Administration pharmacokinetics and dosage Administration

Typical antipsychotic drugs

The major uses of the antipsychotic drugs are for the treatment of schizophrenia, mood disorders, and senile psychoses. (3,4) Other indications are discussed elsewhere in this book in the consideration of the management of specific disorders, such as Tourette's syndrome, and aggression. The major advantage of the typical neuroleptic drugs is their ability to improve positive symptoms, i.e. delusions and hallucinations. Administration of typical neuroleptic drugs leads to the complete or nearly complete elimination of positive symptoms and disorganization of thought and affect in about 60 to 70 per cent of patients with schizophrenia and an even higher proportion of those with psychotic mania and psychotic depression.(3) The antipsychotic response in schizophrenia and mania is sometimes apparent within a few days in many patients but usually takes up to several weeks or months. A reasonable duration for a clinical trial with one of these agents is 4 to 6 weeks. It is not appropriate to switch medications after 1 or 2 weeks, even if a response is not apparent, unless side-effects pose a serious problem. Positive symptoms (delusions and hallucinations) do not respond to typical neuroleptic drugs in about 10 per cent of schizophrenic patients even during the first episode. (32) Another 20 per cent of patients with schizophrenia develop resistance to this action of these agents during the subsequent course of their illnesses. (33) Development of resistance to typical neuroleptic drugs may occur at any time during the course of treatment, even after many years of control of positive symptoms. Such patients are more likely to respond to clozapine(34> or one of the other atypical antipsychotics.(3,33> For manic patients, typical neuroleptics are usually prescribed with mood stabilizers such as valproic acid, carbamazepine, or lithium carbonate. For patients with psychotic depression, combination with an antidepressant, for example one of the tricyclic antidepressants, selective serotonin reuptake inhibitors ( SSRIs), or mixed reuptake inhibitors is usually required.

The average doses of the typical neuroleptic drugs are given in Table 1... The best results with these drugs in terms of efficacy and side-effects may be expected with the lowest dose needed to produce control of positive symptoms with the fewest extrapyramidal side-effects. (3,4) There are some patients for whom higher doses are indicated, but most controlled studies have failed to find benefits from increasing the dose or combining two or more of these agents. Increasing the dose of these agents when patients fail to respond rapidly, for example within days, is not recommended. A trial should be 4 to 6 weeks in duration. Augmentation with a benzodiazepine may be useful to decrease anxiety until the lower doses of neuroleptic drugs produce adequate control of positive symptoms. (34) Patients who may require higher doses of neuroleptic drugs to respond adequately are at greater risk of tardive dyskinesia and are better treated with an atypical antipsychotic drug.

Table 1 Antipsychotic drugs available in the United States: dosage ranges and forms

However, the improvement in positive symptoms which is often achievable with the typical antipsychotic drug is only one element in the treatment of schizophrenia and is not sufficient grounds for judging response to be adequate. Additional efficacy factors of major importance are improvement in negative symptoms, depression, suicidality, anxiety, and especially cognitive function. (31,) Tolerability and safety factors, such as compliance, tardive dyskinesia, weight gain, and medical morbidity are also major elements in outcome and are influenced by the choice of a typical or atypical antipsychotic drug. Typical neuroleptic drugs do not significantly improve the negative symptoms of schizophrenia in the majority of patients/,3 ,36) There is a consensus that typical neuroleptic drugs can improve negative symptoms that are secondary to positive symptoms and depression while at the same time possibly causing negative symptoms due to their ability to produce extrapyramidal side-effects.(36> Abnormalities in attention, executive function, working memory, storage memory, and semantic memory (verbal fluency) are present in first-episode schizophrenic patients at a moderate to severe level and show slight to moderate, rarely severe, deterioration during the course of illness. (1,37) Approximately 85 per cent of patients with schizophrenia are clinically impaired in one or more domains of cognition. (38) Cognition has been shown to be of critical importance for improving work function, social skills development, and social problem solving. (3.9 Some schizophrenic patients with persistent positive symptoms have normal or near-normal cognition. Typical neuroleptic drugs usually do not improve cognitive function. (1Z) Those typical neuroleptic drugs such as thioridazine and mesoridazine, which have strong antimuscarinic properties, may produce further impairment in some memory functions. (1Z>

All of the typical neuroleptic drugs are likely to be equally effective in treating either the initial presentation for the treatment of psychosis or recurrent psychosis due to breakthrough of symptoms, despite compliance, or because of having stopped medication. (343.5> First-episode patients with schizophrenia usually require much lower doses than patients with two or more episodes, suggesting some progression of the disease process or development of tolerance to the mechanism of action of these drugs/40,' Doses for more chronic patients should be in the range of 5 to 10 mg haloperidol equivalents per day for up to 4 to 6 weeks unless there is a major need for chemical means to prevent harm to self or others, to decrease excitement, or induce sleep. (41 Auxiliary medications for anxiety and sleeplessness, for example benzodiazepines, may supplement these low doses of antipsychotics.(42) Parenteral injections of haloperidol, chlorpromazine, or other neuroleptics may be needed for patients who refuse oral medication or where very rapid onset of action is needed. Oral medication should be substituted as soon as feasible. If positive symptoms fail to respond to a single trial of a typical neuroleptic drug at adequate doses in patients with schizophrenia, there is evidence that switching to another typical antipsychotic, even of a different chemical class, is unlikely to produce greater control. (3,4,33> This is likely to be true for other indications for the use of antipsychotic agents as well.

Atypical antipsychotic drugs

As implied above, there are major advantages for many patients to be treated with the atypical antipsychotic drugs and it is generally recommended that, where possible, these agents be considered as the first-line treatment.(43) The atypical antipsychotic drugs have already become the dominant antipsychotic treatment for schizophrenia, mania, and psychotic depression in clinical practice in the United States; by 1999, they already accounted for 50 to 60 per cent of all new antipsychotic drug prescriptions in that country. Risperidone and olanzapine account for about 20 to 25 per cent each while clozapine and quetiapine account for about 4 to 5 per cent of all antipsychotic drug prescriptions. There is considerable international variation in their usage. Clozapine is much more widely used than any other atypical antipsychotic in Shanghai and Beijing. By contrast, the atypical antipsychotics that are 5-HT 2A antagonists are used in only about 15 per cent of patients in the United Kingdom and Europe (see C.hap.teL4.3:Z). Amisulpride, which is not yet available in the United States, is widely used in France. Cost factors explain part of the variance in the use of these agents within and between countries. The typical neuroleptic drugs are no longer covered by patent protection and are available in inexpensive generic forms. There are a number of patients whose psychosis is adequately controlled by these agents and they (and their families and prescribers) are content to continue them even when informed of the potential advantages of the newer antipsychotic agents. When only the cost of medication is considered, it may seem that fiscal reasons argue for continuation of typical neuroleptic drug treatment since the atypical agents can cost up to 100 times more. However, this view is shortsighted because medication costs account for, at most, 5 per cent of the total costs of schizophrenia, with the major costs being hospitalization and indirect costs such as lost income and disability income to support patients in the community. More effective and tolerable medications can offset their greater cost. (44)

One significant deficiency with the atypical agents is expected to be corrected by the years 2000 to 2002. This is the lack of a long-acting parenteral or oral formulation that would be able to provide the same type of benefit for non-compliant patients provided by long-acting forms of typical neuroleptics, i.e. biweekly or monthly parenterally administered fluphenazine and haloperidol decanoate. (45> Short-acting parenteral formulations of ziprasidone and other atypical antipsychotic agents should also become available, thus increasing the desirability of using these agents for most indications. However, there may be a need for combination of both types of agents in some patients, for example when a greater degree of D2-receptor blockade may be desirable. The individual atypical antipsychotic drugs will now be discussed.

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