3 Classification, aetiology, management and prognostic factors

Introduction

This chapter begins with a discussion of the classification of psychiatric disorders. This includes two major internationally used classifications: the International Classification of Diseases, 10th Revision (ICD-10) of the World Health Organization and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) of the American Psychiatric Association. Factors that cause psychiatric disorders are considered next, followed by a look at the main ways in which such disorders can be treated. The chapter ends by considering prognostic factors.

Classification

Types of psychiatric disorder

As shown in Figure 3.1, most psychiatric disorders can be divided into organic psychiatric disorders, which are secondary to known physical causes, and ‘functional’ disorders. As research in the neurosciences progresses, the underlying physical causes of the functional disorders are being discovered, for example at a neuronal, genetic and biochemical level. Therefore, it could be argued that the traditional dichotomy between organic and functional disorders is gradually becoming less appropriate.

Figure 3.1 • Classification of psychiatric disorders.

Organic psychiatric disorders

Psychiatric symptoms can be caused by organic disorders, such as cerebral tumours and endocrine disorders. For example, depressed mood may result from hypothyroidism or from primary hypoadrenalism (Addison’s disease). Psychiatric symptoms can also result from the abuse of alcohol and drugs, that is, psychoactive substance use disorders. For example, soon after injecting amphetamine intravenously, a drug abuser may experience and exhibit symptomatology indistinguishable from that seen in acute schizophrenia.

Functional disorders

Neuroses/psychoneuroses

In neuroses, or psychoneuroses, the symptoms that occur are understandable and it is possible to empathize with them. The symptoms differ from normal in a quantitative but not a qualitative way. For example, most normal people have experienced anxiety; the more severe neurotic counterpart of this is an anxiety disorder (of which there are several types).Similarly, most normal people will have rechecked something once or twice, for example that their front door is locked or that they have switched off the iron. In the more severe neurotic counterpart of this, obsessive–compulsive disorder, rechecking may occur repeatedly many times.

Diagnostic hierarchy

Figure 3.2 shows the diagnostic hierarchy used for the above types of disorder. The highest level in this hierarchy takes precedence over those below it when a diagnosis is being made. For example, if an otherwise well patient presents with symptoms seen in acute schizophrenia, which turn out to be secondary to intravenous amphetamine abuse, then the diagnosis is psychoactive substance use disorder and not schizophrenia. Similarly, if a patient with chronic schizophrenia has depressive symptoms, the diagnosis is schizophrenia rather than a mood disorder.

Figure 3.2 • Diagnostic hierarchy.

• A given diagnosis takes precedence over those below it.

Developmental and behavioural disorders

There are a number of developmental and behavioural disorders that are not usually classed under the organic psychiatric disorders, psychoses or neuroses. These include personality disorders, learning disability (mental retardation), eating disorders and psychosexual disorders. It is possible to see both a developmental or behavioural disorder and an organic, psychotic or neurotic disorder in the same patient. In such cases both diagnoses are given. For example, a patient with a personality disorder may also suffer from a depressive disorder. A patient with a learning disability may in addition suffer from schizophrenia.

ICD-10

The International Classification of Diseases (ICD) of the World Health Organization (WHO) contains clinical descriptions and diagnostic guidelines for psychiatric disorders. In 1992 the WHO published the 10th revision of the ICD, named ICD-10. For each psychiatric disorder, ICD-10 provides a description of the main clinical features, associated features, and usually also diagnostic guidelines. A supplement for providing diagnostic criteria for research is also available, which gives more structured (‘operationally defined’) criteria for psychiatric diagnoses. Reference is made to ICD-10 diagnoses throughout this book, and the appendix contains a summary of the ICD-10 classification.

DSM-IV-TR/DSM-5

DSM-IV refers to the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders, published by the American Psychiatric Association in 1994. The text accompanying the classification was published in revised form in 2000, giving the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR). DSM IV-TR is a multiaxial classification system. A multiaxial evaluation entails the assessment of each patient on several axes, each of which refers to a different class of information, such as the psychiatric disorder, a description of personality features, physical disorders and the severity of any psychosocial stressors. Although primarily intended for use in the USA, the previous versions of DSM – DSM-III (1983) and DSM-III-R (1987) – have been used in many other countries. This is partly because, unlike the ICD, they gave operational definitions for diagnoses, so making them very useful in research.

The next edition of the DSM will be named DSM-5 and is due to be published in 2013.

Aetiology

In this section a chronological classification of causes of psychiatric disorders is first outlined, followed by a description of individual causes.

Chronological classification

A psychiatric disorder in a single patient can have multiple causes. These can usefully be classified chronologically into predisposing, precipitating and perpetuating factors for a given patient (Figure 3.3).

Figure 3.3 • Chronological classification of causes of psychiatric disorders.

• Predisposing factors are those predisposing a person to being vulnerable to suffering from a psychiatric disorder. Examples include the person’s genetic makeup and personality, and obstetric complications.

• Precipitating factors are those arising just before a psychiatric disorder starts and which appear to have precipitated it. Examples include life events, such as the death of a parent.

• Perpetuating factors are those causing an existing psychiatric disorder to continue. An example is social withdrawal, which itself is often a result of psychiatric disorders (such as depression and schizophrenia).

Individual causes

Psychiatric disorders usually have a multifactorial aetiology. Some individual causes include:

• genetic

• biochemical and neurotransmitter changes

• psychoneuroendocrinological

• psychoimmunological

• electrophysiological

• neuropathological and neuroanatomical

• prenatal and perinatal factors

• infections

• psychosocial stressors

• personality

• psychological

• psychodynamic.

Note that in some cases, for example biochemical and endocrine factors, the changes may contribute to symptoms of the psychiatric disorder and/or may also be secondary to the disorder itself. Further details of the biopsychosocial approach are given in Chapters 1 and 2.

Genetic causes play an important role in many psychiatric disorders, including schizophrenia, mood disorders, Huntington’s disease and a number of individual causes of learning disability such as Down’s syndrome.

For some disorders caused by chromosomal abnormalities, such as Down’s syndrome, the abnormalities can be determined directly by karyotyping.

In the case of Huntington’s disease, the genetic cause is an increased number of CAG repeats at a locus on chromosome 4p16. Therefore, patients with this disorder, and indeed also presymptomatic gene-positive subjects, can be identified by measuring the CAG triplet repeat number at this genetic locus.

Studies in molecular genetics aim to characterize causative genes (as was successfully managed in the case of Huntington’s disease in 1993).

For many psychiatric disorders, the main causative or contributing genes are not currently known. In such cases, the role of genetic factors can be investigated through family studies, twin studies, adoption studies and studies in molecular genetics. Consider the case of a psychiatric disorder in which genetic factors play an important part. In such a case, family studies are likely to show that the lifetime risk for developing the disorder is greater in the biological relatives of an affected individual, or proband, than in the general population. Moreover, the risk is likely to be greater in first-degree relatives, such as full siblings and parents (who have on average 50% of the genome in common with the proband), than in second-degree relatives, such as aunts and uncles (who share 25% of the genome, on average, with the proband). In the case of twins, twin studies would be likely to show that when one twin has the disorder, then the rate of concurrence (the concordance rate) of the disorder in the sibling twin (or co-twin) is greater if the twins are monozygotic (identical) than if they are dizygotic (fraternal). This is because monozygotic twins are genetically identical, whereas dizygotic twins are simply first-degree relatives sharing, on average, 50% of the genome.

Adoption studies look at the rates of occurrence of the disorder in the children of affected biological parents, when these children have been brought up by adoptive parents who either do or do not suffer from the disorder. (Other variants of adoption studies, such as looking at the rate of illness in the children of unaffected biological parents brought up by affected adoptive parents can also be carried out.)

An important cause of some psychiatric symptoms is epilepsy, particularly that affecting the temporal lobe (complex partial seizures of the temporal lobe or temporal lobe epilepsy). For example, complex partial seizures can give rise to features typical of schizophrenia.

Prenatal infection can affect the developing brain in utero and may cause or predispose an individual to certain psychiatric disorders, such as learning disabilities and possibly schizophrenia, (similarly with perinatal head injury during a prolonged forceps delivery, for example, and prolonged hypoxia).

Major stressful events are sometimes associated with the onset of psychiatric disorders. Examples include marriage, divorce, the death of a loved one and losing one’s job. They are known as life events. Another psychosocial stressor that can be important is migration.

Long-term unemployment can lead to low morale, poor self-esteem, social isolation and depressed mood. These, in turn, can act as perpetuating factors not only for depression but also for other psychiatric disorders such as schizophrenia.

There is often a relationship between the incidence and prevalence of psychiatric disorders and social class and marital status. The direction of causality is not necessarily from social class to the disorder. In schizophrenia, for example, the disorder can lead to social drift downwards.

Psychological causes may play an important role in the development of certain psychiatric disorders, such as phobias and psychoactive substance use disorders, and in the development of modes of behaviour in pre-existing psychiatric disorders such as chronic schizophrenia and learning disabilities.

One important group of psychological causes involves behavioural (learning) theory. Learning can be defined as a relatively permanent change in behaviour brought about as a result of prior experience. It may occur through associations being made between two or more phenomena. Two forms of such associative learning are recognized: classical conditioning and operant conditioning. Cognitive learning is a more complex process in which current perceptions are interpreted in the context of previous information in order to solve unfamiliar problems. Social learning theory is based on evidence that learning can also take place through the observation and imitation of others (modelling).

Psychodynamic factors are concerned with unconscious processes that can lead to such psychiatric disorders as hysterical conversion disorders.

Management

When considering the management of a new patient, it is important to determine whether this should take place in the community or in an inpatient setting. The types of treatment available can be considered to fall into the following three groups: physical, psychological and psychosocial. Forms of treatment from these three groups are not mutually exclusive for any given patient. Rather, an integrated approach, in the setting of the multidisciplinary team approach, is required.

Hospitalization

Most patients with psychiatric disorders can be assessed and managed as outpatients. However, there are cases in which hospitalization is necessary. Such cases include first episodes of disorders such as schizophrenia in which appropriate investigations need to be carried out. Hospitalization is also necessary when the patient’s life is at risk, for example because of suicidal thoughts in depression and schizophrenia, and in cases of severe weight and electrolyte loss in anorexia nervosa. In some cases compulsory admission may be necessary under the appropriate mental health legislation.

For patients who are recovering from a psychiatric disorder and who require some help during the day, but who do not need full inpatient care, day hospital places can be used. Day patients attend a particular ward on an agreed number of days each week, enabling monitoring of their mental state and response to medication. Day patients are often offered therapeutic activities such as occupational therapy.

The most appropriate setting for the management of individual disorders is given in the corresponding chapters later in this book.

Physical treatments

The most important type of physical treatment currently in use is pharmacotherapy (drug treatment). Individual classes of the most widely used psychotropic drugs are considered in this section. This is followed by details of other types of physical treatment.

Antipsychotic drugs (neuroleptics)

Antipsychotic drugs are also called neuroleptics. Their main uses are in the treatment of schizophrenia, the acute symptoms of mania and psychotic symptoms resulting from organic disorders and psychoactive substance use. Figure 3.4 shows a classification of some of the main antipsychotic drugs according to whether they are typical (conventional or first-generation) or atypical (second-generation).

Figure 3.4 • Types of antipsychotic drugs.

Typical or first-generation antipsychotics

These block postsynaptic dopamine D₂ receptors in the central nervous system. The main central dopaminergic systems are the:

• mesolimbic system

• tuberoinfundibular system

• nigrostriatal system

• retinal pathways.

The antidopaminergic action on the mesolimbic system is the effect required, as this is thought to be largely responsible for the antipsychotic activity of the typical antipsychotics.

The antidopaminergic action on the tuberoinfundibular system results in unwanted hormonal side-effects. Dopamine is prolactin inhibitory factor, so typical antipsychotics cause hyperprolactinaemia. This, in turn, results in galactorrhoea, gynaecomastia, menstrual disturbances, reduced sperm count and reduced libido.

The antidopaminergic action on the nigrostriatal system results in the following unwanted extrapyramidal side-effects:

• parkinsonism

• dystonias

• akathisia

• tardive dyskinesia.

Details of these drug-induced movement disorders are given in Chapter 8.

Other side-effects of chlorpromazine, the archetypal antipsychotic, are shown in Figure 3.5. Most of these side-effects also occur, in varying degrees, with other typical (first-generation) antipsychotics. Many of these side-effects are the result of antagonist action on the following neurotransmitters:

• dopamine

• acetylcholine (muscarinic receptors)

• adrenaline/noradrenaline

• histamine.

Figure 3.5 • Side-effects of chlorpromazine.

• Effects are not shown (see text).

The effects of the central antidopaminergic actions have been mentioned above. Peripheral antimuscarinic (anticholinergic) symptoms include:

Central antimuscarinic actions can lead to convulsions and pyrexia. Antiadrenergic effects include postural hypotension and failure of ejaculation. Drowsiness is an antihistaminic effect.

The most serious unwanted action of antipsychotics is a rare but potentially fatal toxic delirious state called the neuroleptic malignant syndrome. It is characterized by:

• autonomic dysfunction: hyperthermia; tachycardia; labile blood pressure; pallor; sweating

• fluctuating level of consciousness

• muscular rigidity

• urinary incontinence

and requires urgent medical treatment. Between 0.5% and 1% of patients exposed to neuroleptics develop neuroleptic malignant syndrome. It can also occur with some non-neuroleptic drugs, such as tricyclic antidepressants.

Laboratory investigations commonly, but not always, show:

• increased serum creatinine kinase

• increased white blood cell count.

Chlorpromazine can also lead to photosensitivity. Patients should be warned about this and may need to be offered a topical preparation to block ultraviolet light, especially on sunny days.

Long-term pharmacotherapy with high doses can lead to eye and skin changes, including opacities of the lens and cornea, and a purplish pigmentation of the skin, conjunctiva, cornea and retina.

Typical antipsychotics are available in the form of slow-release depot preparations. These should be administered by deep intramuscular injection, usually at intervals of two to eight weeks. Their advantage over the oral forms is one of improved compliance. Examples of commonly administered depot preparations are given in Table 3.1.

Table 3.1 Commonly administered antipsychotic depot preparations

First-generation antipsychotics

Flupentixol decanoate

Fluphenazine decanoate

Haloperidol decanoate

Pipotiazine palmitate

Zuclopenthixol decanoate

Second-generation antipsychotics

Risperidone

Owing to their sedative side-effects, patients on typical antipsychotics, particularly phenothiazines, should, in general, be advised not to drive. (In Britain, the Driver and Vehicle Licensing Agency requires that: ‘Drugs having anticholinergic side-effects should be avoided in drivers. These include tricyclic antidepressants and phenothiazines.’)

Atypical or second-generation antipsychotics

Atypical or second-generation antipsychotics (see Figure 3.4) have a lower propensity to causeextrapyramidal symptoms (although, in general, they do have potential to cause tardive dyskinesia). This results from the fact that their primary action is not dopaminergic D₂ receptor blockade, although most do bind to these receptors. Instead, they have a greater action than typical antipsychotics on other receptors, such as other dopaminergic receptors and serotonergic (5-HT) receptors. As with typical antipsychotics, neuroleptic malignant syndrome can occur with atypical antipsychotic treatment.

The archetypal atypical antipsychotic is clozapine, which has a higher potency than typical antipsychotics on 5-HT₂, D₄, D₁, muscarinic and α-adrenergic receptors. Important side-effects of clozapine are neutropenia and potentially fatal agranulocytosis. As a result, patients taking this medication must undergo regular haematological monitoring. This should be weekly for the first 18 weeks and then at least fortnightly during the first year of treatment. After one year, if treatment with clozapine is continued and the blood count is stable, the haematological monitoring should be at least four-weekly. It should also be carried out four weeks after discontinuation. Clozapine treatment should be withdrawn permanently if the leucocyte count falls below 3000 mm^–3 or the absolute neutrophil count falls below 1500 mm^–3. Other side-effects are given in Table 3.2 and also include hypersalivation, ECG changes, impaired temperature regulation and hypertension.

Table 3.2 Side-effects of second-generation (atypical) antipsychotic drugs

Weight gain, dizziness, postural hypotension (particularly during initial dose titration)

Hyperglycaemia and possibly type 2 diabetes mellitus (particularly with clozapine, olanzapine and risperidone). Therefore, body mass and plasma glucose should be monitored regularly

Neuroleptic malignant syndrome may occur rarely

The atypical antipsychotic risperidone is indicated for psychoses in which both positive and negative symptoms (see Chapter 8) are prominent. Risperidone is an antagonist at 5-HT_2A, 5-HT₇, D₂, α₁– and α₂-adrenergic and histamine H₁ receptors, but not at cholinergic receptors. Side-effects are shown in Table 3.2 and also include gastrointestinal disturbances and hyperprolactinaemia (which may be associated with galactorrhoea, menstrual cycle changes, amenorrhoea and gynaecomastia). In order to avoidinitial orthostatic hypotension, treatment should begin with a three-day escalating dose titration: usually 2 mg in one to two divided doses on the first day, followed by 4 mg in one to two divided doses on the second day, with the usual dose range of 4–6 mg daily being achieved on the third day; a slower titration may be appropriate in some patients. The atypical antipsychotic paliperidone is a metabolite of risperidone. Risperidone is the first second-generation (atypical) antipsychotic to be made available in the form of a long-acting depot injection (see Table 3.1).

The atypical antipsychotic quetiapine is indicated for the treatment of both positive and negative symptoms of schizophrenia. It has a higher affinity for cerebral 5-HT₂ receptors than for cerebral D₁ and D₂ receptors. It also has high affinity for histaminergic and α₁-adrenergic receptors, but not for cholinergic receptors. As it may cause QT interval prolongation, quetiapine should be used with caution in patients with cardiovascular disease. Other side-effects are outlined in Table 3.2.

The atypical antipsychotic olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who respond to initial treatment. Olanzapine has a similar structure to clozapine. It has a binding affinity to D₂ receptors that is less than that of typical antipsychotics but greater than that of clozapine. It is an antagonist at several 5-HT receptor subtypes (including 5-HT_2A/2C, 5-HT₃ and 5-HT₆), and α₁– and α₂-adrenergic, histamine H₁ and muscarinic receptors. Side-effects are given in Table 3.2.

The atypical antipsychotic amisulpride is indicated for the treatment of both positive and negative symptoms of schizophrenia. It is a highly selective antagonist at D₂ and D₃ receptors, and therefore produces mild extrapyramidal side-effects and hyperprolactinaemia, which may manifest as galactorrhoea, amenorrhoea, gynaecomastia, breast pain and sexual dysfunction. Other side-effects are given in Table 3.2.

Aripiprazole has high affinity for D₂ (as a partial agonist), D_3, 5-HT_1A (as a partial agonist) and 5-HT_1B receptors. Side-effects are given in Table 3.2.

Zotepine has a molecular structure similar to that of clozapine. It has high affinity for 5-HT_2A receptors. Before treatment and each time the dose of zotepine is increased, the patient’s plasma electrolytes and ECG (to check for QT interval prolongation) should be monitored. Other side-effects are given in Table 3.2.

Antipsychotic drugs

• Antipsychotic drugs (neuroleptics) are used to treat schizophrenia, mania and psychotic states resulting from organic illnesses and psychoactive substance use.

• Typical (first-generation) antipsychotics (e.g. chlorpromazine, haloperidol and fluphenazine decanoate) block D₂ receptors and therefore affect central dopaminergic systems: they also block muscarinic, adrenergic and histaminergic receptors.

• Atypical (second-generation) antipsychotics (e.g. clozapine, amisulpride, aripiprazole, olanzapine, paliperidone, quetiapine, risperidone and zotepine) have a low propensity to cause extrapyramidal side-effects.

• Both typical and atypical antipsychotics may, rarely, cause the potentially fatal toxic delirious state neuroleptic malignant syndrome (hyperthermia, fluctuating level of consciousness, muscular rigidity and autonomic dysfunction).

• Compliance with antipsychotic treatment can be improved by using depot preparations.

Antimuscarinic drugs used in parkinsonism

When antipsychotic drug treatment causes parkinsonian symptoms, these may be amenable to treatment with antimuscarinic (anticholinergic) drugs (see Table 3.3).

Table 3.3 Antimuscarinic drugs used in the treatment of parkinsonism resulting from pharmacotherapy with antipsychotics

Procyclidine

Trihexyphenidyl (benzhexol)

Orphenadrine

Antimuscarinic drugs should not routinely be prescribed to patients being treated with typical antipsychotics. They should only be considered when such patients are affected by parkinsonism, because:

• not all patients develop parkinsonism while being treated with typical antipsychotics

• antimuscarinic drugs can clearly cause antimuscarinic side-effects

• antimuscarinic drugs can worsen tardive dyskinesia.

The use of these drugs is discussed further in Chapter 9.

One type of extrapyramidal side-effect of typical antipsychotics is an abnormal involuntary movement caused by slow and continuous muscle contraction or spasm. The collective name for such movements is dystonias. Types of acute drug-induced dystonic reactions include:

• tongue protrusion

• grimacing

• opisthotonos – involving most of the body

• torticollis – involving the neck

• oculogyric crisis – the eyes move superiorly and laterally.

The treatment for an acute dystonic reaction is the parenteral administration of an antimuscarinic (such as procyclidine).

Lithium

Lithium salts are used in the:

• prophylaxis of bipolar mood disorder

• treatment of mania/hypomania

• treatment of resistant depression

• prophylaxis of recurrent depression

• treatment of aggression

• treatment of self-mutilation.

The commonest lithium salts used in clinical psychiatry are lithium carbonate and lithium citrate. Lithium is simply a cation (Li⁺), which is, therefore, not metabolized. It is excreted mainly by the kidneys. Therefore, before starting lithium therapy, the patient’s renal function must be checked. In most patients this involves assessing the plasma urea, electrolytes and creatinine levels. However, if there is any suggestion of poor renal function, full renal function studies must be carried out.

Lithium has a low therapeutic index (the ratio of toxic dose to therapeutic dose). Therefore, regular monitoring of plasma lithium levels is required once a patient is started on lithium therapy. Plasma levels are estimated 8–12 hours after the preceding dose. The lithium dose is adjusted to achieve a lithium level of between 0.4 and 1.0 mmol L^–1 for prophylactic purposes (the lower levels are required in the elderly). Plasma lithium concentrations are checked up to twice weekly when the drug is first started. In established maintenance lithium therapy, the frequency of plasma monitoring can be reduced to once every three months. Plasma urea, electrolytes and creatinine levels can be checked at the same time to monitor renal function. Thyroid function tests should be carried out every six months because thyroid function disturbances can result from long-term lithium treatment.

Side-effects are shown in Figure 3.6. Oedema should not be treated with diuretics because thiazide and loop diuretics reduce lithium excretion and so could cause lithium intoxication. Figure 3.7 shows signs of lithium intoxication. At plasma levels of above 2 mmol L^–1 the following effects can occur:

• hyperreflexia and hyperextension of limbs

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