Pharmacotherapy of Schizophrenia

Clinical manifestations, diagnostic and clinical manifestation of schizophrenia

1. S chizophrenia RVS Chaitanya Koppala

2. Introduction The concept of schizophrenia can be difficult to understand. People who do not suffer from schizophrenia can have little idea of what the experience of hallucinations and delusions is like. There are also many misconceptions about the condition of schizophrenia that have led to prejudice against sufferers of the illness. People with schizophrenia are commonly thought to have low intelligence and to be dangerous . In fact, only a minority shows violent behaviour , with social withdrawal being a more common picture. Up to 10 % of people with schizophrenia commit suicide.

3. Schizophrenia & The Dopamine Hypothesis Dopamine is a neurotransmitter that transports signals between nerve endings in the brain. It is thought that the brains of people with schizophrenia and other psychotic disorders produce  too much dopamine . There is evidence that supports and counters the dopamine hypothesis. The main support for the theory that too much dopamine causes schizophrenia is the fact that antipsychotic medications, which are used to treat schizophrenia, block dopamine receptors. The medications are designed to bind to dopamine receptors in the brain , and their effects have helped many people cope with symptoms. Secondly , drugs that increase levels of dopamine, like amphetamines, often cause psychotic symptoms and a schizophrenic-like paranoid state.

4. Classification Kraepelin , in the late 1890s, coined the term D ementia praecox (early madness) to describe an illness where there was a deterioration of the personality at a young age. C atatonic (where motor symptoms are prevalent and changes in activity vary), ‘ Hebephrenic ’ (silly, childish behaviour , affective symptoms and thought disorder prominence) P aranoid (clinical picture dominated by paranoid delusions). A few years later Bleuler , termed ‘ schizophrenia’ : skhizo (to split) and phren (mind) Two systems for the classification of schizophrenia are widely used: The Diagnostic and Statistical Manual of Mental Disorders, 4th edition ( DSM IV ; American Psychiatric Association, 1994)and The International Classification of Diseases, 10th edition ( ICD 10 ; World Health Organization, 1992).

5. Symptoms and diagnosis To establish a definite diagnosis of schizophrenia it is important to follow the diagnostic criteria in either DSM IV or ICD 10, Acute phase of a psychotic illness include the following: A wkward social behavior ( preoccupied, perplexed and withdrawn) S howing unexpected changes in behavior I nitial vagueness in speech ( stream of thought or poverty of thought) Abnormality of mood ( anxiety, depression, irritability or euphoria) A uditory hallucinations, the most common of which are referred to as ‘voices’; such voices can give commands to patients or may discuss the person in the third person, or comment on their actions D elusions, of which those relating to control of thoughts are the most diagnostic L ack of insight into the illness. These symptoms are commonly called positive symptoms.

6. Factors affecting diagnosis and prognosis There is a reluctance to classify people as suffering schizophrenia on the basis of one acute psychotic illness, There are a number of features which aid prediction of whether an acute illness will become chronic. These features include: A ge of onset, which, typically for schizophrenia, is late teenage to 30 years R eports of a childhood which indicate the individual did not mix or was a rather shy and withdrawn personality A poor work record A desire for social isolation B eing single and not seeming to have sexual relationships A gradual onset of the illness and deterioration from the Previous level of functioning G rossly disorganised behaviour

7. Treatment There is a wide range of antipsychotic drugs available for the treatment of a psychotic illness. Almost antipsychotic drugs are equally effective in the treatment of psychotic symptoms, Some individuals respond better to one drug than another. There is controversy over how long people should remain on an antipsychotic drug following their first acute illness. If the prognosis is poor, long-term therapy should be advocated . Others would want to see a second illness before advocating long-term therapy.

8. Chronic schizophrenia Between 60% and 80% of patients who suffer from an acute psychotic illness will suffer further illness and become chronically affected. For these patients the diagnosis of schizophrenia can be applied. As schizophrenia progresses, there may be periods of relapse with acute symptoms but the underlying trend is towards symptoms of lack of drive, social withdrawal and emotional apathy . Such symptoms are sometimes called negative symptoms and respond poorly to most antipsychotic drugs.

9. Causes of schizophrenia Although the cause of schizophrenia remains unknown, there are many theories and models. Vulnerability model: The vulnerability model postulates that the persistent characteristic of schizophrenia is not the schizophrenic episode itself but the vulnerability to the development of such episodes of the disorder. The episodes of the illness are time limited but the vulnerability remains, awaiting the trigger of some stress . Such vulnerability can depend on premorbid personality , the individual's social network or the environment . Manipulation and avoidance of stress can abort a potential schizophrenic episode.

10. Developmental model T here are critical periods in the development of neuronal cells which, if adversely affected, may result in schizophrenia. Two such critical periods are postulated to occur when migrant neural cells do not reach their goal in fetal development and when supernumerary neural cells slough off at adolescence . This model is supported by neuroimaging studies which show structural brain abnormalities in patients with schizophrenia. Ecological model The ecological model postulates that external factors involving social , cultural and physical forces in the environment, such as population density, individual space, socio-economic status and racial status , influence the development of the disorder. The evidence in support of such a model remains weak.

11. Genetic model: There is undoubtably a genetic component to schizophrenia, with a higher incidence in the siblings of schizophrenics. However, even in monozygotic twins there are many cases where only one sibling has developed schizophrenia. Transmitter abnormality model: The suggestion that schizophrenia is caused primarily by an abnormality of dopamine receptors and, in particular, D2 receptors, has largely emerged from research into the effect of antipsychotic drugs. Such a theory is increasingly being questioned.

12. Other factors Numerous other factors have been implicated in the development and cause of schizophrenia. These include Migration, Socio-economic factors, Perinatal insult, Infections, Season of birth, Viruses, Toxins and Family environment. Social, familial and biological factors may lead to premorbid vulnerability and subsequently influence both the acute psychosis and the progression to chronic states. I nfluence both the development and progression of schizophrenia

13. Drug treatment Mode of action of antipsychotic drugs Although the cause of schizophrenia is the subject of controversy, an understanding of the mode of action of antipsychotic drugs has led to the dopamine theory of schizophrenia. This theory postulates that the symptoms experienced in schizophrenia are caused by an alteration to the level of dopamine activity in the brain. At least six dopamine receptors exist in the brain, with much activity being focused on the D2 receptor as being responsible for antipsychotic drug action. However, drugs such as pimozide , that claim to have a more specific effect on D2 receptors, do not appear superior in antipsychotic effect when compared to other agents.

14. Although a variety of social and psychological therapies are helpful in the treatment of schizophrenia, drugs form the essential cornerstone. The aim of all therapies is to minimize the level of handicap and achieve the best level of mental functioning. Drugs do not cure schizophrenia and are only partially effective at eradicating some symptoms such as delusions and negative symptoms. At the same time, benefits have to be balanced against side effects and whether the need to suppress particular symptoms is important Rationale for use of drugs

15. It is now accepted that antipsychotic drugs can control or modify symptoms such as hallucinations and delusions that are evident in the acute episode of illness. Except for clozapine and the other atypicals , there is little evidence for antipsychotic drugs being of value in the treatment of the negative symptoms, although the matter remains controversial

16. Drug selection and dose Over the years there have been many changes to the range of antipsychotic drugs available. Despite the availability of newer agents many of the issues relevant to drug selection and dose have remained similar for the last 50 years and include: Individual response Drug selection should not be based on chemical group alone, since individual response to a particular drug or dose may be more important. Side effects For older, typical antipsychotic drugs, side effects such as hypotension, extrapyramidal symptoms and anticholinergic effects are key factors in the choice of drug. In contrast, with the newer atypical drugs, side effects such as diabetes, sexual dysfunction and weight gain affect adherence in many patients. Sedation remains a factor for all antipsychotic drugs.

17. Those that caused these side effects (EPSEs ) were called typical antipsychotic drugs and those that did not were called atypical. EPSEs when used at higher doses and the side effects of the different atypicals can vary considerably. EPSEs include: Akathisia or motor restlessness. This causes patients to pace up and down, constantly shift their leg position or tap their feet. Dystonia is the result of sustained muscle contraction. It can present as grimacing and facial distortion, neck twisting and laboured breathing. In addition to these eye movements, the mouth is usually wide open, the tongue protruding and the head tilting backwards. Parkinson-like side effects usually present as tremor, rigidity and poverty of facial expression. Drooling and excessive salivation are also common.

18. Neuroleptic equivalence Although antipsychotic drugs vary in potency, studies on relative dopamine receptor binding have led to the concept of chlorpromazine equivalents as a useful method of transferring dosage from one product to another. Quoted chlorpromazine equivalents of the butyrophenones and the conversion of depot doses to oral doses . For research purposes the concept of proportion of the maximum dose stated in the British National Formulary (BNF) has been developed as a standardised method for calculating average doses used in practice.

19. Equivalence of typical antipsychotic drugs to 100mg of chlorpromazine

20. SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS Sedation Weight gain Diabetes QT prolongation Cardiac risk Anticholinergic risk Extrapyramidal side effects Hormonal effects and sexual dysfunction Postural hypotension and photosensitivity Neuroleptic malignant syndrome (NMS)

21. Anticholinergic drugs Anticholinergic drugs are prescribed to counter the EPSEs of typical antipsychotics. Possible exception of the first few weeks of treatment with antipshigh incidence of EPSEs, anticholinergic drugs should only be prescribed when a need has been shown. Up to 60% of patients may be affected by re-emergence of symptoms and between 25% and 30% of patients will have a continuing need for anticholinergic drugs. The anticholinergic drugs are not without problems , having their own range of side effects that include dry mouth, constipation and blurred vision . T rihexyphenid yl in particular, is renowned for its euphoric effects and withdrawal problems can include cholinergic rebound. One of the benefits of the atypical antipsychotic drugs is the reduced need for co-prescription of anticholinergic drugs.