Antipsychotic and anticholinergic drugs. Topics covered:

• Introduction
• The classes of antipsychotic drugs
• Pharmacology
• Administration, pharmacokinetics, and dosage
  • Administration
  • Pharmacokinetics, metabolism, and drug interactions
• Side-effects
  • Typical neuroleptics
  • Atypical antipsychotic drugs
• Indications and contraindications
• Antiparkinsonian agents
  • Anticholinergic drugs
  • Other drugs
• Conclusions 
• References

Introduction

The discovery by Delay and Denicker in 1953 that chlorpromazine was effective in treating core psychotic symptoms, i.e. delusions, hallucinations, and disorganized thinking, was one of the most important ever made in psychiatry and among the most important in all of medicine. Chlorpromazine and the other antipsychotic drugs which followed have proven to be of immense benefit to vast numbers of people who experience psychotic symptoms as a component of a diverse group of neuropsychiatric and medical disorders, as well as the result of adverse drug reactions. These drugs have been invaluable in providing clues to the aetiology of schizophrenia and other forms of mental illness with psychotic features and as tools in understanding fundamental neural processes, especially those involving dopamine, the key neurotransmitter involved in psychosis. This article will describe the various classes of antipsychotic agents, with emphasis on the newer classes of agents, their mechanism of action, their benefits and adverse effects, and recommendations for their use in clinical practice. The drugs used to treat the extrapyramidal side-effects produced by these agents are also considered.

The classes of antipsychotic drugs

Antipsychotic drugs have been classified into typical and atypical groups, although the latter term is somewhat controversial. (1) Typical antipsychotic drugs are those which produce extrapyramidal side-effects at clinically effective doses in the majority of patients. Extrapyramidal side-effects include parkinsonism (muscle rigidity, loss of associated movements), acute dystonic reactions, dyskinesias, akathisia (restlessness), and tardive dyskinesia. They are also called neuroleptics because of their inhibitory effect upon locomotion activity. Atypical antipsychotic drugs are those with a significantly lower propensity to produce extrapyramidal side-effects at clinically effective doses. (1) They are sometimes referred to as novel antipsychotic drugs, reflecting the later development of most of these compounds (with the exception of clozapine) or by their pharmacology, for example multireceptor antagonists or serotonin (5-hydroxytryptamine) 2A antagonists. (2)

The major classes of typical antipsychotic drugs are benzamides (e.g. sulpiride), butyrophenones (e.g. haloperidol, moperone), dibenzoxazepines (e.g. loxapine, amoxapine), dihydroindolones (e.g. molindone), diphenylbutylpiperidines (pimozide), phenothiazines, of which there are three subtypes (aliphatic (e.g. chlorpromazine), piperidine (e.g. thioridazine, mesoridazine), and piperazine (e.g. fluphenazine, perphenazine, trifluoperazine), and thioxanthenes (e.g. thiothixene, zuclopenthixol). It is useful to classify typical antipsychotic drugs according to potency. Low-potency agents are those in which the usual dose range in schizophrenia is equal to or greater than 200 mg/day (e.g. sulpiride, chlorpromazine, thioridazine, mesoridazine). Mid- to high-potency agents are those in which the dose range is between 2 and 120 mg/day (e.g. haloperidol, fluphenazine, loxapine, molindone, trifluoperazine, thiothixene, etc). In general, the low-potency drugs are more sedative and more hypotensive than the high-potency agents and also have less of a tendency to produce extrapyramidal side-effects. The typical antipsychotic drugs differ with regard to potential for other side-effects but have comparable efficacy as antipsychotic agents. (3,4)

The prototypical atypical antipsychotic drug is clozapine, a dibenzodiazepine. (5) Others include olanzapine, which is a thienobenzodiazepine, (6) quetiapine, which is a dibenzothiazepine,(7) and risperidone, which is a benzisoxazol. (8) Iloperidone(9) and ziprasidone are in late stages of development and have a similar pharmacology. (10) These drugs are all potent 5-HT 2A antagonists as well as multireceptor antagonists. (2,11) Sertindole has a similar pharmacology (12) but was withdrawn, at least temporarily, due to apparent adverse cardiovascular side-effects. Amisulpride and remoxipride are substituted benzamides. Both are selective D 2/D3 antagonists.(2) Remoxipride was withdrawn shortly after its introduction because of a high rate of aplastic anaemia. There is no evidence that amisulpride has a similar vulnerability.

As will be discussed, the atypical antipsychotic drugs differ not only with regard to side-effects but also with regard to efficacy. (13,14) In addition to treating psychosis, some of the atypical antipsychotic agents also appear quite useful in treating mood symptoms in both schizophrenia and mood disorders, (15) and to improve cognitive dysfunction in schizophrenia and perhaps other psychiatric disorders. (16,17 and 18)

Pharmacology

There is abundant evidence that dopamine plays a key role in the aetiology of psychosis and the action of antipsychotic drugs. Studies with drugs such as amphetamine and methamphetamine that exacerbate delusions and hallucinations in schizophrenics, and can produce them with chronic administration in non-schizophrenics as well, have established the importance of dopamine in their aetiology. Stimulation of a subgroup of dopamine receptors, the D 2 receptors, which are negatively coupled to the second messenger adenyl cyclase in the mesolimbic system is a key factor in the aetiology of psychotic symptoms. (19,20) The mesolimbic dopamine neurones reside in the ventral tegmentum, the so-called A10 area, and have terminals in the nucleus accumbens, stria terminalis, and olfactory tubercle. The outflow of these regions to the thalamus and the cortex is believed to mediate psychotic symptoms. The firing rate of the mesolimbic dopaminergic neurones are subject to multiple influences, including serotonergic input from the median raphe. (21) The antipsychotic action of the atypical antipsychotic drugs is highly correlated with their affinities for D2 receptors.(19) The origin of the dopamine neurones that terminate on cholinergic neurones in the basal ganglia is the substantia nigra, the so-called A9 region.(19) Blockade of striatal D2 receptors leads to the extrapyramidal side-effects produced by antipsychotic agents. A group of ventral tegmental dopamine neurones project to various regions of the cortex and comprise the mesocortical dopamine system. There is extensive evidence that these neurones are important for cognition, especially working memory. (22) The prefrontal cortex has relatively low concentrations of D 2 receptors and has a higher density of D3 and D4 dopamine receptors.(20) Despite this, drugs which selectively block D 4 receptors have not been found to have an antipsychotic effect. (23) There are no relevant clinical data yet on the antipsychotic action of drugs which are selective for the D 3 receptor. Both agonists and antagonists of D 3 receptors are of potential interest as antipsychotic agents. Neuroleptic drugs occupy 80 to 95 per cent of striatal D 2 receptors in patients with schizophrenia at clinically effective doses, with extrapyramidal side-effects occurring above 80 per cent occupancy of these receptors. (24) Blockade of D2 receptors in the anterior pituitary gland is the basis for their ability to stimulate prolactin secretion.(17)

The typical antipsychotic drugs vary in their in vitro and in vivo affinities for receptors such as the dopamine D1, histamine H1, muscarinic, a1,a2-adrenergic, and serotonergic receptors, which modulate their effects on arousal, extrapyramidal, cognitive, cardiovascular, gastrointestinal, and genitourinary function. Thioridazine is a relatively potent antimuscarinic agent. Most of the low-potency antipsychotic agents are potent a 1 and H1 antagonists. The specific receptor profile of each atypical antipsychotic is of special interest because it may account for the difference among these compounds. Clozapine has high affinities for the 5-HT 2A, 5-HT2C, 5-HT6, 5-HT7, a1, muscarinic, and H1 receptors. (25,26) Risperidone has high affinities for the 5-HT 2A, 5-HT3, D2, D3, D4, H1, a1, and a2 receptors, and weak affinities for the 5-HT2C, 5-HT6, and muscarinic receptors. (25,26) Olanzapine has high affinities for the 5-HT 2A, 5-HT2C, D1, D2, D4, a1, H1, and M1 and M2 muscarinic receptors. It is also a potent 5-HT6 and a weak 5-HT7 antagonist. (25,26) Quetiapine has weaker affinities for receptors than the other atypical antipsychotic but among those receptors for which it has its highest affinities are the 5-HT 2A, 5-HT7, D2, 5-HT 1A, and a1. It is a weak 5-HT2C and 5-HT6 antagonist. (25,26) Ziprasidone has high affinities for the 5-HT2A, 5-HT2C, 5-HT1, 5-HT6, 5-HT7, D2, D3, a1, and H1 receptors and moderate affinity for the D1 receptor. (25,27) Ziprasidone is also a partial agonist at the 5-HT 1A receptors. (27) Iloperidone has a high affinity for the 5-HT 2A, 5-HT6, 5-HT7, D2, D3, D4, a1, and H1 receptors. It is a relatively weak 5-HT2C antagonist. (9)

All of the above compounds are more potent 5-HT2A than D2 receptor antagonists. This is the most consistent way yet discovered to produce a separation between antipsychotic action and interference with motor function. This principle arose from examining the pharmacology of clozapine, the prototypical atypical antipsychotic drug, and a series of other antipsychotic compounds which had typical or atypical properties. (28) These studies suggested that the low potential for extrapyramidal side-effects of clozapine, olanzapine, quetiapine, risperidone, iloperidone, and ziprasidone are due, in part, to their 5-HT 2 antagonist and weak D2 antagonist properties. Several agents which have only 5-HT 2A-receptor blocking properties, and which lack D 2-receptor antagonism are in testing at the current time, for example SR43469B and M100907. (21) They are active in animal models as antipsychotics. However, M100907 was reported to be less effective than haloperidol, but more so than placebo, in treating acutely psychotic patients. There are no data on SR43469B as yet. It is likely that if such compounds are effective, they will require concomitant treatment with low doses of typical antipsychotics to block D 2 receptors.

The atypical antipsychotic agents have the ability to increase prefrontal cortical dopaminergic activity compared with subcortical and cortical dopaminergic activity. (29) The ability to increase the release of dopamine in the prefrontal cortex may be important for atypical antipsychotic agents to improve cognition and negative symptoms. It may also contribute to decreasing the release of dopamine in the mesolimbic region, because prefrontal dopamine neurones modulate the activity of corticolimbic glutamatergic neurones that influence the release of dopamine from nerve terminals in the limbic region. (22) The atypical antipsychotics also increase the expression of the early intermediate gene c- fos, in the prefrontal cortex and the shell of the nucleus accumbens, while sparing the core of the latter region and the striatum. Typical neuroleptic drugs have the opposite effect on c- fos expression. Sparing the dorsal striatum is believed to be related to the low potential for extrapyramidal side-effects of these agents. (2,21) Clozapine and some of the other atypical antipsychotic drugs also produces marked increases in prefrontal cortical acetylcholine efflux. (30) This may be related to their ability to improve cognitive function. All of the atypical agents also produce marked increase in noradrenaline efflux in the prefrontal cortex which is correlated in time and magnitude with the increase in extracellular dopamine. (31) The basis for and significance of this combined increase in dopamine and noradrenaline in the prefrontal region is unknown. Clozapine, olanzapine, risperidone, and quetiapine are able to block the interference in prepulse inhibition produced by D-amphetamine, apomorphine, or phencyclidine at doses that do not interfere with locomotor function. Clozapine and M100907, a highly selective 5-HT 2A antagonist, are able to block the effects of phencyclidine, an N-methyl-D-aspartate receptor antagonist, on locomotor activity in rodents. This suggests the ability of rat 5-HT2A-receptor blockade to block some of the effects of phencyclidine which is one of the more important models for schizophrenia. (2,21)

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. (32,33) 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 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. (3,4) 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. 

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. (35,36) 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. (17,37) 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. (39) Some schizophrenic patients with persistent positive symptoms have normal or near-normal cognition. Typical neuroleptic drugs usually do not improve cognitive function. (17) Those typical neuroleptic drugs such as thioridazine and mesoridazine, which have strong antimuscarinic properties, may produce further impairment in some memory functions. (17)

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. (3,4,35) 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 Chapter 4.3.7). 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 D 2-receptor blockade may be desirable. The individual atypical antipsychotic drugs will now be discussed.

Clozapine

Clozapine was synthesized in 1959 as part of a project to discover antipsychotic drugs with low potential for extrapyramidal side-effects. It proved to be one of the most interesting and clinically important compounds ever discovered. It was labelled as atypical because of its ability to block amphetamine-induced locomotor activity, one of the most widely accepted models for antipsychotic activity, without producing catalepsy in rodent, the leading indicator for causation of extrapyramidal side-effects in humans. Subsequent clinical studies showed it to have the lowest extrapyramidal side-effects of any antipsychotic drug known. (5,46) Clinical trials in the 1960s and 1970s suggested it was also superior in efficacy with regard to control of positive symptoms, but given the standards of clinical trials of that era, these conclusions could not be relied upon. (47) In 1975, 6 years after its introduction in Europe, clozapine's ability to cause granulocytopenia or agranulocytosis was first reported. Six deaths occurred in clozapine-treated patients in a geographically restricted area of Finland over a short period of time. The role of clozapine in these deaths is still uncertain because no other such clustering has ever occurred in Finland, or elsewhere. Nevertheless, clozapine was withdrawn from general use, although it remained available for humanitarian use in patients who had previously received it, for individual cases where it seemed indicated because of its low potential for extrapyramidal side-effects, and for research purposes. (46)

Clozapine was reintroduced in 1989 after it was demonstrated to be superior to chlorpromazine to improve positive and negative symptoms in 300 patients who were resistant to the action of at least three typical neuroleptics. (48) Thirty per cent of the patients treated with clozapine responded after 6 weeks of treatment compared to 4 per cent of the chlorpromazine-treated patients. Subsequent studies have shown that up to 60 to 70 per cent of patients will respond within 6 months of treatment. Patients with shorter duration of illness tend to respond better. Some predictors of response include weight gain and absence of atrophy in the prefrontal cortex. (34) Clozapine has been reported in several studies to reduce the risk of suicide. (34) It has been shown in a large number of studies to improve some aspects of cognitive function, especially verbal fluency, immediate and delayed verbal learning and memory, and attention. (16,17 and 18) It has little effect upon executive function. Its advantages for cognitive symptoms may be greater in patients not resistant to neuroleptics than in treatment-resistant patients. Because of the importance of cognitive function for work and social function, the advantages of clozapine for cognition warrant consideration of using it in patients treated with typical antipsychotics or other atypical antipsychotics whose positive symptoms may be controlled, but who have not been able to achieved desired work or social function. Monitoring the white blood count for the development of agranulocytosis or granulocytopenia, as well as improved methods of treating agranulocytosis, have made it much safer to use. The frequency of monitoring varies from country to country but should include weekly monitoring for the first 26 weeks, the peak period of agranulocytosis. This will be discussed in more detail subsequently.

Because of the side-effect profile of clozapine, it is not generally used as a first-line drug. However, any patient with an unsatisfactory response to the typical neuroleptics and at least one atypical antipsychotic should be considered for clozapine treatment. This amounts to at least 20 per cent of schizophrenics, assuming that one-third of the neuroleptic-resistant patients will respond to risperidone, olanzapine, or quetiapine. Determination of clozapine plasma levels is useful whenever patients are not responding adequately. Typical or non-atypical antipsychotic drugs should be discontinued either before beginning clozapine or by eliminating them over a 1- to 2-week period as the dose of clozapine is increased. Because clozapine produces only about 40 to 50 per cent occupancy of striatal D 2 receptors,(49) and some of its key advantages are believed to be related to its low D 2-receptor blockade, concomitant administration of typical neuroleptic drugs would be predicted to interfere with some of the benefits of clozapine and, thus, should not ordinarily be prescribed with clozapine. However, some patients with persistent positive symptoms despite an adequate trial of clozapine monotherapy might be expected to benefit from the addition of low-dose haloperidol, or its equivalent, to provide additional low level D2-receptor blockade. Clozapine is usually given twice daily, but sometimes more than half of the dose or the entire dose is given at sleep time to minimize sedation. If response is inadequate, various approaches to augment response have been utilized. In addition to adding a low dose of a typical neuroleptic, as mentioned above, it may be useful to augment clozapine treatment with electroconvulsive therapy, valproic acid or other mood stabilizer, anxiolytic drugs, or an antidepressant. (34) It is difficult to postulate a rationale for adding another atypical antipsychotic, with the exception of amisulpride, because of their similarity in pharmacology to clozapine. It should be discontinued if side-effects are intolerable, or if there is no apparent response after a 6-month trial of clozapine alone and subsequent trials with augmentation therapy. It should be noted that discontinuation of clozapine can precipitate a severe relapse even when clozapine is slowly tapered. (51)

The dose of clozapine in patients with acute mania is comparable to that of schizophrenia. Maintenance doses are lower. Elderly patients with schizophrenia or mood disorders usually respond to doses of 50 to 200 mg/day. The dose in Parkinson's disease is usually between 12.5 and 75 mg/day. (50)

Risperidone

Risperidone is useful as a first-line drug for the treatment of all forms of schizophrenia, including residual schizophrenia. (8,52,53 and 54) Definitive data are lacking for its efficacy in patients who are neuroleptic resistant or who have failed to respond to olanzapine, quetiapine, or clozapine. (3,54) Clinical experience is not supportive of widespread efficacy in these groups but there may be some responders. However, risperidone may be useful in patients who fail to tolerate other antipsychotic agents because of side-effects not shared by risperidone. Risperidone is well-tolerated in low doses by the elderly and has been widely used in the United States for the treatment of a variety of senile psychoses. (55,56) Its efficacy against haloperidol was established in a series of multicentre trials which demonstrated advantages for risperidone in overall psychopathology in mainly chronic schizophrenic patients in an acute exacerbation at doses in the 6 to 8 mg/day range. (8,52) However, these doses have proven to be higher than is needed for most patients in clinical practice, possibly reflecting some of the problems in generalizing from controlled clinical trials. The doses for schizophrenia most often used in non-elderly adults are now 3 to 5 mg/day. Some first-episode patients may respond to 1 to 2 mg/day. Some treatment-resistant patients may need doses higher than 6 mg/day. Whether prolonged trials, i.e. up to 6 months, are useful in such patients, as they are in clozapine patients, is not yet known.

Risperidone has more of a tendency to produce extrapyramidal side-effects than any of the other atypical antipsychotics but this can be minimized by using the lowest dose which controls positive symptoms and adding an anticholinergic drug, if necessary. (56) Addition of a typical neuroleptic to risperidone will increase the risk of extrapyramidal side-effects. Risperidone is not well tolerated by patients with Parkinson's disease because of extrapyramidal side-effects. There are some data suggesting the risk of tardive dyskinesia in patients with schizophrenia, and especially the elderly, with risperidone is less than that of the typical neuroleptic drugs. (57)

The issue of whether the improvement in negative symptoms by risperidone and other atypical antipsychotic drugs is due to an effect on so-called primary negative symptoms versus secondary negative symptoms has been much debated. Data from the large multicentre trials of risperidone versus clozapine show an effect on primary negative symptoms as residual change left after adjusting for improvement due to decreases in positive or depressive symptoms and extrapyramidal side-effects.(58) Risperidone has a greater ability to improve cognition in schizophrenia than the typical neuroleptic drugs. (17) Improvement in working memory has been the strongest finding. Improvement in attention, executive function, and verbal learning and memory has also been reported.

As with clozapine, risperidone has been used in patients with bipolar mania and psychotic depression. (14) It appears to be at least as effective as typical neuroleptic drugs and is better tolerated. Considering the risk of tardive dyskinesia in such patients, it is clearly a superior choice for these patients. Risperidone is also widely used in treating the agitation, aggression, and paranoia of patients with senile psychoses. (56) Low doses (e.g. 0.5–2 mg/day) are usually adequate.

In summary, risperidone is a highly useful addition to the treatment of schizophrenia and other forms of psychosis. It may produce significant advantages over typical neuroleptic drugs with regard to negative symptoms, cognition, and extrapyramidal side-effects, but it does produce equivalent increases in serum prolactin levels. Its tolerability with regard to extrapyramidal side-effects is highly dose dependent so that it must be used at the lower doses where possible.

Olanzapine

Olanzapine is indicated as a first-line treatment for all forms of schizophrenia (6,53,59) with the caveat that it has not been shown to be as effective as clozapine in neuroleptic-resistant patients. (8,60) However, some patients of this type do respond to olanzapine. (60) There are no means yet to determine which of this group of patients will respond to olanzapine (or risperidone) so some clinicians may elect a trial with either of these agents before considering clozapine.

The efficacy of olanzapine in treating psychosis and negative symptoms in patients with an acute exacerbation of schizophrenia has been firmly established in a variety of large-scale, multicentre trials. (6) In these trials, olanzapine at doses of 10 to 20 mg/day has been superior to placebo and equivalent or superior to haloperidol in some measures of total psychopathology, positive, or negative symptoms. For example, in the North American multicentre trial, high-dose olanzapine (15 ± 5 mg/day) was superior to haloperidol (15 ± 5 mg/day) in the treatment of negative symptoms. (59) The effect of olanzapine to improve negative symptoms was found to be on primary rather than secondary negative symptoms.(61) Olanzapine has also been found to be effective as a maintenance treatment of schizophrenia. (61) The estimated relapse rates, defined as the need for hospitalization, during a 1-year period in three studies of patients receiving olanzapine for maintenance treatment were 19.6 to 28.6 per cent. These rates were significantly lower than those in patients receiving placebo, ineffective doses of olanzapine, or haloperidol. (62) Olanzapine has some efficacy in treating the depression associated with schizophrenia or schizoaffective disorder. (63) It is also effective in some cases of treatment-resistant depression, especially in conjunction with SSRIs. (64) It is additionally useful in some forms of mania. (15)

The average clinical dose of olanzapine is 12.5 to 15 mg/day but some patients respond to lower doses. Doses higher than 20 mg/day are rarely more effective than lower doses. Augmentation of olanzapine with typical neuroleptic drugs or risperidone should be done sparingly to avoid extrapyramidal side-effects and possibly compromising efficacy. Studies of the effect of olanzapine on measures of attention, executive function, verbal learning and memory, and verbal fluency are underway. The data available to date indicates effects comparable to those with clozapine. (17,18)

In summary, olanzapine has found wide acceptance as an atypical antipsychotic drug because of its once-a-day administration, efficacy for negative symptoms, improvement in cognitive function, and low extrapyramidal side-effect profile. Significant weight gain may be a problem for some patients.

Quetiapine

Quetiapine has been shown to be as effective as typical antipsychotics, with fewer extrapyramidal side-effects and no effect on serum prolactin levels. (7,64,65) It does not appear to have efficacy comparable to clozapine for treatment-resistant patients. There is no evidence regarding efficacy of quetiapine in patients who fail to respond to risperidone or olanzapine. Preliminary data on the effect of quetiapine on cognition in schizophrenia suggests it may be superior to haloperidol in some domains of cognition.

It has a flat dose–response curve with some patients responding to 150 mg/day and others requiring 750 mg/day. (7,64) Average clinical dose appears to be between 300 and 500 mg/day. The median dose in the elderly is 100 mg/day. (64) There have not yet been data to suggest efficacy advantages over typical neuroleptic drugs but tolerability appears good because of its low side-effect profile. It is well tolerated by patients with Parkinson's disease.

Ziprasidone

Ziprasidone, like quetiapine, has been shown to be superior to placebo for the reduction of total psychopathology and positive and negative symptoms. (10,66) There is limited evidence to suggest superiority over typical neuroleptics with regard to improvement in positive and negative symptoms. (10,66) Ziprasidone significantly improved negative symptoms and reduced the risk of relapse compared to placebo in a 1-year maintenance study in stable hospitalized chronic schizophrenic patients. (67) The dose range of ziprasidone for acute treatment appears to be between 40 and 160 mg/day. Maintenance doses appear to be at the lower end of this range. Preliminary data on the cognitive effects of ziprasidone are encouraging. A parenteral formulation of ziprasidone has been developed which should be useful in situations where oral medication is unacceptable or more rapid action is needed. In summary, ziprasidone appears to be a useful additional atypical antipsychotic agent because of its favourable side-effect profile, including no weight gain—a major problem with olanzapine and clozapine—and no prolactin elevation, which is a less serious side-effect of risperidone.

Sertindole

Sertindole has been shown in several large-scale clinical trials to be antipsychotic with virtually no extrapyramidal side-effects. (12) However, it has been suspected of causing prolongation of the QTc interval, leading to serious cardiovascular complications, in sufficient numbers of patients to require close ECG monitoring at the initiation of treatment. It has, therefore, been withdrawn from use worldwide despite the fact that it appears to have the lowest potential for extrapyramidal side-effects of any agent other than clozapine.

Iloperidone

Clinical trials are currently taking place with this atypical agent to determine its efficacy and side-effect profile compared with typical and other atypical antipsychotic drugs. It has the potential to be made into a long-acting form, which would be of great value.

Amisulpride

High-dose amisulpride (400–800 mg/day) is effective for treating positive symptoms as well as negative symptoms. (68,69) Low-dose amisulpride (300 mg/day) has been shown to be effective in treating negative symptoms in schizophrenics with predominantly negative symptoms. (70,71 and 72) Evaluation of the effect of amisulpride in patients with minimal extrapyramidal side-effects and positive symptoms suggests amisulpride is able to improve primary negative symptoms, even in patients with deficit syndrome schizophrenia. (70,71 and 72) At both dose ranges, amisulpride produces minimal extrapyramidal side-effects and does not increase serum prolactin levels. Amisulpride has not been directly compared with any of the atypical antipsychotic drugs, which is of particular interest for negative symptoms. It is unknown if it is effective in neuroleptic-resistant patients. Because its pharmacology is quite distinct from that of the 5-HT 2A-based receptor antagonists previously discussed, amisulpride may be useful in patients who fail to tolerate that class of drugs.

Pharmacokinetics, metabolism, and drug interactions

The metabolism of most drugs used in clinical practice is carried out by a group of biochemically distinct human live cytochrome-linked enzymes that have been classified into subfamilies. The two most important are the cytochrome P-450 2D6 and 3A subfamilies. There are various forms of the 2D6 in the population. Individuals who have an ineffective form of the 2D6 are slow metabolizers and will have high levels of drugs metabolized by this enzyme. They can be identified by administering derisoquin, sparteine, or dextromethorphan.

The typical neuroleptics are well absorbed when administered orally or parenterally. Intramuscular injection leads to more rapid and higher plasma levels. Peak plasma levels are reached in 30 min after intramuscular injection and 1 to 4 h after oral injection. Steady state is achieved in 3 to 5 days. The half-life for elimination is in the range of 10 to 30 h. Substantial amounts of the antipsychotics are stored in lipids, including in the brain. There is controversy about how long these drugs persist in the system after discontinuation. By the criterion of elevations of plasma prolactin levels, the concentrations are too low to be biologically active within 48 h after discontinuing oral medication. On the other hand, some rodent and human positron emission tomography studies suggest that long-acting forms of haloperidol or fluphenazaine may persist for 1 to 3 months. Metabolism of the typical and atypical antipsychotic drugs occurs in the liver for the most part, via conjugation with glucuronic acid, hydroxylation, oxidation, demethylation and sulphoxide formation. Some metabolites have significant biological activity, for example 9-hydroxyrisperidone, mesoridazine, and 7-hydroxyloxapine. Typical neuroleptics and SSRIs inhibit the 2D6 family. The typical antipsychotics are mainly substrates of CYP1A or CYP2D6, or both.

The pharmacokinetics of the atypical antipsychotic drugs will now be discussed in more detail. There are wide variations in the pharmacokinetics of clozapine in patients. The average half-life is 6 to 12 h. Plasma concentrations are higher in Chinese patients than in Caucasian patients, in non-smokers than smokers, and in females than males. The bioavailability is not affected by food intake, metabolism occurs mainly in the liver. The chief metabolite is N-desmethylclozapine, which has some biological activity. Clozapine is metabolized by CYP1A2. Many antidepressants, especially fluvoxamine, and to a lesser extent fluoxetine, may increase plasma levels of clozapine. (5) Plasma levels of clozapine of approximately 350 ng/ml are more often associated with good response than lower levels. (73)

Risperidone is a prodrug in that is extensively metabolized in the liver by CYP2D6 to 9-hydroxyrisperidone in approximately 92 to 94 per cent of Caucasians. (8,74) Thus, this metabolite is the active species in the majority of patients. About 6 to 8 per cent of Caucasians and a small proportion of Asians have a polymorphism of the CYP2D6 gene, which leads to poor metabolism of risperidone. For poor metabolizers of risperidone, the active moiety is mainly the parent compound. The receptor binding profile of 9-OH-risperidone is very similar to that of risperidone itself. (25) The half-life of the 9-hydroxy metabolite is about 21 h whereas the half-life of risperidone is about 3 h. Thus, risperidone can be used on a once-a-day schedule for normal metabolizers whereas multiple doses are needed for those who are poor metabolizers. Risperidone should be titrated from 2 to 5 mg/day over a 3-day period to minimize hypotensive side-effects. Risperidone is well absorbed from the gut. (8)

Olanzapine has a half-life of 24 to 30 h, which indicates that single daily administration is adequate. (6) The metabolic pathways of olanzapine involves CYP2D6, CYP1A2 and flavin-containing mono-oxygenases, as well as N-glucuronidation. It has a low potential for drug–drug interactions and requires extremely high concentrations not likely to be achieved under clinical conditions to inhibit cytochrome P-450 systems. Plasma levels of approximately 9.3 ng/ml have been reported to predict better clinical response to olanzapine in inpatients with an acute exacerbation. (75)

Quetiapine is well absorbed and is approximately 83 per cent protein bound. (7) It has a half-life of 6 h. It is metabolized in the liver by CYP3A4 to inactive metabolites. Quetiapine has significant interactions with phenytoin, carbamazepine, barbiturates, rifampicin (rifampin), and glucocorticoids; co-administration with these agents may require dosage adjustment. Despite the short half-life, a clinical trial compared three dosing regimens (450 mg/day given in two or three divided doses, and 50 mg/day given twice daily). Both of the higher-dose groups were superior to the low-dose group and there were no differences between the two high-dose schedules. Quetiapine is absorbed better after eating. (7)

Ziprasidone has a half-life of 4 to 10 h. Twice-daily administration is possible despite this relatively short half-life. Ziprasidone should be taken after eating in order to facilitate absorption. Ziprasidone is metabolized mainly by CYP3A4 and has little interaction with any of the other CYP enzymes at clinically relevant dosages. (10)

Iloperidone has a half-life of 12 to 15 h. Its absorption is not affected by food. It should be titrated slowly because of orthostatic hypotension. The optimal dose has not yet been established but is likely to be in the 5 to 10 mg/day range. Amisulpride has a half-life of 10 to 15 h. It is well tolerated. There are no known drug interactions.

Side-effects

Typical neuroleptics

High-potency neuroleptic drugs such as haloperidol and fluphenazine are more likely to produce extrapyramidal side-effects than low-potency agents such as chlorpromazine and thioridazine. The latter may have lower potential for extrapyramidal side-effects than other typical neuroleptics because of its relatively higher affinity for muscarinic receptors. There are a wide range of extrapyramidal side-effects produced by the typical neuroleptics, including dystonic reactions when first administered, parkinsonism during the first weeks with variable persistence, neuroleptic malignant syndrome at any time point but usually in the initial weeks, and tardive dyskinesia.

Dystonic reactions due to neuroleptic drugs can be treated with intravenous anticholinergic agents or diphenhydramine, an antihistamine with some anticholinergic properties. The use of anticholinergic and other agents to manage parkinsonism due to typical neuroleptic drugs will be discussed subsequently.

Tardive dyskinesia emerges at various rates depending upon age, sex, and diagnosis. (76) The rate in younger patients is between 3 and 5 per cent per year. It is higher in bipolar than schizophrenic patients and much higher in people above the age of 60. It is related to dose and will be less likely with lower doses. Tardive dyskinesia is ordinarily reversible and mild but extremely severe and rarely life-threatening forms occur. The best way to minimize its occurrence is to use an atypical antipsychotic drug in lieu of a typical agent. Patients with mood disorders should not receive maintenance treatment with antipsychotic drugs unless mood stabilizers alone prove insufficient because they are at greater risk for tardive dyskinesia.

Neuroleptic malignant syndrome is a rare life-threatening side-effect related to an apparent compromise of the neuromuscular and sympathetic nervous systems. (77) It usually occurs at the initiation of treatment with a high-potency agent but may occur with any of the typical (or atypical agents) at any point. Immediate discontinuation of the medication is essential. The condition is characterized by muscle rigidity, breakdown of muscle fibres leading to large increases in plasma creatine kinase activity, fever, autonomic instability, changing levels of consciousness, and sometimes death. It may be treated by discontinuing all antipsychotic drug treatment, applying external hypothermia, supporting blood pressure, and administering a direct-acting dopamine agonist such as bromocriptine or pergolide, and sodium dantrolene, which blocks the release of intracellular stored calcium ions. After its successful treatment, an atypical antipsychotic should be used even though these agents, including clozapine, may also induce neuroleptic malignant syndrome.

The typical neuroleptic drugs produce a wide variety of other side-effects, including weight gain, seizures (especially pimozide), sedation, hypotension, elevated liver enzymes, retinitis pigmentosa (thioridazine), and anticholinergic effects (mesoridazine and thioridazine). All the typical neuroleptic drugs produce marked increases in serum prolactin levels, with the increases being greater in females than males. (77) Prolactin elevations may affect sexual function in both males and females, with difficulty achieving erection or orgasm among the most common side-effects. (77)

Atypical antipsychotic drugs

Clozapine

Agranulocytosis

It has now been reliably established that clozapine produces agranulocytosis in slightly less than 1 per 100 patients. (78) This is 15 to 30 times the rate associated with the phenothiazines and possibly higher than that for the butyrophenones. The peak of agranulocytosis with clozapine occurs between 4 and 18 weeks, and then falls off sharply. The incidence at various periods after 6 months has never been precisely calculated. Weekly monitoring of the white cell or absolute neutrophil count is required for 26 weeks in most countries, with the frequency decreasing to biweekly or monthly thereafter, sometimes on a voluntary basis. The cost-effectiveness of monitoring after a year has not been studied but it is probably in the range that would lead to its abandonment by current standards. With monitoring, agranulocytosis can usually be detected before infection sets in or becomes overwhelming. Discontinuation of clozapine, beginning treatment with colony cell stimulating factors, and the usual procedures for treating an infection are usually effective in restoring the white cell line.

Other side-effects

Clozapine produces a wide range of side-effects. (79) These can generally be managed by dose adjustment and concomitant medications. Clozapine produces hypotension because of its potent a1-adrenoceptor antagonism and must be slowly titrated in most patients. Low-dose glucocorticoid treatment may be helpful in some patients with severe hypotension. Clozapine rarely if ever produces significant extrapyramidal side-effects, although some cases of akathisia and neuroleptic malignant syndrome have been reported. Tardive dyskinesia and especially tardive dystonia are usually improved by clozapine. Major motor seizures are another important side-effect of clozapine. They are dose related, with the incidence being about 2 per cent in patients at low doses and 6 per cent at doses greater than 600 mg/day. They are sometimes preceded by myoclonic jerks. Valproic acid and dose reductions are usually effective in preventing the progression of myoclonic jerks or treating major motor seizures. Other anticonvulsants can be combined with clozapine if needed. Hypersalivation is another side-effect. It usually responds to anticholinergic therapy or to clonidine. Exacerbation of obsessive–compulsive symptoms has been reported with clozapine. Augmentation with an SSRI or lithium carbonate is usually effective. Weight gain is a frequent side-effect of clozapine, with about 30 per cent of patients gaining more than 7 per cent of body weight. (79) Diet and exercise are useful in minimizing this effect. A related problem is the emergence of type II diabetes or exacerbation of existing diabetes. Somnolence, tachycardia, hypertension, and stuttering are also produced by clozapine. Tachycardia is treated only when the pulse is greater than 100. b-Blockers are effective to reduce the heart rate. (79)

Risperidone

Risperidone is also associated with moderate weight gain, comparable to that of typical neuroleptic drugs, and less than that of clozapine and olanzapine. (80) Risperidone also produces some postural hypotension because of its a 1-adrenoceptor blocking properties. Risperidone produces greater increases in serum prolactin secretion than any of the other atypical antipsychotic drugs. The increases appear to be at least comparable to those of typical neuroleptics. (80) Risperidone, like clozapine and other agents of this type, can sometimes exacerbate or induce symptoms of obsessive–compulsive disorder and tics, probably due to its antiserotonergic properties. This can be counteracted in some patients by the addition of an SSRI. Risperidone is not associated with agranulocytosis or increased risk of seizures.

Olanzapine

Olanzapine produces dose-dependent extrapyramidal side-effects, including some dystonic reactions in patients with schizophrenia, but these are less frequent and severe than those produced by typical neuroleptic drugs. (80) Olanzapine is less well tolerated than clozapine in patients with Parkinson's disease. Olanzapine may be associated with a lower risk of tardive dyskinesia than haloperidol.

The major side-effect of olanzapine is weight gain. (80) Large weight gains due to increased appetite occur in 10 to 15 per cent of olanzapine-treated patients during the first 6 months of treatment. Another 20 to 35 per cent gain between 7 and 10 per cent of body weight. These gains tend to become permanent for as long as patients continue the medication. Some patients develop adult-onset diabetes. Weight gain is associated with increased total cholesterol, and high-density lipoproteins. Olanzapine is also associated with some increase in liver enzymes, orthostatic hypotension, anticholinergic side-effects, and sedation. Olanzapine produces transient increases in serum prolactin levels, which are smaller in magnitude than those produced by typical neuroleptic drugs. (80)

Olanzapine, like other agents of this type, can occasionally exacerbate or induce symptoms of obsessive–compulsive disorder and tics, probably due to its antiserotonergic properties. This can be counteracted in some patients by the addition of an SSRI. Olanzapine is not associated with agranulocytosis or increased risk of seizures.

Quetiapine

Quetiapine appears to have fewer extrapyramidal side-effects than either risperidone or olanzapine. (80) Quetiapine is tolerated in patients with Parkinson's disease to a much greater extent than risperidone or olanzapine. The incidence of extrapyramidal side-effects with quetiapine in schizophrenic patients appears to be comparable to placebo. The major side-effects with quetiapine are headache, agitation, dry mouth, dizziness, weight gain, and postural hypotension. (80) Decreased serum thyroid hormone levels, increased hepatic transaminases and elevated serum lipids have been reported. Animal studies suggest an increased risk of cataracts. (80)

Ziprasidone

Ziprasidone does not increase serum prolactin levels and is virtually devoid of extrapyramidal side-effects and weight gain. Its major side-effects are nasal congestion and somnolence. (80) There has been some concern of cardiovascular side-effects, for example increased QTc interval; however, perusal of the available data does not reveal a significant problem in this regard. However, further study is indicated.

Indications and contraindications

The main indication for the antipsychotic drugs is the treatment of all phases of schizophrenia, including acute, florid symptoms of psychosis, prevention of relapse, and deficit symptoms. Important other uses include the psychotic phase and prophylaxis of mania, depression with psychotic features, the psychosis, agitation, and aggression of various dementias, the treatment of psychoses due to L-dopa or other dopamine agonists in Parkinson's disease, Tourette's syndrome, treatment-resistant obsessive–compulsive disorder, self-injurious behaviour, porphyria, antiemesis, intractable hiccoughs, and as antipruritics. Some current research has suggested that the antipsychotic drugs may be of use to prevent the onset of schizophrenia by administering them to individuals who are in the prodromal phase of the illness.

The atypical antipsychotic drugs are being tried on an experimental basis in patients with treatment resistant non-psychotic depression and various character disorders such as borderline, schizoid, and schizotypal personality disorders. Clozapine, which has the lowest incidence of extrapyramidal side-effects of any of the antipsychotic drugs, has some special applications in neurological conditions such as essential tremor and the treatment of the water intoxication syndrome in schizophrenic patients. The uses of the classical antipsychotics such as chlorpromazine and haloperidol have been limited by their side-effects, especially parkinsonism and tardive dyskinesia, a slowly developing, sometimes irreversible series of abnormal involuntary movements involving facial, limb, and girdle muscles.

As has been discussed, the atypical antipsychotic drugs such as clozapine, olanzapine, quetiapine, and risperidone, as well as iloperidone and ziprasidone, which are in development, have significant advantages with regard to parkinsonism. Clozapine definitely has a vastly reduced risk of tardive dyskinesia and the other atypical agents most likely have a risk that is less than that of the typical neuroleptic drugs but more than clozapine. Uses in other psychiatric and neurological conditions may be expected to emerge as the safety profile of these agents is better described.

Antiparkinsonian agents

Anticholinergic drugs

Antiparkinsonian medications, including anticholinergic, antihistaminic, benzodiazepines, dopamine agonists, and b-blockers are of importance in the management of extrapyramidal side-effects. They are usually needed with the typical neuroleptic drugs but some patients will require antiparkinsonian treatment with olanzapine, risperidone, or quetiapine. The anticholinergics and the antihistaminics (e.g. diphenhydramine) are used to treat acute dyskinesias and dystonias, pseduoparkinsonian symptoms (tremor, rigidity, bradykinesia, shuffling gait), and akathisia. These agents act centrally in the basal ganglia to block the effects of increased acetylcholine release due to D 2-receptor blockade. The most widely used anticholinergic drugs are benztropine, biperiden, procyclidine, and trihexyphenidyl. Benztropine is given in doses of 1 to 8 mg/day usually in divided doses. Biperiden is given in doses of 2 to 24 mg/day in two or three doses. Procyclidine is given in divided doses of 5 to 30 mg/day. Trihexylphenidyl is given in doses of 4 to 30 mg/day, in a single or divided dose.

These agents are competitive antagonists of the five subtypes of muscarinic receptors that have been identified and which are labelled M 1 to M5. They have minimal antagonist effect at nicotinic cholinergic receptors. Blockade of cholinergic receptors on intrastriatal neurones by these agents restores the cholinergic balance, which is disrupted by blockade of D2 dopamine receptors by some antipsychotic agents. Other central effects include impairment of various forms of memory. Elderly patients in particular may develop anticholinergic-induced agitation, irritability, disorientation, hallucinations and delirium because of the natural loss of cholinergic neurones with aging.

Side-effects

These agents have some preference for the central nervous system but some peripheral anticholinergic effects are to be expected. Blockade of vagal tone in the heart produces tachycardia. Other adverse effects include decreased bladder function and urinary retention and decreased bowel motility leading to constipation and impaction. Decreased saliva and bronchial secretion contribute to dry mouth and increased dental caries while decreased sweating increases the risk of heat stroke. Blockade of muscarinic receptors in the eye cause pupillary dilation and inhibition of accommodation, leading to photophobia and blurred vision. Rarely, narrow-angle glaucoma may ensue. The muscarinic receptors in the basal ganglia are predominantly M 2 whereas those in the periphery are M1. The rank order of the anticholinergic drugs for relative selectivity for the M 2 receptor is biperiden, procycliden, trihexylphenidyl, and benztropine. All these agents can cause dry mouth, blurred vision, urinary retention, constipation and increased intraocular pressure. They may cause anticholinergic delirium in elderly patients or after taking high doses. Biperidine is less likely to cause peripheral anticholinergic effects. Benztropine, biperiden, and trihexyphenidyl may cause euphoria because of their ability to inhibit dopamine reuptake and may be subject to abuse.

Indications

The anticholinergic drugs or the antihistamine diphenhydramine are given intramuscularly for the treatment of acute dystonic reactions. They are usually effective within minutes and may have to be repeated. It is not usually necessary to prescribe an anticholinergic following a dystonic reaction. These agents should not be given prophylactically unless it is well established that the patient generally will have extrapyramidal side-effects at the dose of antipsychotic which is being started. If akathisia or parkinsonism develops following treatment with a typical neuroleptic drug, the first consideration should be whether to continue to use the offending agent and drop the dosage or to substitute an atypical antipsychotic drug. If decreasing the dose of antipsychotic drugs does not suffice, substituting an atypical antipsychotic drug is clearly the recommended choice since it avoids all the unpleasant side-effects of the anticholinergic agents. Clozapine has the least likelihood of causing extrapyramidal side-effects, followed by olanzapine and quetiapine, with the greatest likellihood being for risperidone.

Other drugs

Amantadine, which also has antiviral actions, is able to increase the release of dopamine in the basal ganglia, which diminishes the release of acetylcholine. It may improve acute dystonias, akathisia, akinesia, parkinsonism, and tardive dyskinesia. It has also been reported to improve sexual function and decrease weight gain due to neuroleptic drugs. It may cause increased arousal, agitation, and indigestion, however. The usual oral dose is 100 to 400 mg/day.

Beta-blockers such as propranolol, atenolol, and pindolol are useful for treating akathisia and tremor. They cause bradycardia and should not be stopped abruptly due to rebound tachycardia.

Benzodiazepines, such as clonazepam, lorazepam, and diazepam, are useful for treating akathisia, acute dystonias, and acute dyskinesias. They can cause drowsiness and lethargy.

Conclusions

Antipsychotic drugs are invaluable tools in treating a large variety of patients with schizophrenia, mood disorders with psychotic features, senile and other organic psychoses, dopaminomimetic psychoses associated with Parkinson's disease, and a variety of other miscellaneous conditions. Their main benefits are, in fact, to treat psychotic symptoms, but the newer agents in particular may improve cognition, mood, anxiety, and aggression as well. The evidence for atypical antipsychotic drugs to improve cognition is steadily increasing and this should be one of the driving forces behind the substitution of these agents for the typical antipsychotic drugs. They are useful as both acute and maintenance treatments to prevent the recurrence of psychotic symptoms. The extrapyramidal side-effects and greater tardive dyskinesia risk of the typical antipsychotics, coupled with their lesser efficacy to improve negative symptoms and cognition suggest that newer agents are preferred.

Clozapine, despite its risk of agranulocytosis, is the treatment of choice for patients who fail to respond to other typical or atypical antipsychotic agents. Risperidone, olanzapine, and quetiapine have somewhat different pharmacologic profiles. It is not clear which of these agents should be tried in a given patient but on-going research may clarify that. Amisulpride has a mechanism of action different from that of the other atypical agents, with some preference for treating negative symptoms. These compounds, as well as others expected to be approved for use in the near future, for example iloperidone and ziprasidone, will need to be compared with each other to determine if differential indications exist. Side-effect differences among these drugs as well as the availability of long-acting preparations may help clinicians chose among them.

Cost-effective analyses currently favour use of the atypical antipsychotic drugs because of better compliance leading to less frequent relapses and shorter hospital stays. They also facilitate retention of work skills and return to work which decreases the indirect costs of illness in patients still young enough to be able to work. As long as the typical antipsychotics remain in use, and for some patients who receive atypical agents, anticholinergic and other antiparkinsonian drugs will continue to be necessary to treat extrapyramidal side-effects.

Because of the compliance problem, which is less with the atypical than the typical antipsychotics, it is important to develop a long-acting atypical antipsychotic. While the current group of atypical antipsychotic drugs is predominantly characterized by relatively more potent 5-HT 2A than D2 receptor antagonism, it is likely that a number of different strategies will emerge for compounds which produce fewer extrapyramidal side-effects than the typical neuroleptics. Because these compounds are so effective in that regard, the real challenge is to develop agents which address other key features of schizophrenia, especially cognitive impairment and negative symptoms, without the side-effect burden of this group of compounds. 

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