the term ‘manic depressive insanity’ to describe the whole spectrum of mood disorders, in a far wider sense than it is usually used today.

In Kraepelin’s classification this would include ‘unipolar’ clinical depression, as well as bipolar disorder and other mood disorders such as cyclothymia. These are characterised by problems with mood control and the psychotic episodes appear associated with disturbances in mood, and patients often have periods of normal functioning between psychotic episodes even without medication. Schizophrenia is characterised by psychotic episodes that appear unrelated to disturbances in mood, and most non-medicated patients show signs of disturbance between psychotic episodes.

Treatment

Early civilisations considered madness a supernaturally inflicted phenomenon. Archaeologists have unearthed skulls with clearly visible drillings, some datable back to 5000 BC suggesting that trepanning was a common treatment for psychosis in ancient times. Written record of supernatural causes and resultant treatments can be traced back to the New Testament. Mark 5:8-13 describes a man displaying what would today be described as psychotic symptoms. Christ cured this “demonic madness” by casting out the demons and hurling them into a herd of swine. Exorcism is still utilised in some religious circles as a treatment for psychosis presumed to be demonic possession. A research study of out-patients in psychiatric clinics found that 30% of religious patients attributed the cause of their psychotic symptoms to evil spirits. Many of these patients underwent exorcistic healing rituals that, though largely regarded as positive experiences by the patients, had no effect on symptomology. Results did, however, show a significant worsening of psychotic symptoms associated with exclusion of medical treatment for coercive forms of exorcism.

The medical teachings of the fourth-century philosopher and physician Hippocrates of Cos proposed a natural, rather than supernatural, cause of human illness. In Hippocrates’ work, the Hippocratic corpus, a holistic explanation for health and disease was developed to include madness and other “diseases of the mind.” Hippocrates writes:

Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter, and jests, as well as our sorrows, pains, griefs and tears. Through it, in particular, we think, see, hear, and distinguish the ugly from the beautiful, the bad from the good, the pleasant from the unpleasant…. It is the same thing which makes us mad or delirious, inspires us with dread and fear, whether by night or by day, brings sleeplessness, inopportune mistakes, aimless anxieties, absentmindedness, and acts that are contrary to habit.

Hippocrates espoused a theory of humouralism wherein disease is resultant of a shifting balance in bodily fluids including blood, phlegm, black bile, and yellow bile. According to humouralism, each fluid or “humour” has temperamental or behavioural correlates. In the case of psychosis, symptoms are thought to be caused by an excess of both blood and yellow bile. Thus, the proposed surgical intervention for psychotic or manic behaviour was bloodletting.

18th-century physician, educator, and widely considered “founder of American psychiatry”, Benjamin Rush, also prescribed bloodletting as a first-line treatment for psychosis. Although not a proponent of humouralism, Rush believed that active purging and bloodletting were efficacious corrections for disruptions in the circulatory system, a complication he believed was the primary cause of “insanity”. Although Rush’s treatment modalities are now considered antiquated and brutish, his contributions to psychiatry, namely the biological underpinnings of psychiatric phenomenon including psychosis, have been invaluable to the field. In honour of such contributions, Benjamin Rush’s image is in the official seal of the American Psychiatric Association.

Early 20th-century treatments for severe and persisting psychosis were characterized by an emphasis on shocking the nervous system. Such therapies include insulin shock therapy, cardiazol shock therapy, and electroconvulsive therapy. Despite considerable risk, shock therapy was considered highly efficacious in the treatment of psychosis including schizophrenia. The acceptance of high-risk treatments led to more invasive medical interventions including psychosurgery.

In 1888, Swiss psychiatrist Gottlieb Burckhardt performed the first medically sanctioned psychosurgery in which the cerebral cortex was excised. Although some patients showed improvement of symptoms and became more subdued, one patient died and several developed aphasia or seizure disorders. Burckhardt would go on to publish his clinical outcomes in a scholarly paper. This procedure was met with criticism from the medical community and his academic and surgical endeavours were largely ignored. In the late 1930s, Egas Moniz conceived the leucotomy (AKA prefrontal lobotomy) in which the fibres connecting the frontal lobes to the rest of the brain were severed. Moniz’s primary inspiration stemmed from a demonstration by neuroscientists John Fulton and Carlyle’s 1935 experiment in which two chimpanzees were given leucotomies and pre- and post-surgical behaviour was compared. Prior to the leucotomy, the chimps engaged in typical behaviour including throwing faeces and fighting. After the procedure, both chimps were pacified and less violent. During the Q&A, Moniz asked if such a procedure could be extended to human subjects, a question that Fulton admitted was quite startling. Moniz would go on to extend the controversial practice to humans suffering from various psychotic disorders, an endeavour for which he received a Nobel Prize in 1949. Between the late 1930s and early 1970s, the leucotomy was a widely accepted practice, often performed in non-sterile environments such as small outpatient clinics and patient homes. Psychosurgery remained standard practice until the discovery of antipsychotic pharmacology in the 1950s.

The first clinical trial of antipsychotics (also commonly known as neuroleptics) for the treatment of psychosis took place in 1952. Chlorpromazine (brand name: Thorazine) passed clinical trials and became the first antipsychotic medication approved for the treatment of both acute and chronic psychosis. Although the mechanism of action was not discovered until 1963, the administration of chlorpromazine marked the advent of the dopamine antagonist, or first generation antipsychotic. While clinical trials showed a high response rate for both acute psychosis and disorders with psychotic features, the side effects were particularly harsh, which included high rates of often irreversible Parkinsonian symptoms such as tardive dyskinesia. With the advent of atypical antipsychotics (also known as second generation antipsychotics) came a dopamine antagonist with a comparable response rate but a far different, though still extensive, side-effect profile that included a lower risk of Parkinsonian symptoms but a higher risk of cardiovascular disease. Atypical antipsychotics remain the first-line treatment for psychosis associated with various psychiatric and neurological disorders including schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia, and some autism spectrum disorders.

Dopamine is now one of the primary neurotransmitters implicated in psychotic symptomology. Blocking dopamine receptors (namely, the dopamine D2 receptors) and decreasing dopaminergic activity continues to be an effective but highly unrefined effect of antipsychotics, which are commonly used to treat psychosis. Recent pharmacological research suggests that the decrease in dopaminergic activity does not eradicate psychotic delusions or hallucinations, but rather attenuates the reward mechanisms involved in the development of delusional thinking; that is, connecting or finding meaningful relationships between unrelated stimuli or ideas. The author of this research paper acknowledges the importance of future investigation:

The model presented here is based on incomplete knowledge related to dopamine, schizophrenia, and antipsychotics – and as such will need to evolve as more is known about these. Shitij Kapur, From dopamine to salience to psychosis – linking biology, pharmacology and phenomenology of psychosis.

Freud’s former student Wilhelm Reich explored independent insights into the physical effects of neurotic and traumatic upbringing, and published his holistic psychoanalytic treatment with a schizophrenic. With his incorporation of breathwork and insight with the patient, a young woman, she achieved sufficient self-management skills to end the therapy.

Lacan extended Freud’s ideas to create a psychoanalytic model of psychosis based upon the concept of ” foreclosure”, the rejection of the symbolic concept of the father.

Society

Psychiatrist David Healy has criticised pharmaceutical companies for promoting simplified biological theories of mental illness that seem to imply the primacy of pharmaceutical treatments while ignoring social and developmental factors that are known important influences in the aetiology of psychosis.

Research

Further research in the form of randomised controlled trials is needed to determine the effectiveness of treatment approaches for helping adolescents with psychosis.

What is Early Intervention in Psychosis?

Introduction

Early intervention in psychosis is a clinical approach to those experiencing symptoms of psychosis for the first time. It forms part of a new prevention paradigm for psychiatry and is leading to reform of mental health services, especially in the United Kingdom and Australia.

This approach centres on the early detection and treatment of early symptoms of psychosis during the formative years of the psychotic condition. The first three to five years are believed by some to be a critical period. The aim is to reduce the usual delays to treatment for those in their first episode of psychosis. The provision of optimal treatments in these early years is thought to prevent relapses and reduce the long-term impact of the condition. It is considered a secondary prevention strategy.

The duration of untreated psychosis (DUP) has been shown as an indicator of prognosis, with a longer DUP associated with more long-term disability.

Components of the Model

There are a number of functional components of the early psychosis model, and they can be structured as different sub-teams within early psychosis services. The emerging pattern of sub-teams are currently:

  • Early psychosis treatment teams;
  • Early detection function; and
  • Prodrome clinics.

Early Psychosis Treatment Teams

Multidisciplinary clinical teams providing an intensive case management approach for the first three to five years. The approach is similar to assertive community treatment, but with an increased focus on the engagement and treatment of this previously untreated population and the provision of evidence based, optimal interventions for clients in their first episode of psychosis. For example, the use of low-dose antipsychotic medication is promoted (“start low, go slow”), with a need for monitoring of side effects and an intensive and deliberate period of psycho-education for patients and families that are new to the mental health system. In addition, researchers in Spain showed that family intervention for psychosis (FIP) reduced relapse rates, hospitalization duration, and psychotic symptoms along with increasing functionality in first-episode psychosis (FEP) up to 24 months, according to a recent review published in Schizophrenia Bulletin. Interventions to prevent a further episodes of psychosis (a “relapse”) and strategies that encourage a return to normal vocation and social activity are a priority. There is a concept of phase specific treatment for acute, early recovery and late recovery periods in the first episode of psychosis.

Early Detection Function

Interventions aimed at avoiding late detection and engagement of those in the course of their psychotic conditions. Key tasks include being aware of early signs of psychosis and improving pathways into treatment. Teams provide information and education to the general public and assist GPs with recognition and response to those with suspected signs, for example:

  • EPPIC’s Youth Access Team (YAT) (Melbourne, Australia);
  • OPUS (Denmark);
  • TIPS (Norway);
  • REDIRECT (Birmingham, UK);
  • LEO CAT (London, UK); and
  • STEP’s Population Health approach to early detection.

The development and implementation of quantitative tools for early detection of at-risk individuals is an active research area. This includes development of risk calculators and methods for large-scale population screening.

Prodrome Clinics

Prodrome or at risk mental state clinics are specialist services for those with subclinical symptoms of psychosis or other indicators of risk of transition to psychosis. The Pace Clinic in Melbourne, Australia, is considered one of the origins of this strategy, but a number of other services and research centres have since developed. These services are able to reliably identify those at high risk of developing psychosis and are beginning to publish encouraging outcomes from randomised controlled trials that reduce the chances of becoming psychotic, including evidence that psychological therapy and high doses of fish oil have a role in the prevention of psychosis. However, a meta-analysis of five trials found that while these interventions reduced risk of psychosis after 1 year (11% conversion to psychosis in intervention groups compared to 32% in control groups), these gains were not maintained over 2-3 years of follow-up. These findings indicate that interventions delay psychosis, but do not reduce the long-term risk. There has also been debate about the ethics of using antipsychotic medication to reduce the risk of developing psychosis, because of the potential harms involved with these medications.

In 2015, the European Psychiatric Association issued guidance recommending the use of the Cognitive Disturbances scale (COGDIS), a subscale of the basic symptoms scale, to assess psychosis risk; a meta-analysis conducted for the guidance found that while rates of conversion to psychosis were similar to those who meet Ultra High Risk (UHR) criteria up to 2 years after assessment, they were significantly higher after 2 years for those patients who met the COGDIS criteria. The COGDIS criteria measure subjective symptoms, and include such symptoms as thought interference, where irrelevant and emotionally unimportant thought contents interfere with the main line of thinking; thought block, where the current train of thought halts; thought pressure, where thoughts unrelated to a common topic appear uncontrollably; referential ideation that is immediately corrected; and other characteristic disturbances of attention and the use or understanding of language.

Brief History

Early intervention in psychosis is a preventive approach for psychosis that has evolved as contemporary recovery views of psychosis and schizophrenia have gained acceptance. It subscribes to a “post Kraepelin” concept of schizophrenia, challenging the assumptions originally promoted by Emil Kraepelin in the 19th century, that schizophrenia (“dementia praecox”) was a condition with a progressing and deteriorating course. The work of Post, whose kindling model, together with Fava and Kellner, who first adapted staging models to mental health, provided an intellectual foundation. Psychosis is now formulated within a diathesis-stress model, allowing a more hopeful view of prognosis, and expects full recovery for those with early emerging psychotic symptoms. It is more aligned with psychosis as continuum (such as with the concept of schizotypy) with multiple contributing factors, rather than schizophrenia as simply a neurobiological disease.

Within this changing view of psychosis and schizophrenia, the model has developed from a divergence of several different ideas, and from a number of sites, beginning with the closure of psychiatric institutions signalling a move toward community based care. In 1986, the Northwick Park study discovered an association between delays to treatment and disability, questioning the service provision for those with their first episode of schizophrenia. In the 1990s, evidence began to emerge that cognitive behavioural therapy was an effective treatment for delusions and hallucinations. The next step came with the development of the EPPIC early detection service in Melbourne, Australia in 1996 and the prodrome clinic led by Alison Yung. This service was an inspiration to other services, such as the West Midlands IRIS group, including the carer charity Rethink Mental Illness; the TIPS early detection randomised control trial in Norway; and the Danish OPUS trial. In 2001, the United Kingdom Department of Health called the development of early psychosis teams “a priority”. The International Early Psychosis Association, founded in 1998, issued an international consensus declaration together with the World Health Organisation in 2004. Clinical practice guidelines have been written by consensus.

Clinical Outcome Evidence

A number of studies have been carried out to see whether the early psychosis approach reduces the severity of symptoms, improves relapse rates, and decreases the use of inpatient care, in comparison to standard care. Advocates of early intervention for psychosis have been accused of selectively citing findings that support the benefits of early intervention, but ignoring findings that do not. It has been argued that the scientific reporting of evidence on early intervention in psychosis is characterised by a high prevalence of ‘spin’ and ‘bias’. An analysis of the summaries of articles found that 75% implied positive results, whereas examination of the findings with primary measures from these studies found that only 13% were positive.

Evidence on Cost

Studies have been published claiming that early psychosis services cost less than standard services, largely through reduced in-patient costs, and also save other costs to society. However, the claimed savings have been disputed. A 2012 systematic review of the evidence concluded that: “The published literature does not support the contention that early intervention for psychosis reduces costs or achieves cost-effectiveness”.

Reform of Mental Health Services

United Kingdom

The United Kingdom has made significant service reform with their adoption of early psychosis teams following the first service in Birmingham set up by Professor Max Birchwood in 1994 and used as a blueprint for national roll-out, with early psychosis now considered as an integral part of comprehensive community mental health services. The Mental Health Policy Implementation Guide outlines service specifications and forms the basis of a newly developed fidelity tool. There is a requirement for services to reduce the duration of untreated psychosis, as this has been shown to be associated with better long-term outcomes. The implementation guideline recommends:

  • 14 to 35 year age entry criteria.
  • First three years of psychotic illness.
  • Aim to reduce the duration of untreated psychosis to less than 3 months.
  • Maximum caseload ratio of 1 care coordinator to 10-15 clients.
  • For every 250,000 (depending on population characteristics), one team:
    • Total caseload 120 to 150.
    • 1.5 doctors per team.
    • Other specialist staff to provide specific evidence based interventions.

Australia and New Zealand

In Australia the EPPIC initiative provides early intervention services. In the Australian government’s 2011 budget, $222.4 million was provided to fund 12 new EPPIC centres in collaboration with the states and territories. However, there have been criticisms of the evidence base for this expansion and of the claimed cost savings.

On 19 August 2011, Patrick McGorry, South Australian Social Inclusion Commissioner David Cappo AO and Frank Quinlan, CEO of the Mental Health Council of Australia, addressed a meeting of the Council of Australian Governments (COAG), chaired by Prime Minister Julia Gillard, on the future direction of mental health policy and the need for priority funding for early intervention. The invitation, an initiative of South Australian Premier Mike Rann, followed the release of Cappo’s “Stepping Up” report, supported by the Rann Government, which recommended a major overhaul of mental health in South Australia, including stepped levels of care and early intervention.

New Zealand has operated significant early psychosis teams for more than 20 years, following the inclusion of early psychosis in a mental health policy document in 1997. There is a national early psychosis professional group, New Zealand Early Intervention for Psychosis Society (NZEIPS), organising a biannual training event, advocating for evidenced based service reform and supporting production of local resources.

Scandinavia

Early psychosis programmes have continued to develop from the original TIPS services in Norway and the OPUS randomised trial in Denmark.

North America

Canada has extensive coverage across most provinces, including established clinical services and comprehensive academic research in British Columbia (Vancouver), Alberta (EPT in Calgary), Quebec (PEPP-Montreal), and Ontario (PEPP, FEPP).

In the United States, the Early Assessment Support Alliance (EASA) is implementing early psychosis intervention throughout the state of Oregon.

In the United States, the implementation of Coordinated Specialty Care (CSC), as a recovery-oriented treatment program for people with first episode psychosis (FEP), has become a US health policy priority. CSC promotes shared decision making and uses a team of specialists who work with the client to create a personal treatment plan. The specialists offer psychotherapy, medication management geared to individuals with FEP, family education and support, case management, and work or education support, depending on the individual’s needs and preferences. The client and the team work together to make treatment decisions, involving family members as much as possible. The goal is to link the individual with a CSC team as soon as possible after psychotic symptoms begin because a longer period of unchecked and untreated illness might be associated with poorer outcomes.

Asia

The first meeting of the Asian Network of Early Psychosis (ANEP) was held in 2004. There are now established services in Singapore, Hong Kong and South Korea.

Is Neuroanalysis a Useful Method for Brain-Related Neuroscientific Diagnosis of Mental Disorders?

Research Paper Title

Neuroanalysis: a method for brain-related neuroscientific diagnosis of mental disorders.

Background

As an Ancient Chinese proverb says “The beginning of wisdom is to call things by their right names” thus we must start calling mental disorders by the names of their underlying brain disturbances. Without knowledge of the causes of mental disorders, their cures will remain elusive.

Methods

Neuroanalysis is a literature-based re-conceptualisation of mental disorders as disturbances of brain organisation. Psychosis and schizophrenia can be re-conceptualised as disturbances to connectivity and hierarchical dynamics in the brain; mood disorders can be re-conceptualised as disturbances to optimization dynamics and free energy in the brain, and finally personality disorders can be re-conceptualised as disordered default-mode networks in the brain.

Results and Conclusions

Knowledge and awareness of the disease algorithms of mental disorders will become critical because powerful technologies for controlling brain activity are developing and becoming available. The time will soon come when psychiatrists will be asked to define the exact ‘algorithms’ of disturbances in their psychiatric patients. Neuroanalysis can be a starting point for the response to that challenge.

Reference

Peled, A. (2020) Neuroanalysis: a method for brain-related neuroscientific diagnosis of mental disorders. Medical Hypotheses. 78(5), pp.636-640. doi: 10.1016/j.mehy.2012.01.043. Epub 2012 Feb 18.