What is Zuclopenthixol?

Introduction

Zuclopenthixol (brand names Cisordinol, Clopixol and others), also known as zuclopentixol, is a medication used to treat schizophrenia and other psychoses.

It is classed, pharmacologically, as a typical antipsychotic. Chemically it is a thioxanthene. It is the cis-isomer of clopenthixol (Sordinol, Ciatyl). Clopenthixol was introduced in 1961, while zuclopenthixol was introduced in 1978.

Zuclopenthixol is a D1 and D2 antagonist, α1-adrenergic and 5-HT2 antagonist. While it is approved for use in Australia, Canada, Ireland, India, New Zealand, Singapore, South Africa and the UK it is not approved for use in the United States.

Brief History

Zuclopenthixol was introduced by Lundbeck in 1978.

Medical Uses

Available Forms

Zuclopenthixol is available in three major preparations:

  1. As zuclopenthixol decanoate (Clopixol Depot, Cisordinol Depot), it is a long-acting intramuscular (IM) injection.
    1. Its main use is as a long-acting injection given every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.
    2. There is some evidence it may be more helpful in managing aggressive behaviour.
  2. As zuclopenthixol acetate (Clopixol-Acuphase, Cisordinol-Acutard), it is a shorter-acting intramuscular injection used in the acute sedation of psychotic inpatients.
    1. The effect peaks at 48-72 hours providing 2-3 days of sedation.
  3. As zuclopenthixol dihydrochloride (Clopixol, Cisordinol), it is a tablet used in the treatment of schizophrenia in those who are compliant with oral medication.

It is also used in the treatment of acute bipolar mania.

Dosing

As a long-acting injection, zuclopenthixol decanoate comes in a 200 mg and 500 mg ampoule. Doses can vary from 50 mg weekly to the maximum licensed dose of 600 mg weekly. In general, the lowest effective dose to prevent relapse is preferred. The interval may be shorter as a patient starts on the medication before extending to 3 weekly intervals subsequently. The dose should be reviewed and reduced if side effects occur, though in the short-term an anticholinergic medication benztropine may be helpful for tremor and stiffness, while diazepam may be helpful for akathisia. 100 mg of zuclopenthixol decanoate is roughly equivalent to 20 mg of flupentixol decanoate or 12.5 mg of fluphenazine decanoate.

In acutely psychotic and agitated inpatients, 50-200 mg of zuclopenthixol acetate may be given for a calming effect over the subsequent three days, with a maximum dose of 400 mg in total to be given. As it is a long-acting medication, care must be taken not to give an excessive dose.

In oral form zuclopenthixol is available in 10, 25 and 40 mg tablets, with a dose range of 20-60 mg daily.

Side Effects

Chronic administration of zuclopenthixol (30 mg/kg/day for two years) in rats resulted in small, but significant, increases in the incidence of thyroid parafollicular carcinomas and, in females, of mammary adenocarcinomas and of pancreatic islet cell adenomas and carcinomas. An increase in the incidence of mammary adenocarcinomas is a common finding for D2 antagonists which increase prolactin secretion when administered to rats. An increase in the incidence of pancreatic islet cell tumours has been observed for some other D2 antagonists. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear.

Withdrawal syndrome: Abrupt cessation of therapy may cause acute withdrawal symptoms (eg, nausea, vomiting, or insomnia). Symptoms usually begin in 1 to 4 days of withdrawal and subside within 1 to 2 weeks.

Other permanent side effects are similar to many other typical antipsychotics, namely extrapyramidal symptoms as a result of dopamine blockade in subcortical areas of the brain. This may result in symptoms similar to those seen in Parkinson’s disease and include a restlessness and inability to sit still known as akathisia, a slow tremor and stiffness of the limbs. Zuclopenthixol is thought to be more sedating than the related flupentixol, though possibly less likely to induce extrapyramidal symptoms than other typical depots. As with other dopamine antagonists, zuclopenthixol may sometimes elevate prolactin levels; this may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Any unexpected deterioration in mental state with confusion and muscle stiffness should be seen by a physician.

Zuclopenthixol decanoate induces a transient dose-dependent sedation. However, if the patient is switched to maintenance treatment with zuclopenthixol decanoate from oral zuclopenthixol or from IM zuclopenthixol acetate the sedation will be no problem. Tolerance to the unspecific sedative effect develops rapidly.

  • Very common Adverse Effects (≥10% incidence):
    • Dry Mouth.
    • Somnolence.
    • Akathisia.
    • Hyperkinesia.
    • Hypokinesia.
  • Common (1%≤incidence≤10%):
    • Tachycardia.
    • Palpitations.
    • Vertigo.
    • Accommodation disorder.
    • Vision abnormal.
    • Salivary hypersecretion.
    • Constipation.
    • Vomiting.
    • Dyspepsia.
    • Diarrhoea.
    • Asthenia.
    • Fatigue.
    • Malaise.
    • Pain (at the injection site).
    • Increased appetite.
    • Weight gain.
    • Myalgia.
    • Tremor.
    • Dystonia.
    • Hypertonia.
    • Dizziness.
    • Headache.
    • Paraesthesia.
    • Disturbance in attention.
    • Amnesia.
    • Gait abnormal.
    • Insomnia.
    • Depression.
    • Anxiety.
    • Nervousness.
    • Abnormal dreams.
    • Agitation.
    • Libido decreased.
    • Nasal congestion.
    • Dyspnoea.
    • Hyperhidrosis.
    • Pruritus.
  • Uncommon (0.1%≤incidence≤1%):
    • Hyperacusis.
    • Tinnitus.
    • Oculogyration.
    • Mydriasis.
    • Abdominal pain.
    • Nausea.
    • Flatulence.
    • Thirst.
    • Injection site reaction.
    • Hypothermia.
    • Pyrexia.
    • Liver function test abnormal.
    • Decreased appetite.
    • Weight loss.
    • Muscle rigidity.
    • Trismus.
    • Torticollis.
    • Tardive dyskinesia.
    • Hyperreflexia.
    • Dyskinesia.
    • Parkinsonism.
    • Syncope.
    • Ataxia.
    • Speech disorder.
    • Hypotonia.
    • Convulsion.
    • Migraine.
    • Apathy.
    • Nightmare.
    • Libido increased.
    • Confusional state.
    • Ejaculation failure.
    • Erectile dysfunction.
    • Female orgasmic disorder.
    • Vulvovaginal.
    • Dryness.
    • Rash.
    • Photosensitivity reaction.
    • Pigmentation disorder.
    • Seborrhoea.
    • Dermatitis.
    • Purpura.
    • Hypotension.
    • Hot flush.
  • Rare (0.01%≤incidence≤0.1%):
    • Thrombocytopenia.
    • Neutropenia.
    • Leukopenia.
    • Agranulocytosis.
    • Electrocardiogram QT prolonged.
    • Hyperprolactinaemia.
    • Hypersensitivity.
    • Anaphylactic reaction.
    • Hyperglycaemia.
    • Glucose tolerance impaired.
    • Hyperlipidaemia.
    • Gynaecomastia.
    • Galactorrhoea.
    • Amenorrhoea.
    • Priapism.
    • Withdrawal symptoms.
  • Very rare (incidence<0.01%):
    • Cholestatic hepatitis.
    • Jaundice.
    • Neuroleptic malignant syndrome.
    • Venous thromboembolism.

Pharmacology

Pharmacodynamics

Zuclopenthixol antagonises both dopamine D1 and D2 receptors, α1-adrenoceptors and 5-HT2 receptors with a high affinity, but has no affinity for cholinergic muscarine receptors. It weakly antagonises the histamine (H1) receptor but has no α2-adrenoceptor blocking activity.

Evidence from in vitro work and clinical sources (i.e. therapeutic drug monitoring databases) suggests that both CYP2D6 and CYP3A4 play important roles in zuclopenthixol metabolism.

What is Ziprasidone?

Introduction

Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder.

It may be used by mouth and by injection into a muscle (IM). The IM form may be used for acute agitation in people with schizophrenia.

Common side effects include dizziness, drowsiness, dry mouth, and twitches. Although it can also cause weight gain, the risk is much lower than for other atypical antipsychotics. How it works is not entirely clear but is believed to involve effects on serotonin and dopamine in the brain.

Ziprasidone was approved for medical use in the United States in 2001. The pills are made up of the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form is the mesylate, ziprasidone mesylate trihydrate, and is provided as a lyophilised powder. In 2017, it was the 261st most commonly prescribed medication in the United States, with more than one million prescriptions.

Brief History

Ziprasidone is chemically similar to risperidone, of which it is a structural analogue. It was first synthesized in 1987 at the Pfizer central research campus in Groton, Connecticut.

Phase I trials started in 1995. In 1998 ziprasidone was approved in Sweden. After the FDA raised concerns about long QT syndrome, more clinical trials were conducted and submitted to the FDA, which approved the drug on 05 February 2001.

Medical Uses

Ziprasidone is approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia as well as acute mania and mixed states associated with bipolar disorder. Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate.

In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, ziprasidone demonstrated mild-standard effectiveness. 15% more effective than lurasidone and iloperidone, approximately as effective as chlorpromazine and asenapine, and 9-13% less effective than haloperidol, quetiapine, and aripiprazole. Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective than olanzapine, and equally as effective compared to quetiapine. There are higher discontinuation rates for lower doses of ziprasidone, which are also less effective than higher doses.

Adverse Effects

Ziprasidone (and all other second generation antipsychotics (SGAs)) received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.

Sleepiness and headache are very common adverse effects (>10%).

Common adverse effects (1-10%), include producing too much saliva or having dry mouth, runny nose, respiratory disorders or coughing, nausea and vomiting, stomach aches, constipation or diarrhoea, loss of appetite, weight gain (but the smallest risk for weight gain compared to other antipsychotics), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety. Extrapyramidal symptoms are also common and include tremor, dystonia (sustained or repetitive muscle contractions), akathisia (the feeling of a need to be in motion), parkinsonism, and muscle rigidity; in a 2013 meta-analysis of 15 antipsychotic drugs, ziprasidone ranked 8th for such side effects.

Ziprasidone is known to cause activation into mania in some bipolar patients.

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.

Recently, the FDA required the manufacturers of some atypical antipsychotics to include a warning about the risk of hyperglycaemia and Type II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone does not cause insulin resistance to the degree of other atypical antipsychotics, such as olanzapine. Weight gain is also less of a concern with ziprasidone compared to other atypical antipsychotics. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall. According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs), which is significantly lower than other atypical antipsychotics, making this medication better for patients that are concerned about their weight. In December 2014, the FDA warned that ziprasidone could cause a potentially fatal skin reaction, Drug Reaction with Eosinophilia and Systemic Symptoms, although this was believed to occur only rarely.

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.

Pharmacology

Pharmacodynamics

Correspondence to Clinical Effects

Ziprasidone mostly affects the receptors of dopamine (D2), serotonin (5-HT2A, partially 5-HT1A, 5-HT2C, and 5-HT1D) and epinephrine/norepinephrine (α1) to a high degree, while of histamine (H1) – moderately. It also somewhat inhibits reuptake of serotonin and norepinephrine, though not dopamine.

Ziprasidone’s efficacy in treating the positive symptoms of schizophrenia is believed to be mediated primarily via antagonism of the dopamine receptors, specifically D2. Blockade of the 5-HT2A receptor may also play a role in its effectiveness against positive symptoms, though the significance of this property in antipsychotic drugs is still debated among researchers. Blockade of 5-HT2A and 5-HT2C and activation of 5-HT1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms. The relatively weak antagonistic actions of ziprasidone on the α1-adrenergic receptor likely in part explains some of its side effects, such as orthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any anticholinergic side effects. Like most other antipsychotics, ziprasidone is sedating due primarily to serotonin and dopamine blockade.

Pharmacokinetics

The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.

After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier. Steady state plasma concentrations are achieved within one to three days. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

The bioavailability of the drug is reduced by approximately 50% if a meal is not eaten before Ziprasidone ingestion.

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4). Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.

Its biological half-life time is 10 hours at doses of 80-120 milligrams.

Society and Culture

Lawsuit

In September 2009, the US Justice Department announced that Pfizer had been ordered to pay a historic fine of $2.3 billion as a penalty for fraudulent marketing of several drugs, including Geodon. Pfizer had illegally promoted Geodon and submitted false claims to government health care programs for uses that were not medically accepted indications. The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe Geodon, as well as other drugs. This was the largest civil fraud settlement in history against a pharmaceutical company.

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 the Diathesis-Stress Model?

Introduction

The diathesis-stress model, also known as the vulnerability-stress model, is a psychological theory that attempts to explain a disorder, or its trajectory, as the result of an interaction between a predispositional vulnerability, the diathesis, and a stress caused by life experiences. The term diathesis derives from the Greek term (διάθεσις) for a predisposition, or sensibility. A diathesis can take the form of genetic, psychological, biological, or situational factors. A large range of differences exists among individuals’ vulnerabilities to the development of a disorder.

The diathesis, or predisposition, interacts with the individual’s subsequent stress response. Stress is a life event or series of events that disrupts a person’s psychological equilibrium and may catalyse the development of a disorder. Thus the diathesis-stress model serves to explore how biological or genetic traits (diatheses) interact with environmental influences (stressors) to produce disorders such as depression, anxiety, or schizophrenia. The diathesis-stress model asserts that if the combination of the predisposition and the stress exceeds a threshold, the person will develop a disorder. The use of the term diathesis in medicine and in the specialty of psychiatry dates back to the 1800s; however, the diathesis-stress model was not introduced and used to describe the development of psychopathology until it was applied to explaining schizophrenia in the 1960s by Paul Meehl.

The diathesis-stress model is used in many fields of psychology, specifically for studying the development of psychopathology. It is useful for the purposes of understanding the interplay of nature and nurture in the susceptibility to psychological disorders throughout the lifespan. Diathesis-stress models can also assist in determining who will develop a disorder and who will not. For example, in the context of depression, the diathesis-stress model can help explain why Person A may become depressed while Person B does not, even when exposed to the same stressors. More recently, the diathesis-stress model has been used to explain why some individuals are more at risk for developing a disorder than others. For example, children who have a family history of depression are generally more vulnerable to developing a depressive disorder themselves. A child who has a family history of depression and who has been exposed to a particular stressor, such as exclusion or rejection by his or her peers, would be more likely to develop depression than a child with a family history of depression that has an otherwise positive social network of peers. The diathesis-stress model has also served as useful in explaining other poor (but non-clinical) developmental outcomes.

Protective factors, such as positive social networks or high self-esteem, can counteract the effects of stressors and prevent or curb the effects of disorder. Many psychological disorders have a window of vulnerability, during which time an individual is more likely to develop disorder than others. Diathesis-stress models are often conceptualised as multi-causal developmental models, which propose that multiple risk factors over the course of development interact with stressors and protective factors contributing to normal development or psychopathology. The differential susceptibility hypothesis is a recent theory that has stemmed from the diathesis-stress model.

Diathesis

The term diathesis is synonymous with vulnerability, and variants such as “vulnerability-stress” are common within psychology. A vulnerability makes it more or less likely that an individual will succumb to the development of psychopathology if a certain stress is encountered. Diatheses are considered inherent within the individual and are typically conceptualised as being stable, but not unchangeable, over the lifespan. They are also often considered latent (i.e. dormant), because they are harder to recognise unless provoked by stressors.

Diatheses are understood to include genetic, biological, physiological, cognitive, and personality-related factors. Some examples of diatheses include genetic factors, such as abnormalities in some genes or variations in multiple genes that interact to increase vulnerability. Other diatheses include early life experiences such as the loss of a parent, or high neuroticism. Diatheses can also be conceptualised as situational factors, such as low socio-economic status or having a parent with depression.

Stress

Stress can be conceptualised as a life event that disrupts the equilibrium of a person’s life. For instance, a person may be vulnerable to become depressed, but will not develop depression unless they are exposed to a specific stress, which may trigger a depressive disorder. Stressors can take the form of a discrete event, such the divorce of parents or a death in the family, or can be more chronic factors such as having a long-term illness, or ongoing marital problems. Stresses can also be related to more daily hassles such as school assignment deadlines. This also parallels the popular (and engineering) usage of stress, but note that some literature defines stress as the response to stressors, especially where usage in biology influences neuroscience.

It has been long recognised that psychological stress plays a significant role in understanding how psychopathology develops in individuals. However, psychologists have also identified that not all individuals who are stressed, or go through stressful life events, develop a psychological disorder. To understand this, theorists and researchers explored other factors that affect the development of a disorder and proposed that some individuals under stress develop a disorder and others do not. As such, some individuals are more vulnerable than others to develop a disorder once stress has been introduced. This led to the formulation of the diathesis-stress model.

Genetics

Sensory processing sensitivity (SPS) is a temperamental or personality trait involving “an increased sensitivity of the central nervous system and a deeper cognitive processing of physical, social and emotional stimuli”. The trait is characterised by “a tendency to ‘pause to check’ in novel situations, greater sensitivity to subtle stimuli, and the engagement of deeper cognitive processing strategies for employing coping actions, all of which is driven by heightened emotional reactivity, both positive and negative”.

Sensory processing sensitivity captures sensitivity to environment in a heritable, evolutionary-conserved trait, associated with increased information processing in the brain. Moderating sensitivity to environments in a for-better-and-for-worse fashion. Interaction with negative experiences increases risk for psychopathology. Whereas interaction with positive experiences (including interventions), increases positive outcomes. Mast cells are long-lived tissue-resident cells with an important role in many inflammatory settings including host defence to parasitic infection and in allergic reactions. Stress is known to be a mast cell activator.

There is evidence that children exposed to prenatal stress may experience resilience driven by epigenome-wide interactions.” Early life stress interactions with the epigenome show potential mechanisms driving vulnerability towards psychiatric illness. ancestral stress alters lifetime mental health trajectories via epigenetic regulation.

Carriers of congenital adrenal hyperplasia have a predeposition to stress, due to the unique nature of this gene. True rates of prevalence are not known but common genetic variants of the human Steroid 21-Hydroxylase Gene (CYP21A2) are related to differences in circulating hormone levels in the population.

Psychological distress is a known feature of generalised joint hypermobility (gJHM), as well as of its most common syndromic presentation, namely Ehlers-Danlos syndrome, hypermobility type (a.k.a. joint hypermobility syndrome – JHS/EDS-HT), and significantly contributes to the quality of life of affected individuals. Interestingly, in addition to the confirmation of a tight link between anxiety and gJHM, preliminary connections with depression, attention deficit (and hyperactivity) disorder, autism spectrum disorders, and obsessive-compulsive personality disorder were also found.

Protective Factors

Protective factors, while not an inherent component of the diathesis-stress model, are of importance when considering the interaction of diatheses and stress. Protective factors can mitigate or provide a buffer against the effects of major stressors by providing an individual with developmentally adaptive outlets to deal with stress. Examples of protective factors include a positive parent-child attachment relationship, a supportive peer network, and individual social and emotional competence.

Throughout the Lifespan

Many models of psychopathology generally suggest that all people have some level of vulnerability towards certain mental disorders, but posit a large range of individual differences in the point at which a person will develop a certain disorder. For example, an individual with personality traits that tend to promote relationships such as extroversion and agreeableness may engender strong social support, which may later serve as a protective factor when experiencing stressors or losses that may delay or prevent the development of depression. Conversely, an individual who finds it difficult to develop and maintain supportive relationships may be more vulnerable to developing depression following a job loss because they do not have protective social support. An individual’s threshold is determined by the interaction of diatheses and stress.

Windows of vulnerability for developing specific psychopathologies are believed to exist at different points of the lifespan. Moreover, different diatheses and stressors are implicated in different disorders. For example, breakups and other severe or traumatic life stressors are implicated in the development of depression. Stressful events can also trigger the manic phase of bipolar disorder and stressful events can then prevent recovery and trigger relapse. Having a genetic disposition for becoming addicted and later engaging in binge drinking in college are implicated in the development of alcoholism. A family history of schizophrenia combined with the stressor of being raised in a dysfunctional family raises the risk of developing schizophrenia.

Diathesis-stress models are often conceptualised as multi-causal developmental models, which propose that multiple risk factors over the course of development interact with stressors and protective factors contributing to normal development or psychopathology. For example, a child with a family history of depression likely has a genetic vulnerability to depressive disorder. This child has also been exposed to environmental factors associated with parental depression that increase their vulnerability to developing depression as well. Protective factors, such as strong peer network, involvement in extracurricular activities, and a positive relationship with the non-depressed parent, interact with the child’s vulnerabilities in determining the progression to psychopathology versus normative development.

Some theories have branched from the diathesis-stress model, such as the differential susceptibility hypothesis, which extends the model to include a vulnerability to positive environments as well as negative environments or stress. A person could have a biological vulnerability that when combined with a stressor could lead to psychopathology (diathesis-stress model); but that same person with a biological vulnerability, if exposed to a particularly positive environment, could have better outcomes than a person without the vulnerability.

What is Dementia Praecox?

Introduction

Dementia praecox (meaning a “premature dementia” or “precocious madness”) is a disused psychiatric diagnosis that originally designated a chronic, deteriorating psychotic disorder characterised by rapid cognitive disintegration, usually beginning in the late teens or early adulthood. Over the years, the term dementia praecox was gradually replaced by schizophrenia, which remains in current diagnostic use.

The term dementia praecox was first used in 1891 by Arnold Pick (1851-1924), a professor of psychiatry at Charles University in Prague. In a brief clinical report, he described a person with a psychotic disorder resembling “hebephrenia” (schizophrenia). German psychiatrist Emil Kraepelin (1856-1926) popularised the term dementia praecox in his first detailed textbook descriptions of a condition that eventually became a different disease concept and relabelled as schizophrenia. Kraepelin reduced the complex psychiatric taxonomies of the nineteenth century by dividing them into two classes: manic-depressive psychosis and dementia praecox. This division, commonly referred to as the Kraepelinian dichotomy, had a fundamental impact on twentieth-century psychiatry, though it has also been questioned.

The primary disturbance in dementia praecox was seen to be a disruption in cognitive or mental functioning in attention, memory, and goal-directed behaviour. Kraepelin contrasted this with manic-depressive psychosis, now termed bipolar disorder, and also with other forms of mood disorder, including major depressive disorder. He eventually concluded that it was not possible to distinguish his categories on the basis of cross-sectional symptoms.

Kraepelin viewed dementia praecox as a progressively deteriorating disease from which no one recovered. However, by 1913, and more explicitly by 1920, Kraepelin admitted that while there may be a residual cognitive defect in most cases, the prognosis was not as uniformly dire as he had stated in the 1890s. Still, he regarded it as a specific disease concept that implied incurable, inexplicable madness.

Brief History

“[T]he history of dementia praecox is really that of psychiatry as a whole.” Adolf Meyer.

First Use of the Term

Dementia is an ancient term which has been in use since at least the time of Lucretius in 50 B.C.E. where it meant “being out of one’s mind”. Until the seventeenth century, dementia referred to states of cognitive and behavioural deterioration leading to psychosocial incompetence. This condition could be innate or acquired, and the concept had no reference to a necessarily irreversible condition. It is the concept in this popular notion of psychosocial incapacity that forms the basis for the idea of legal incapacity. By the eighteenth century, at the period when the term entered into European medical discourse, clinical concepts were added to the vernacular understanding such that dementia was now associated with intellectual deficits arising from any cause and at any age. By the end of the nineteenth century, the modern ‘cognitive paradigm’ of dementia was taking root. This holds that dementia is understood in terms of criteria relating to aetiology, age and course which excludes former members of the family of the demented such as adults with acquired head trauma or children with cognitive deficits. Moreover, it was now understood as an irreversible condition and a particular emphasis was placed on memory loss in regard to the deterioration of intellectual functions.

The term démence précoce was used in passing to describe the characteristics of a subset of young mental patients by the French physician Bénédict Augustin Morel in 1852 in the first volume of his Études cliniques. and the term is used more frequently in his textbook Traité des maladies mentales which was published in 1860. Morel, whose name will be forever associated with religiously inspired concept of degeneration theory in psychiatry, used the term in a descriptive sense and not to define a specific and novel diagnostic category. It was applied as a means of setting apart a group of young men and women who were suffering from “stupor.” As such their condition was characterised by a certain torpor, enervation, and disorder of the will and was related to the diagnostic category of melancholia. He did not conceptualise their state as irreversible and thus his use of the term dementia was equivalent to that formed in the eighteenth century as outlined above.

While some have sought to interpret, if in a qualified fashion, the use by Morel of the term démence précoce as amounting to the “discovery” of schizophrenia, others have argued convincingly that Morel’s descriptive use of the term should not be considered in any sense as a precursor to Kraepelin’s dementia praecox disease concept. This is due to the fact that their concepts of dementia differed significantly from each other, with Kraepelin employing the more modern sense of the word and that Morel was not describing a diagnostic category. Indeed, until the advent of Pick and Kraepelin, Morel’s term had vanished without a trace and there is little evidence to suggest that either Pick or indeed Kraepelin were even aware of Morel’s use of the term until long after they had published their own disease concepts bearing the same name. As Eugène Minkowski succinctly stated, ‘An abyss separates Morel’s démence précoce from that of Kraepelin.’

Morel described several psychotic disorders that ended in dementia, and as a result he may be regarded as the first alienist or psychiatrist to develop a diagnostic system based on presumed outcome rather than on the current presentation of signs and symptoms. Morel, however, did not conduct any long-term or quantitative research on the course and outcome of dementia praecox (Kraepelin would be the first in history to do that) so this prognosis was based on speculation. It is impossible to discern whether the condition briefly described by Morel was equivalent to the disorder later called dementia praecox by Pick and Kraepelin.

Time Component

Psychiatric nosology in the nineteenth-century was chaotic and characterised by a conflicting mosaic of contradictory systems. Psychiatric disease categories were based upon short-term and cross-sectional observations of patients from which were derived the putative characteristic signs and symptoms of a given disease concept. The dominant psychiatric paradigms which gave a semblance of order to this fragmentary picture were Morelian degeneration theory and the concept of “unitary psychosis” (Einheitspsychose). This latter notion, derived from the Belgian psychiatrist Joseph Guislain (1797-1860), held that the variety of symptoms attributed to mental illness were manifestations of a single underlying disease process. While these approaches had a diachronic aspect they lacked a conception of mental illness that encompassed a coherent notion of change over time in terms of the natural course of the illness and based upon an empirical observation of changing symptomatology.

In 1863, the Danzig-based psychiatrist Karl Ludwig Kahlbaum (1828-1899) published his text on psychiatric nosology Die Gruppierung der psychischen Krankheiten (The Classification of Psychiatric Diseases). Although with the passage of time this work would prove profoundly influential, when it was published it was almost completely ignored by German academia despite the sophisticated and intelligent disease classification system which it proposed. In this book Kahlbaum categorised certain typical forms of psychosis (vesania typica) as a single coherent type based upon their shared progressive nature which betrayed, he argued, an ongoing degenerative disease process. For Kahlbaum the disease process of vesania typica was distinguished by the passage of the sufferer through clearly defined disease phases: a melancholic stage; a manic stage; a confusional stage; and finally a demented stage.

In 1866 Kahlbaum became the director of a private psychiatric clinic in Görlitz (Prussia, today Saxony, a small town near Dresden). He was accompanied by his younger assistant, Ewald Hecker (1843-1909), and during a ten-year collaboration they conducted a series of research studies on young psychotic patients that would become a major influence on the development of modern psychiatry.

Together Kahlbaum and Hecker were the first to describe and name such syndromes as dysthymia, cyclothymia, paranoia, catatonia, and hebephrenia. Perhaps their most lasting contribution to psychiatry was the introduction of the “clinical method” from medicine to the study of mental diseases, a method which is now known as psychopathology.

When the element of time was added to the concept of diagnosis, a diagnosis became more than just a description of a collection of symptoms: diagnosis now also defined by prognosis (course and outcome). An additional feature of the clinical method was that the characteristic symptoms that define syndromes should be described without any prior assumption of brain pathology (although such links would be made later as scientific knowledge progressed). Karl Kahlbaum made an appeal for the adoption of the clinical method in psychiatry in his 1874 book on catatonia. Without Kahlbaum and Hecker there would be no dementia praecox.

Upon his appointment to a full professorship in psychiatry at the University of Dorpat (now Tartu, Estonia) in 1886, Kraepelin gave an inaugural address to the faculty outlining his research programme for the years ahead. Attacking the “brain mythology” of Meynert and the positions of Griesinger and Gudden, Kraepelin advocated that the ideas of Kahlbaum, who was then a marginal and little known figure in psychiatry, should be followed. Therefore, he argued, a research programme into the nature of psychiatric illness should look at a large number of patients over time to discover the course which mental disease could take. It has also been suggested that Kraepelin’s decision to accept the Dorpat post was informed by the fact that there he could hope to gain experience with chronic patients and this, it was presumed, would facilitate the longitudinal study of mental illness.

Quantitative Component

Understanding that objective diagnostic methods must be based on scientific practice, Kraepelin had been conducting psychological and drug experiments on patients and normal subjects for some time when, in 1891, he left Dorpat and took up a position as professor and director of the psychiatric clinic at Heidelberg University. There he established a research programme based on Kahlbaum’s proposal for a more exact qualitative clinical approach, and his own innovation: a quantitative approach involving meticulous collection of data over time on each new patient admitted to the clinic (rather than only the interesting cases, as had been the habit until then).

Kraepelin believed that by thoroughly describing all of the clinic’s new patients on index cards, which he had been using since 1887, researcher bias could be eliminated from the investigation process. He described the method in his posthumously published memoir:

… after the first thorough examination of a new patient, each of us had to throw in a note [in a “diagnosis box”] with his diagnosis written on it. After a while, the notes were taken out of the box, the diagnoses were listed, and the case was closed, the final interpretation of the disease was added to the original diagnosis. In this way, we were able to see what kind of mistakes had been made and were able to follow-up the reasons for the wrong original diagnosis.

The fourth edition of his textbook, Psychiatrie, published in 1893, two years after his arrival at Heidelberg, contained some impressions of the patterns Kraepelin had begun to find in his index cards. Prognosis (course and outcome) began to feature alongside signs and symptoms in the description of syndromes, and he added a class of psychotic disorders designated “psychic degenerative processes”, three of which were borrowed from Kahlbaum and Hecker: dementia paranoides (a degenerative type of Kahlbaum’s paranoia, with sudden onset), catatonia (per Kahlbaum, 1874) and dementia praecox, (Hecker’s hebephrenia of 1871). Kraepelin continued to equate dementia praecox with hebephrenia for the next six years.

In the March 1896 fifth edition of Psychiatrie, Kraepelin expressed confidence that his clinical method, involving analysis of both qualitative and quantitative data derived from long term observation of patients, would produce reliable diagnoses including prognosis:

What convinced me of the superiority of the clinical method of diagnosis (followed here) over the traditional one, was the certainty with which we could predict (in conjunction with our new concept of disease) the future course of events. Thanks to it the student can now find his way more easily in the difficult subject of psychiatry.

In this edition dementia praecox is still essentially hebephrenia, and it, dementia paranoides and catatonia are described as distinct psychotic disorders among the “metabolic disorders leading to dementia”.

Kraepelin’s Influence on The Next Century

In the 1899 (6th) edition of Psychiatrie, Kraepelin established a paradigm for psychiatry that would dominate the following century, sorting most of the recognized forms of insanity into two major categories: dementia praecox and manic-depressive illness. Dementia praecox was characterised by disordered intellectual functioning, whereas manic-depressive illness was principally a disorder of affect or mood; and the former featured constant deterioration, virtually no recoveries and a poor outcome, while the latter featured periods of exacerbation followed by periods of remission, and many complete recoveries. The class, dementia praecox, comprised the paranoid, catatonic and hebephrenic psychotic disorders, and these forms were found in the Diagnostic and Statistical Manual of Mental Disorders (DSM) until the fifth edition was released, in May 2013. These terms, however, are still found in general psychiatric nomenclature.

Change in Prognosis

In the seventh, 1904, edition of Psychiatrie, Kraepelin accepted the possibility that a small number of patients may recover from dementia praecox. Eugen Bleuler reported in 1908 that in many cases there was no inevitable progressive decline, there was temporary remission in some cases, and there were even cases of near recovery with the retention of some residual defect. In the eighth edition of Kraepelin’s textbook, published in four volumes between 1909 and 1915, he described eleven forms of dementia, and dementia praecox was classed as one of the “endogenous dementias”. Modifying his previous more gloomy prognosis in line with Bleuler’s observations, Kraepelin reported that about 26% of his patients experienced partial remission of symptoms. Kraepelin died while working on the ninth edition of Psychiatrie with Johannes Lange (1891-1938), who finished it and brought it to publication in 1927.

Cause

Though his work and that of his research associates had revealed a role for heredity, Kraepelin realized nothing could be said with certainty about the aetiology of dementia praecox, and he left out speculation regarding brain disease or neuropathology in his diagnostic descriptions. Nevertheless, from the 1896 edition onwards Kraepelin made clear his belief that poisoning of the brain, “auto-intoxication,” probably by sex hormones, may underlie dementia praecox – a theory also entertained by Eugen Bleuler. Both theorists insisted dementia praecox is a biological disorder, not the product of psychological trauma. Thus, rather than a disease of hereditary degeneration or of structural brain pathology, Kraepelin believed dementia praecox was due to a systemic or “whole body” disease process, probably metabolic, which gradually affected many of the tissues and organs of the body before affecting the brain in a final, decisive cascade. Kraepelin, recognising dementia praecox in Chinese, Japanese, Tamil and Malay patients, suggested in the eighth edition of Psychiatrie that, “we must therefore seek the real cause of dementia praecox in conditions which are spread all over the world, which thus do not lie in race or in climate, in food or in any other general circumstance of life…”

Treatment

Kraepelin had experimented with hypnosis but found it wanting, and disapproved of Freud’s and Jung’s introduction, based on no evidence, of psychogenic assumptions to the interpretation and treatment of mental illness. He argued that, without knowing the underlying cause of dementia praecox or manic-depressive illness, there could be no disease-specific treatment, and recommended the use of long baths and the occasional use of drugs such as opiates and barbiturates for the amelioration of distress, as well as occupational activities, where suitable, for all institutionalised patients. Based on his theory that dementia praecox is the product of autointoxication emanating from the sex glands, Kraepelin experimented, without success, with injections of thyroid, gonad and other glandular extracts.

Use of Term Spreads

Kraepelin noted the dissemination of his new disease concept when in 1899 he enumerated the term’s appearance in almost twenty articles in the German-language medical press. In the early years of the twentieth century the twin pillars of the Kraepelinian dichotomy, dementia praecox and manic depressive psychosis, were assiduously adopted in clinical and research contexts among the Germanic psychiatric community. German-language psychiatric concepts were always introduced much faster in America (than, say, Britain) where émigré German, Swiss and Austrian physicians essentially created American psychiatry. Swiss-émigré Adolf Meyer (1866-1950), arguably the most influential psychiatrist in America for the first half of the 20th century, published the first critique of dementia praecox in an 1896 book review of the 5th edition of Kraepelin’s textbook. But it was not until 1900 and 1901 that the first three American publications regarding dementia praecox appeared, one of which was a translation of a few sections of Kraepelin’s 6th edition of 1899 on dementia praecox.

Adolf Meyer was the first to apply the new diagnostic term in America. He used it at the Worcester Lunatic Hospital in Massachusetts in the fall of 1896. He was also the first to apply Eugen Bleuler’s term “schizophrenia” (in the form of “schizophrenic reaction”) in 1913 at the Henry Phipps Psychiatric Clinic of the Johns Hopkins Hospital.

The dissemination of Kraepelin’s disease concept to the Anglophone world was facilitated in 1902 when Ross Diefendorf, a lecturer in psychiatry at Yale, published an adapted version of the sixth edition of the Lehrbuch der Psychiatrie. This was republished in 1904 and with a new version, based on the seventh edition of Kraepelin’s Lehrbuch appearing in 1907 and reissued in 1912. Both dementia praecox (in its three classic forms) and “manic-depressive psychosis” gained wider popularity in the larger institutions in the eastern United States after being included in the official nomenclature of diseases and conditions for record-keeping at Bellevue Hospital in New York City in 1903. The term lived on due to its promotion in the publications of the National Committee on Mental Hygiene (founded in 1909) and the Eugenics Records Office (1910). But perhaps the most important reason for the longevity of Kraepelin’s term was its inclusion in 1918 as an official diagnostic category in the uniform system adopted for comparative statistical record-keeping in all American mental institutions, The Statistical Manual for the Use of Institutions for the Insane. Its many revisions served as the official diagnostic classification scheme in America until 1952 when the first edition of the Diagnostic and Statistical Manual: Mental Disorders, or DSM-I, appeared. Dementia praecox disappeared from official psychiatry with the publication of DSM-I, replaced by the Bleuler/Meyer hybridization, “schizophrenic reaction”.

Schizophrenia was mentioned as an alternate term for dementia praecox in the 1918 Statistical Manual. In both clinical work as well as research, between 1918 and 1952 five different terms were used interchangeably: dementia praecox, schizophrenia, dementia praecox (schizophrenia), schizophrenia (dementia praecox) and schizophrenic reaction. This made the psychiatric literature of the time confusing since, in a strict sense, Kraepelin’s disease was not Bleuler’s disease. They were defined differently, had different population parameters, and different concepts of prognosis.

The reception of dementia praecox as an accepted diagnosis in British psychiatry came more slowly, perhaps only taking hold around the time of World War I. There was substantial opposition to the use of the term “dementia” as misleading, partly due to findings of remission and recovery. Some argued that existing diagnoses such as “delusional insanity” or “adolescent insanity” were better or more clearly defined. In France a psychiatric tradition regarding the psychotic disorders predated Kraepelin, and the French never fully adopted Kraepelin’s classification system. Instead the French maintained an independent classification system throughout the 20th century. From 1980, when DSM-III totally reshaped psychiatric diagnosis, French psychiatry began to finally alter its views of diagnosis to converge with the North American system. Kraepelin thus finally conquered France via America.

From Dementia Praecox to Schizophrenia

Due to the influence of alienists such as Adolf Meyer, August Hoch, George Kirby, Charles Macphie Campbell, Smith Ely Jelliffe and William Alanson White, psychogenic theories of dementia praecox dominated the American scene by 1911. In 1925 Bleuler’s schizophrenia rose in prominence as an alternative to Kraepelin’s dementia praecox. When Freudian perspectives became influential in American psychiatry in the 1920s schizophrenia became an attractive alternative concept. Bleuler corresponded with Freud and was connected to Freud’s psychoanalytic movement, and the inclusion of Freudian interpretations of the symptoms of schizophrenia in his publications on the subject, as well as those of C.G. Jung, eased the adoption of his broader version of dementia praecox (schizophrenia) in America over Kraepelin’s narrower and prognostically more negative one.

The term “schizophrenia” was first applied by American alienists and neurologists in private practice by 1909 and officially in institutional settings in 1913, but it took many years to catch on. It is first mentioned in The New York Times in 1925. Until 1952 the terms dementia praecox and schizophrenia were used interchangeably in American psychiatry, with occasional use of the hybrid terms “dementia praecox (schizophrenia)” or “schizophrenia (dementia praecox)”.

Diagnostic Manuals

Editions of the Diagnostic and Statistical Manual of Mental Disorders since the first in 1952 had reflected views of schizophrenia as “reactions” or “psychogenic” (DSM-I), or as manifesting Freudian notions of “defence mechanisms” (as in DSM-II of 1969 in which the symptoms of schizophrenia were interpreted as “psychologically self-protected”). The diagnostic criteria were vague, minimal and wide, including either concepts that no longer exist or that are now labelled as personality disorders (for example, schizotypal personality disorder). There was also no mention of the dire prognosis Kraepelin had made. Schizophrenia seemed to be more prevalent and more psychogenic and more treatable than either Kraepelin or Bleuler would have allowed.

Summary

As a direct result of the effort to construct Research Diagnostic Criteria (RDC) in the 1970s that were independent of any clinical diagnostic manual, Kraepelin’s idea that categories of mental disorder should reflect discrete and specific disease entities with a biological basis began to return to prominence. Vague dimensional approaches based on symptoms – so highly favoured by the Meyerians and psychoanalysts – were overthrown. For research purposes, the definition of schizophrenia returned to the narrow range allowed by Kraepelin’s dementia praecox concept. Furthermore, after 1980 the disorder was a progressively deteriorating one once again, with the notion that recovery, if it happened at all, was rare. This revision of schizophrenia became the basis of the diagnostic criteria in DSM-III (1980). Some of the psychiatrists who worked to bring about this revision referred to themselves as the “neo-Kraepelinians”.

On This Day … 06 June

People (Births)

  • 1900 – Manfred Sakel, Ukrainian-American psychiatrist and physician (d. 1957).

People (Deaths)

  • 1961 – Carl Gustav Jung, Swiss psychiatrist and psychotherapist (b. 1875).

Manfred Sakel

Manfred Joshua Sakel (06 June 1900 to 02 December 1957) was an Austrian-Jewish (later Austrian-American) neurophysiologist and psychiatrist, credited with developing insulin shock therapy in 1927.

Sakel was born in Nadvirna (Nadwórna), in the former Austria-Hungary Empire (now Ukraine), which was part of Poland between the world wars. Sakel studied Medicine at the University of Vienna from 1919 to 1925, specializing in neurology and neuropsychiatry. From 1927 until 1933 Sakel worked in hospitals in Berlin. In 1933 he became a researcher at the University of Vienna’s Neuropsychiatric Clinic. In 1936, after receiving an invitation from Frederick Parsons, the state commissioner of mental hygiene, he chose to emigrate from Austria to the United States of America. In the US, he became an attending physician and researcher at the Harlem Valley State Hospital.

Dr. Sakel was the developer of insulin shock therapy from 1927 while a young doctor in Vienna, starting to practice it in 1933. It would become widely used on individuals with schizophrenia and other mental patients. He noted that insulin-induced coma and convulsions, due to the low level of glucose attained in the blood (hypoglycaemic crisis), had a short-term appearance of changing the mental state of drug addicts and psychotics, sometimes dramatically so. He reported that up to 88% of his patients improved with insulin shock therapy, but most other people reported more mixed results and it was eventually shown that patient selection had been biased and that it didn’t really have any specific benefits and had many risks, adverse effects and fatalities. However, his method became widely applied for many years in mental institutions worldwide. In the USA and other countries it was gradually dropped after the introduction of the electroconvulsive therapy in the 1940s and the first neuroleptics in the 1950s.

Dr. Sakel died from a heart attack on 02 December 1957, in New York City, NY, USA.

Carl Jung

Carl Gustav Jung (born Karl Gustav Jung, 26 July 1875 to 06 June 1961), was a Swiss psychiatrist and psychoanalyst who founded analytical psychology. Jung’s work has been influential in the fields of psychiatry, anthropology, archaeology, literature, philosophy, psychology and religious studies. Jung worked as a research scientist at the famous Burghölzli hospital, under Eugen Bleuler. During this time, he came to the attention of Sigmund Freud, the founder of psychoanalysis. The two men conducted a lengthy correspondence and collaborated, for a while, on a joint vision of human psychology.

Freud saw the younger Jung as the heir he had been seeking to take forward his “new science” of psychoanalysis and to this end secured his appointment as President of his newly founded International Psychoanalytical Association. Jung’s research and personal vision, however, made it impossible for him to follow his older colleague’s doctrine and a schism became inevitable. This division was personally painful for Jung and resulted in the establishment of Jung’s analytical psychology as a comprehensive system separate from psychoanalysis.

Among the central concepts of analytical psychology is individuation – the lifelong psychological process of differentiation of the self out of each individual’s conscious and unconscious elements. Jung considered it to be the main task of human development. He created some of the best known psychological concepts, including synchronicity, archetypal phenomena, the collective unconscious, the psychological complex and extraversion and introversion.

Jung was also an artist, craftsman, builder and a prolific writer. Many of his works were not published until after his death and some are still awaiting publication.

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 are Hallucinations in Psychosis?

Introduction

Visual hallucinations in psychosis are hallucinations accompanied by delusions, which are abnormal beliefs that are endorsed by patients as real, that persist in spite of evidence to the contrary, and that are not part of a patient’s culture or subculture.

Presentation

Visual hallucinations in psychoses are reported to have physical properties similar to real perceptions. They are often life-sized, detailed, and solid, and are projected into the external world. They typically appear anchored in external space, just beyond the reach of individuals, or further away. They can have three-dimensional shapes, with depth and shadows, and distinct edges. They can be colourful or in black and white and can be static or have movement.

Simple versus Complex

Visual hallucinations may be simple, or non-formed visual hallucinations, or complex, or formed visual hallucinations.

Simple visual hallucinations are also referred to as non-formed or elementary visual hallucinations. They can take the form of multicoloured lights, colours, geometric shapes, indiscrete objects. Simple visual hallucinations without structure are known as phosphenes and those with geometric structure are known as photopsias. These hallucinations are caused by irritation to the primary visual cortex (Brodmann’s area 17).

Complex visual hallucinations are also referred to as formed visual hallucinations. They tend to be clear, lifelike images or scenes, such as faces of animals or people. Sometimes, hallucinations are ‘Lilliputian’, i.e. patients experience visual hallucinations where there are miniature people, often undertaking unusual actions. Lilliputian hallucinations may be accompanied by wonder, rather than terror.

Content

The frequency of hallucinations varies widely from rare to frequent, as does duration (seconds to minutes). The content of hallucinations varies as well. Complex (formed) visual hallucinations are more common than Simple (non-formed) visual hallucinations. In contrast to hallucinations experienced in organic conditions, hallucinations experienced as symptoms of psychoses tend to be more frightening. An example of this would be hallucinations that have imagery of bugs, dogs, snakes, distorted faces. Visual hallucinations may also be present in those with Parkinson’s, where visions of dead individuals can be present. In psychoses, this is relatively rare, although visions of God, angels, the devil, saints, and fairies are common. Individuals often report being surprised when hallucinations occur and are generally helpless to change or stop them. In general, individuals believe that visions are experienced only by themselves.

Causes

Two neurotransmitters are particularly important in visual hallucinations – serotonin and acetylcholine. They are concentrated in the visual thalamic nuclei and visual cortex.

The similarity of visual hallucinations that stem from diverse conditions suggest a common pathway for visual hallucinations. Three pathophysiologic mechanisms are thought to explain this.

The first mechanism has to do with cortical centres responsible for visual processing. Irritation of visual association cortices (Brodmann’s areas 18 and 19) cause complex visual hallucinations.

The second mechanism is deafferentation, the interruption or destruction of the afferent connections of nerve cells, of the visual system, caused by lesions, leading to the removal of normal inhibitory processes on cortical input to visual association areas, leading to complex hallucinations as a release phenomenon.

The third mechanism has to do with the reticular activating system, which plays a role in the maintenance of arousal. Lesions in the brain stem can cause visual hallucinations. Visual hallucinations are frequent in those with certain sleep disorders, occurring more often when drowsy. This suggests that the reticular activating system plays a part in visual hallucinations, although the precise mechanism has still not fully been established.

Prevalence

Hallucinations in those with psychoses are often experienced in colour, and most often are multi-modal, consisting of visual and auditory components. They frequently accompany paranoia or other thought disorders, and tend to occur during the daytime and are associated with episodes of excess excitability. The DSM-V lists visual hallucinations as a primary diagnostic criterion for several psychotic disorders, including schizophrenia and schizoaffective disorder.

The lifetime prevalence of all psychotic disorders is 3.48% and that of the different diagnostic groups are as follows:

  • 0.87% for schizophrenia.
  • 0.32% for schizoaffective disorder.
  • 0.07% for schizophreniform disorder.
  • 0.18% for delusional disorder.
  • 0.24% for bipolar I disorder.
  • 0.35% for major depressive disorder with psychotic features.
  • 0.42% for substance-induced psychotic disorders.
  • 0.21% for psychotic disorders due to a general medical condition.

Visual hallucinations can occur as a symptom of the above psychotic disorders in 24% to 72% of patients at some point in the course of their illness. Not all individuals who experience hallucinations have a psychotic disorder. Many physical and psychiatric disorders can manifest with hallucinations, and some individuals may have more than one disorder that could cause different types of hallucinations.

What is Schizoid Avoidant Behaviour?

Introduction

The relationship between schizoid personality disorder (SPD) and avoidant personality disorder (AvPD) has been a subject of controversy for decades.

Today it is still unclear and remains to be seen if these two personality disorders are linked to genetically distinct, but overlapping, personality disorders or if these two personality disorders are merely two different phenotypic expressions of the same genetic disorder.

Background

Both have been associated with a shared genetic risk factor and the same polymorphism within the ANKK1 gene. There is also some evidence that AvPD (like SPD) is a personality disorder of the schizophrenia spectrum.

Originally, schizoid personality disorder involved social avoidance combined with marked ambivalence regarding the desirability of social contact. It included indifference or even cold disdain oscillating with longing for normal relationships. Through the efforts of Theodore Millon, this complex idea was later divided across two disorders with the emergence of a separate AvPD construct and the idea of ambivalence was lost.

According to the differential diagnosis guidelines provided in the text of the DSM-IV the two conditions are distinguished by the extent to which the individual desires social contact versus being indifferent to it. But such distinctions are often difficult to apply in practice, as patients often have unclear, marginal, or shifting status on those elements thought most crucial for differential diagnosis. In the case of the avoidant and schizoid personality disorders, however, both the problem and its solution may be more academic than real.

  • First, research indicates that all of the avoidant symptoms except social withdrawal correlate negatively with the schizoid symptom list and that differential diagnosis is not difficult.
  • Second, schizoid personality disorder is exceedingly rare and the diagnostic quandary may never occur in practice.

However, new research shows that both personality disorders are linked to hypersensitivity.

On This Day … 19 April

People (Births)

  • 1874 – Ernst Rüdin, Swiss psychiatrist, geneticist, and eugenicist (d. 1952).

Ernst Rudin

Ernst Rüdin (19 April 1874 to 22 October 1952) was a Swiss-born German psychiatrist, geneticist, eugenicist and Nazi. Rising to prominence under Emil Kraepelin and assuming his directorship at what is now called the Max Planck Institute of Psychiatry in Munich. While he has been credited as a pioneer of psychiatric inheritance studies, he also argued for, designed, justified and funded the mass sterilisation and clinical killing of adults and children.

Early Career

Commencing in 1893, Rüdin studied medicine at universities in several countries, graduating in 1898. At the Burghölzli in Zurich, he worked as assistant to Eugen Bleuler who coined the term ‘schizophrenia‘. He completed his PhD, then a psychiatric residency at a Berlin prison. From 1907, he worked at the University of Munich as assistant to Emil Kraepelin, the highly influential psychiatrist who had developed the diagnostic split between ‘dementia praecox’ (‘early dementia’ – reflecting his pessimistic prognosis – renamed schizophrenia) and ‘manic-depressive illness’ (including unipolar depression), and who is considered by many to be the father of modern psychiatric classification. Rüdin became senior lecturer in 1909, as well as senior physician at the Munich Psychiatric Hospital, succeeding Alois Alzheimer.

Kraepelin and Rüdin were both ardent advocates of a theory that the German race was becoming overly ‘domesticated’ and thus degenerating into higher rates of mental illness and other conditions. Fears of degeneration were somewhat common internationally at the time, but the extent to which Rüdin took them may have been unique, and from the very beginning of his career he made continuous efforts to have his research translate into political action. He also repeatedly drew attention to the financial burden of the sick and disabled.

Rüdin developed the concept of “empirical genetic prognosis” of mental disorders. He published influential initial results on the genetics of schizophrenia (known as dementia praecox) in 1916. Rüdin’s data did not show a high enough risk in siblings for schizophrenia to be due to a simple recessive gene as he and Kraepelin thought, but he put forward a two-recessive-gene theory to try to account for this. This has been attributed to a “mistaken belief” that just one or a small number of gene variations caused such conditions. Similarly his own large study on Mood disorders correctly disproved his own theory of simple Mendelian inheritance and also showed environmental causes, but Rüdin simply neglected to publish and continued to advance his eugenic theories. Nevertheless, Rüdin pioneered and refined complex techniques for conducting studies of inheritance, was widely cited in the international literature for decades, and is still regarded as “the father of psychiatric genetics”.

Rüdin was influenced by his then brother-in-law, and long-time friend and colleague, Alfred Ploetz, who was considered the ‘father’ of racial hygiene and indeed had coined the term in 1895. This was a form of eugenics, inspired by social darwinism, which had gained some popularity internationally, as would the voluntary or compulsory sterilization of psychiatric patients, initially in America. Rüdin campaigned for this early on. At a conference on alcoholism in 1903, he argued for the sterilisation of ‘incurable alcoholics’, but his proposal was roundly defeated. In 1904, he was appointed co-editor in chief of the newly founded Archive for Racial Hygiene and Social Biology, and in 1905 was among the co-founders of the German Society for Racial Hygiene (which soon became International), along with Ploetz. He published an article of his own in Archives in 1910, in which he argued that medical care for the mentally ill, alcoholics, epileptics and others was a distortion of natural laws of natural selection, and medicine should help to clean the genetic pool.

Increasing Influence

In 1917, a new German Institute for Psychiatric Research was established in Munich (known as the DFA in German; renamed the Max Planck Institute of Psychiatry after World War II), designed and driven forward by Emil Kraepelin. The Institute incorporated a Department of Genealogical and Demographic Studies (known as the GDA in German) – the first in the world specialising in psychiatric genetics – and Rüdin was put in charge by overall director Kraepelin. In 1924, the Institute came under the umbrella of the prestigious Kaiser Wilhelm Society. From 1925, Rüdin spent three years as full Professor of Psychology at Basel, Switzerland. He returned to the Institute in 1928, with an expanded departmental budget and new building at 2 Kraepelinstrasse, financed primarily by the American Rockefeller Foundation. The institute soon gained an international reputation as leading psychiatric research, including in hereditary genetics. In 1931, a few years after Kraepelin’s death, Rüdin took over the directorship of the entire Institute as well as remaining head of his department.

Rüdin was among the first to attempt to educate the public about the “dangers” of hereditary defectives and the value of the Nordic race as “culture creators”. By 1920, his colleague Alfred Hoche published, with lawyer Karl Binding, the influential “Allowing the Destruction of Life Unworthy of Living”.

In 1930, Rüdin was a leading German representative at the First International Congress for Mental Hygiene, held in Washington, US, arguing for eugenics. In 1932, he became President of the International Federation of Eugenics Organisations. He was in contact with Carlos Blacker of the British Eugenics Society, and sent him a copy of pre-Nazi voluntary sterilisation laws enacted in Prussia; a precursor to the Nazi forced sterilisation laws that Rüdin is said to have already prepared in his desk drawer.

From 1935 to 1945, he was President of the Society of German Neurologists and Psychiatrists (GDNP), later renamed the German Association for Psychiatry, Psychotherapy and Neurology (DGPPN).

The American Rockefeller Foundation funded numerous international researchers to visit and work at Rüdin’s psychiatric genetics department, even as late as 1939. These included Eliot Slater and Erik Stromgren, considered the founding fathers of psychiatric genetics in Britain and Scandinavia respectively, as well as Franz Josef Kallmann who became a leading figure in twins research in the US after emigrating in 1936.[4] Kallmann had claimed in 1935 that ‘minor anomalies’ in otherwise unaffected relatives of schizophrenics should be grounds for compulsory sterilisation.

Rüdin’s research was also supported with manpower and financing from the German National Socialists.

Nazi Expert

In 1933, Ernst Rüdin, Alfred Ploetz, and several other experts on racial hygiene were brought together to form the Expert Committee on Questions of Population and Racial Policy under Reich Interior Minister Wilhelm Frick. The committee’s ideas were used as a scientific basis to justify the racial policy of Nazi Germany and its “Law for the Prevention of Hereditarily Diseased Offspring” was passed by the German government on 01 January 1934. Rüdin was such an avid proponent that colleagues nicknamed him the “Reichsfuhrer for Sterilization”

In a speech to the German Society for Rassenhygiene published in 1934, Rüdin recalled the early days of trying to alert the public to the special value of the Nordic race and the dangers of defectives. He stated: “The significance of Rassenhygiene racial hygiene did not become evident to all aware Germans until the political activity of Adolf Hitler and only through his work has our 30-year-long dream of translating Rassenhygiene into action finally become a reality.” Describing it as a ‘duty of honour’ for society to help implement the Nazi policies, Rüdin declared: “Whoever is not physically or mentally fit must not pass on his defects to his children. The state must take care that only the fit produce children. Conversely, it must be regarded as reprehensible to withhold healthy children from the state.”

From early on, Rüdin had been a ‘racial fanatic’ for the purity of the ‘German people’. However, he was also described in 1988 as “not so much a fanatical Nazi as a fanatical geneticist”. His ideas for reducing new cases of schizophrenia would prove a total failure, despite between 73% and 100% of the diagnosed being sterilised or killed.

Rüdin joined the Nazi party in 1937. In 1939, on his 65th birthday, he was awarded a ‘Goethe medal for art and science’ handed to him personally by Hitler, who honoured him as the ‘pioneer of the racial-hygienic measures of the Third Reich’. In 1944, he received a bronze Nazi eagle medal (Adlerschild des Deutschen Reiches), with Hitler calling him the ‘pathfinder in the field of hereditary hygiene’.

In 1942, speaking about ‘euthanasia’, Rüdin emphasised “the value of eliminating young children of clearly inferior quality”. He supported and financially aided the work of Julius Duessen at Heidelberg University with Carl Schneider, clinical research which from the beginning involving killing children.

Post-War

At the end of the war in 1945, Rüdin claimed he had only ever engaged in academic science, only ever heard rumours of killings at the nearby insane asylums, and that he hated the Nazis. However, some of his Nazi political activities, scientific justifications, and awards from Hitler were already uncovered in 1945 (as were his lecture handouts praising Nordics and disparaging Jews). Investigative journalist Victor H. Bernstein concluded: “I am sure that Prof. Rüdin never so much as killed a fly in his 74 years. I am also sure he is one of the most evil men in Germany.” Rüdin was stripped of his Swiss citizenship which he had held jointly with German, and two months later was placed under house arrest by the Munich Military Government. However, interned in the US, he was released in 1947 after a ‘denazification’ trial where he was supported by former colleague Kallmann (a eugenicist himself) and famous quantum physicist Max Planck[verification needed]; his only punishment was a 500-mark fine.

Speculation about the reasons for his early release, despite having been considered as a potential criminal defendant for the Nuremberg trials, include the need to restore confidence and order in the German medical profession; his personal and financial connections to prestigious American and British researchers, funding bodies and others; and the fact that he repeatedly cited American eugenic sterilization initiatives to justify his own as legal (indeed the Nuremberg trials carefully avoided highlighting such links in general). Nevertheless, Rüdin has been cited as a more senior and influential architect of Nazi crimes than the physician who was sentenced to death, Karl Brandt, or the infamous Josef Mengele who had attended his lectures and been employed by his Institute.

After Rüdin’s death in 1952, the funeral eulogy was held by Kurt Pohlisch, a close friend who had been professor of psychiatry at Bonn University, director of the second-largest genetics research institute in Germany, and expert Nazi advisor on Action T4.

Rüdin’s connections to the Nazis were a major reason for criticisms of psychiatric genetics in Germany after 1945.

He was survived by his daughter, Edith Zerbin-Rüdin, who became a psychiatric geneticist and eugenicist herself. In 1996, Zerbin-Rüdin, along with Kenneth S. Kendler, published a series of articles on his work which were criticised by others for whitewashing his racist and later Nazi ideologies and activities (Elliot S. Gershon also notes that Zerbin-Rüdin acted as defender and apologist for her father in private conversation and in a transcribed interview published in 1988). Kendler and other leading psychiatric genetic authors have been accused as recently as 2013 of producing revisionist historical accounts of Rüdin and his ‘Munich School’. Three types of account have been identified: “(A) those who write about German psychiatric genetics in the Nazi period, but either fail to mention Rüdin at all, or cast him in a favorable light; (B) those who acknowledge that Rüdin helped promote eugenic sterilization and/or may have worked with the Nazis, but generally paint a positive picture of Rüdin’s research and fail to mention his participation in the “euthanasia” killing program; and (C) those who have written that Rüdin committed and supported unspeakable atrocities.”