1. Definition of psychotic disorders

1.1.

The term psychosis refers to a non-specific syndrome characterized by delusions (false beliefs), hallucinations (false sensory perceptions not shared by others), loss of contact with reality and bizarre behaviour. This syndrome can result from a wide range of conditions, including both primary psychiatric disorders (schizophrenia and schizophrenia-related disorders), medical disorders (physical trauma, temporal lobe epilepsy, dementia, neurologic and endocrine disease, metabolic abnormalities) and substance abuse disorders (particularly amphetamines and hallucinogens).

1.2.

Schizophrenia is the most common primary psychosis. It is a severe disorder that typically begins in late adolescence or early adulthood; it is found approximately equally in men and women, though the onset tends to be later in women, who also tend to have a better course and outcome of this disorder. Epidemiological surveys report a point prevalence of 0.4%.

1.3.

Schizophrenia is characterized by fundamental distortions in thinking and perception, and by inappropriate emotions. The disturbance involves the most basic functions that give the normal person a feeling of individuality, uniqueness and self-direction. Behaviour may be seriously disturbed during some phases of the disorder, leading to adverse social consequences. Delusions (strong belief in ideas that are false and without any basis in reality), and hallucinations (commonly auditory hallucinations, e.g. hearing voices) are typical psychotic features of this disorder. Individuals with schizophrenia are usually well oriented to person, place and time.

1.4.

Schizophrenia follows a variable course, with complete symptomatic and social recovery in about one-third of cases. Schizophrenia can, however, follow a chronic or recurrent course, with residual symptoms and incomplete social recovery. Individuals with chronic schizophrenia constituted a large proportion of all residents of mental institutions in the past, and still do where these institutions continue to exist. With modern advances in drug therapy and psychosocial care, almost half the individuals initially developing schizophrenia can expect a full and lasting recovery. Of the remainder, only about one-fifth continue to face serious limitations in their day-to-day activities. Even after the more obvious symptoms of this disorder have disappeared, some residual symptoms may remain. These include lack of interest and initiative in daily activities and work, social incompetence, and inability to take interest in pleasurable activities. These can cause continued disability and poor quality of life. These symptoms can place a considerable burden on families. It has been repeatedly demonstrated that schizophrenia follows a less severe course in developing countries.

1.5.

Health care providers should consider the effect of culture and spirituality on the manifestation of psychiatric symptoms in the primary health care. Different cultures may express psychiatric symptoms in a metaphor or language that differs from the cultural background of the primary care professional and, where necessary and appropriate, interpreters may be used to elicit symptomatology. In addition, some experiences (e.g. hearing voices) may be normal in a culture, while resembling psychopathology. Care must be given to avoid misinterpretation.

2. Preliminary assessment and initial management strategies

2.1.

Health care providers should initially exclude the possibility that an organic illness or a substance abuse disorder is the underlying cause of psychotic symptoms. A detailed medical and psychiatric history, physical and neurologic examination, and mental status assessment should be carried out.

2.2.

In psychoses caused by medical conditions the underlying condition should be treated, with adjunctive psychiatric management for the behavioural problems. In psychoses caused by substance abuse, detoxification or adjustment of medication may be required.

2.3.

In principle, acutely psychotic patients should be evaluated without delay, considering that agitation and uncooperativeness may be present. Health care providers should engage the patient in a dialogue. Family members and friends may represent a valid aid in reducing the level of uncooperativeness.

2.4.

Health care providers may obtain relevant clinical details from individuals who know the patient well. Changes in sleeping pattern, speech, behaviour, or daily routine should be investigated.

2.5.

Health care providers should evaluate whether the patient is contemplating self injury. Suicide attempts may occur at any point in the illness, but the most worrisome periods are during the acute psychotic exacerbations, when a patient may respond to hallucinations or delusions, and during the weeks following an acute psychotic exacerbation, when a patient may experience post-psychotic depressive symptoms.

2.6.

Early intervention for schizophrenia is essential, since there is a relationship between length of untreated psychosis and poor long-term outcome.

2.7.

The management of schizophrenia includes psychosocial intervention. Psychosocial intervention enhances functioning in areas such as independent living, relationships and work. Specific interventions are: family psychoeducation, supported employment, social skill training, teaching illness management skills, cognitive-behavioural therapy and integrated treatment for comorbid substance abuse.

3. Short-term treatment with antipsychotics

3.1.

The primary aim is to reduce the most serious symptoms, including hallucinations, delusions, agitation and disorganised thought and behaviour.

3.2.

Antipsychotic agents are the primary medication for schizophrenia and related psychotic disorders. These agents are particularly effective against psychotic symptoms, while their impact on residual symptoms (lack of interest and initiative, blunted affect) is modest or absent.

3.3.

Before starting antipsychotic therapy, it is generally recommended to check weight and blood pressure. Other suggested monitoring includes electrocardiogram (mandatory in some countries for specific antipsychotics, for example haloperidol), full blood count, urea and electrolytes, creatinine phosphokinase, liver function tests, blood glucose, lipid pattern and prolactin. If these laboratory examinations are not feasible, health care providers should ask the patient and/or family member about the existence of cardiovascular, renal or hepatic abnormalities, and whether drug therapies for these medical conditions have been prescribed and taken.

3.4.

In clozapine users, before starting treatment, obligatory monitoring in many countries includes full blood count. If full blood count is not feasible, clozapine should not be prescribed.

3.5.

In clinical practice antipsychotic agents are classified into conventional or first-generation antipsychotics and atypical or second-generation antipsychotics. First-generation antipsychotics are classified into phenothiazines (chlorpromazine, levomepromazine, promazine, pericyazine, pipotiazine, fluphenazine, perphenazine, prochlorperazine and trifluoperazine), butyrophenones (benperidol and haloperidol), diphenylbutylpiperidines (pimozide), thioxantenes (flupentixol and zuclopentixol) and the substituted benzamides (sulpiride). Second-generation antipsychotics include amisulpride, aripiprazole, clozapine, olanzapine, risperidone, quetiapine, sertindole, ziprasidone, zotepine.

3.6.

With the exception of clozapine (which is more effective than first-generation antipsychotics in the pharmacological treatment of refractory schizophrenia), first- and second-generation antipsychotics are similarly effective in the acute treatment of psychotic symptoms. However, these two groups of agents markedly differ in terms of adverse effects (see 6.1 and 6.2 and 6.3).

3.7.

According to the WHO EML, essential medicines for psychotic disorders are chlorpromazine, fluphenazine decanoate or enantate, haloperidol. These medicines are indicated as an example of the class for which there is the best evidence for effectiveness and safety. Thus chlorpromazine represents phenothiazines; fluphenazine represents injectable long-acting antipsychotics; haloperidol represents butyrophenones.

3.8.

In patients with acute phase schizophrenia or other primary psychotic disorders health care providers should consider the prescription of an oral antipsychotic. If more than one antipsychotic is available, health care providers should chose the most suitable agent for each patient taking into consideration the following aspects: 1) Inclusion in the WHO EML: this list includes the most efficacious, safe and cost-effective medicines; 2) Past history of antipsychotic responsiveness: if a patient has already responded well, without intolerable side-effects to a specific agent, that agent might be chosen; if a patient failed to respond, or had intolerable side-effects, to a specific agent, that agent should generally not be prescribed any more; 3) Treatment adherence: if treatment adherence is a problem, physicians should consider long-acting preparations, such as fluphenazine decanoate; 4) Medical comorbidities: if a patient suffers from specific medical problems, some agents should be avoided (e.g. thioridazine should be avoided in elderly patients with electrocardiogram abnormalities, olanzapine and clozapine should be cautiously prescribed to patients with glucose abnormalities); 5) The subjective impact of adverse reactions: health care providers should discuss with the patient and/or family member the plausible impact of side-effects (e.g. the relevance of weight gain may vary between males and females and in different age groups or cultures); 6) Cost implications: these may change according to the health care system in which antipsychotics are prescribed; 7) New/old agent: as a general rule, it is wise to prescribe well known medicines, since the side-effect profile of new medicines becomes clear only after years of marketing.

3.9.

Treatment should be regularly monitored, and its effect should be assessed after 6-8 weeks. If no improvement is seen after 8 weeks, health care providers may discuss with the patient and/or family member the possibility to switch to another oral antipsychotic. If treatment adherence is a major problem, health care providers may discuss with the patient and/or family member the possibility to switch to a long-acting preparation. If adverse reactions are a major problem, health care providers may discuss with the patient and/or family member the possibility to decrease the dose. If adverse reactions persist despite a dose reduction, a switch to another antipsychotic may be considered.

3.10.

Health care providers should not consider clozapine as first-line pharmacological treatment, as it may cause life-threatening adverse effects of which agranulocytosis is the best known (See 5.6 and 5.7).

3.11.

For prompt control of acute psychotic symptoms health care providers should consider intramuscular treatment only if oral treatment is not feasible. According to the WHO EML, essential medicines are chlorpromazine injection (e.g. 25 mg intramuscular) or haloperidol injection (e.g. 5 mg intramuscular). After intramuscular antipsychotic administration, health care providers should monitor blood pressure, pulse, body temperature and respiratory rate.

3.12.

In addition to pharmacological and non-pharmacological interventions, health care providers should provide information to patients and family members, emphatic listening, reassurance and psychological support. This may help develop a good relationship and a therapeutic alliance that may positively influence the patient subjective well-being and the long-term outcome of the disorder.

3.13.

During antipsychotic treatment, health care providers should check whether neurologic side-effects have developed, including muscular rigidity, tremor, muscular spasm, abnormal involuntary movements of tongue, mouth and face. Health care providers should additionally check weight and blood pressure. Other suggested monitoring includes electrocardiogram (mandatory in some countries for specific antipsychotics, for example haloperidol), full blood count, urea and electrolytes, creatinine phosphokinase, liver function tests, blood glucose, lipid pattern and prolactin. If these laboratory tests are not feasible, health care providers should remember to regularly make a medical examination, including a recent medical history that may help recognize symptoms suggesting the development of cardiovascular, renal or hepatic abnormalities.

4. Long-term treatment with antipsychotics

4.1.

After the acute episode has resolved, it is generally suggested to continue treatment for at least one year. Without treatment, two thirds of patients relapse within one year.

4.2.

There is no reliable strategy to identify the minimum effective dose to prevent relapse. During long-term treatment, health care providers may either maintain or moderately decrease the dose administered during the acute phase, according to clinical status and circumstances.

4.3.

Treatment adherence may be a major problem in the long-term. In these cases, health care providers should discuss with the patient and/or family member the possibility to switch to a long-acting preparation. Non-pharmacological interventions to increase adherence (patient education, family psychoeducation, specific psychotherapeutic interventions) may additionally be implemented.

4.4.

In clozapine users, obligatory monitoring in many countries includes weekly full blood count for 18 weeks, at least every 2 weeks for one year, and monthly thereafter. If these regular checks are not feasible, clozapine should not be prescribed.

5. Administration of antipsychotics

5.1.

It is generally suggested to use one antipsychotic at a time. The concurrent use of two or more antipsychotics do not provide additional benefit, while it produces additional adverse reactions and may interfere with treatment adherence.

5.2.

High doses of antipsychotics increase the risk of adverse reactions without providing additional benefit.

5.3.

It is generally suggested to start with low doses, and to increase gradually. The minimum effective dosage should be prescribed.

5.4.

Long-acting antipsychotics should be prescribed only if treatment adherence constitutes a serious problem. Usually a test dose of a long-acting preparation (e.g. 12.5 mg intramuscular of fluphenazine decanoate) is initially prescribed, then after 4-10 days the dosage is titrated to effective maintenance therapy (e.g. 12.5-50 mg intramuscular of fluphenazine decanoate every 2-4 weeks).

5.5.

Switching from one antipsychotic to another should be performed with caution. Health care providers should gradually reduce the dose of the first antipsychotic while gradually increasing the dose of the new antipsychotic.

5.6.

Clozapine is generally reserved for patients without satisfactory clinical improvement despite the use of adequate doses of at least two antipsychotics prescribed for adequate duration (refractory schizophrenia). Before using clozapine, antipsychotics of different classes are generally prescribed. In clozapine users, treatment effectiveness should be assessed over six months.

5.7.

Prescribing clozapine without white blood cell monitoring may increase the risk of fatal agranulocytosis.

6. Adverse reactions of antipsychotics

6.1.

Antipsychotic side-effects are generally grouped into neurologic and anticholinergic side-effects. Neurologic side-effects include parkinsonian effects (resting tremor, akinesia, rigidity), acute dystonias (slow, prolonged muscular spasms), akathisia (subjective feeling of agitation), neuroleptic malignant syndrome (fever, sweating, confusion, increased blood pressure and pulse, muscular rigidity, very high creatine phospokinase, renal failure), tardive dyskinesia (abnormal involuntary movements of tongue, head, face, mouth), and convulsions. Anticholinergic side-effects include peripheral effects (dry mouth, blurred vision, constipation, urinary retention) and central effects (severe agitation and confusion).

6.2.

If patients develop parkinsonian effects, health care providers should reduce the dose of antipsychotic. If parkinsonian effects persist despite the dose decrease, health care providers may consider the prescription of antiparkinson agents, such as biperiden 2-4 mg/day.

6.3.

Side-effects associated with the use of second-generation antipsychotics include hyperglycaemia, ketoacidosis, diabetes, and lipid dysregulation. Among second-generation antipsychotics, clozapine and olanzapine are associated with the greatest risk of clinically significant weight gain, diabetes mellitus and dyslipidaemia. Antipsychotic related metabolic abnormalities are worrisome, as they are risk factors for cardiovascular morbidity and mortality.

6.4.

Other side-effects associated with antipsychotic use include weight gain, sedation, electrocardiogram abnormalities, orthostatic hypothension, increased prolactin resulting in gynecomastia, galactorrhea, amenorrhea, impotence, leukopenia, agranulocytosis, jaundice, elevated liver enzymes, photosensitivity, skin eruptions, retinal pigmentation.

6.5.

Clozapine can cause serious, life-threatening adverse effects of which agranulocytosis is the best known. Risk of fatal agranulocytosis is around ten times higher in clozapine than other antipsychotic users. This risk is managed by regular monitoring full blood count. It has also been suggested that clozapine is associated with myocarditis, cardio-myopathy and pulmunary embolism.

7. Overdosage of antipsychotics

7.1.

The outcome of antipsychotic overdose is generally favourable unless other central nervous system depressants, such as alcohol and benzodiazepines, have been ingested. Overdosage of phenothiazines may cause more severe symptomatology than other antipsychotic classes.

7.2.

Antipsychotic overdose is characterized by hypotension, tachycardia, hypothermia, arrhythmia, drowsiness, dystonias and seizures.

7.3.

If antipsychotic overdosage of antipsychotics is suspected, referral to acute medical facility is recommended.

8. Special patient populations

8.1.

In elderly patients with behavioural symptoms that may be associated with cognitive impairment or dementia antipsychotics should be prescribed with caution. In general, one half to one third the adult dose is recommended in the elderly, who may be more susceptible to parkinsonian and anticholinergic side-effects. Phenothiazines should be used with caution given the risk of hypotension, and thioridazine may not be considered a first-choice medicine if other antipsychotics are available. Haloperidol has been widely used in the elderly, although the risk of electrocardiogram changes should be monitored.

8.2.

Before prescribing antipsychotics to elderly patients health care providers should take a detailed medical history and a medical examination, and should additionally ask about concurrent drug therapies.

8.3.

If possible, antipsychotics should be avoided during pregnancy, particularly during the first trimester. If absolutely indicated, the use of low doses of haloperidol may be consider after discussion with the patient and/or family member. Haloperidol is excreted into breast milk.

9. Potentially relevant interactions

Alcohol and antipsychotics. Enhanced central nervous system depression may be expected, with impaired concentration, drowsiness and lethargy.

Anticonvulsants and antipsychotics. Antipsychotics lower the seizure threshold and may thus antagonise anticonvulsant action.

Barbiturates and antipsychotics. Enhanced sedative effects is expected.

Carbamazepine and antipsychotics. Carbamazepine reduces haloperidol levels.

Levodopa and antipsychotics. The therapeutic effect of levodopa is antagonised by antipsychotics and vice versa.

10. Essential medicines for psychotic disorders

Chlorpromazine

• Starting dose: 25-50 mg/day orally.
• Therapeutic dose: 75-300 mg/day orally, up to 1 g daily in acute psychoses.
• For prompt control of psychotic symptoms: 25 mg intramuscular injection, may be repeated after one hour if needed, subsequent doses should be 25-50 mg orally 3 times a day. Chlorpromazine injections should not be used intravenously.
• Common adverse effects: akathisia, dystonic extrapyramidal effects, parkinsonian extrapyramidal effects, tardive dyskinesia, tardive dystonia, dry mouth, blurred vision, constipation, urinary retention, nasal congestion, dizziness, drowsiness, orthostatic hypotension, photosensitivity. Intramuscular injection may be painful, may cause hypotension and tachycardia.
• Serious adverse effects: blood dyscrasias, agranulocytosis, leukocytopenia, thrombocytopenia, cholestatic jaundice, neuroleptic malignant syndrome, paralytic ileus, priapism, electrocardiogram changes, including QT prolongation and torsades de pointes, seizures.
• WHO EML: tablet 100 mg; oral liquid 25 mg/5 ml; injection 25 mg.

Fluphenazine

• Starting dose: 2.5-10 mg/day orally.
• Therapeutic dose: 10-20 mg/day orally.
• Long-acting preparations for patients with low treatment adherence: Test dose 12.5 mg intramuscular, after 7 days 12.5-25 mg intramuscular every 3-4 weeks. Do not exceed 50 mg intramuscular every 3-4 weeks.
• Common adverse effects: akathisia, dystonic extrapyramidal effects, parkinsonian extrapyramidal effects, tardive dyskinesia, tardive dystonia, dry mouth, blurred vision, constipation, urinary retention, nasal congestion, dizziness, drowsiness, orthostatic hypotension, photosensitivity.
• Serious adverse effects: blood dyscrasias, agranulocytosis, leukocytopenia, thrombocytopenia, cholestatic jaundice, neuroleptic malignant syndrome, paralytic ileus, priapism, electrocardiogram changes, including QT prolongation and torsades de pointes, seizures, systemic lupus erythematosus-like syndrome, temperature regulation dysfunction.
• WHO EML: long-acting injection 25 mg.

Haloperidol

• Starting dose: 2-5 mg/day orally.
• Therapeutic dose: 4-10 mg/day orally.
• For prompt control of psychotic symptoms: 2 or 5 mg intramuscular, may be repeated after one hour if needed.
• Long-acting preparations for patients with low treatment adherence: Test dose 25 mg intramuscular, after 7 days 50-150 mg intramuscular every 4 weeks.
• Common adverse effects: akathisia, dystonic extrapyramidal effects, parkinsonian extrapyramidal effects, blurred vision, constipation, decreased sweating, dry mouth, nasal congestion, dizziness, drowsiness, orthostatic hypotension, photosensitivity.
• Serious adverse effects: tardive dyskinesia, tardive dystonia, agranulocytosis, cholestatic jaundice, neuroleptic malignant syndrome, paralytic ileus, priapism, electrocardiogram changes, including QT prolongation and torsades de pointes, seizures, systemic lupus erythematosus-like syndrome, temperature regulation dysfunction.
• WHO EML: tablet 2 mg, tablet 5 mg; injection 5 mg.