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specifically associated with QTq interval prolongation bind specifically to the I(kr)42.

Although there is little consensus as to what represents a 'normal' QTq it is generally accepted that a QTq of over 500 ms increases the likelihood of an arrhythmia. When interpreting data on medication-related QTq prlongation it is important to note that the mean daily QTq intrasubject variability is 76ms43.

Other risks factors which increase the likelihood of QTq prolongation include age over 65 years and co-administration of other drugs associated with cardiac arrythmias, such as tricyclic antidepressants. Safety studies are ongoing with both the newer and the older medications, preliminary data suggests that the newer medications do not differ significantly in their likelihood to prolong the QTq interval.

THE NEWER 'ATYPICAL' ANTIPSYCHOTICS

The reintroduction of clozapine in the early 1990s and the subsequent release of several new, 'atypical' antipsychotics has increased optimism in the treatment of schizophrenia. As these are likely to be the mainstay of treatment for schizophrenia in the future, it is worthwhile considering them individually (Figure 4.17 and Table 4.3)44,45.

Clozapine

Clozapine, the prototypical third-generation antipsychotic, has been used since the 1960s for treatment of schizophrenia. However, after reports of several deaths from neutropenia, in most countries clozapine can be used only in patients unresponsive to two other antipsychotics given at an adequate dose for an adequate duration, or those with tardive dyskinesia or severe extrapyramidal symptoms, and only with blood monitoring. Each patient has to be registered and the drug is dispensed only after a normal white cell count. In the UK, a blood count is performed every week for 18 weeks, then every 2 weeks for the next year, and thereafter monthly. In the USA, blood monitoring is weekly throughout treatment. Clozapine is contraindicated for those with previous neutropenia.

Important aspects of clozapine's pharmacology include its low affinity for the D2 receptor, in comparison with older antipsychotics. Clozapine has higher affinity at the Di and D4 receptors than at the D2 receptor and also binds to the extra-striatal D2-like receptor, the D3 receptor. It is thought that the low incidence of extrapyramidal side-effects is due to the low activity at the D2 receptor. Clozapine also has antagonistic activity at the 5HT1A, 5HT2A , 5HT2C and 5HT3

Antipsychotics Receptor Affinity

Figure 4.17 A representation of the absolute receptor affinity of haloperidol in comparison with some of the newer 'atypical' antipsychotics drawn from data in reference 112. Each line represents a single receptor, the further along the bar on a given line the higher the affinity of that medication for that receptor. Each of the gradations on the lines represents 10 times greater affinity for that receptor. What can be seen from this is that clozapine, quetiapine and to a lesser extent olanzapine have much lower affinities for the dopamine D2 receptor than haloperidol. This may be why they are 'atypical' i n terms of producing fewer extrapyrimidal side-effects than antipsychotics such as haloperidol. Risperidone and ziprasidone have similar D2 receptor affinities to haloperidol and yet they too are 'atypical'. It has been hypothesized that very high affinity for the serotonin-2A receptor, (5-HT2A), may underlie the atypicality of ziprasidone and risperidone. Indeed this may be important for 'atypicality' perse, as all of the newer medications have a higher affinity for the 5-HT2A than for the D2 receptor. Amisulpride, by contrast to the medications in this figure, only has appreciable affinity for D2 and D3 receptors and has high equipotent affinity for both receptors, as can be seen in Table 4.3. Data from reference 45

Figure 4.17 A representation of the absolute receptor affinity of haloperidol in comparison with some of the newer 'atypical' antipsychotics drawn from data in reference 112. Each line represents a single receptor, the further along the bar on a given line the higher the affinity of that medication for that receptor. Each of the gradations on the lines represents 10 times greater affinity for that receptor. What can be seen from this is that clozapine, quetiapine and to a lesser extent olanzapine have much lower affinities for the dopamine D2 receptor than haloperidol. This may be why they are 'atypical' i n terms of producing fewer extrapyrimidal side-effects than antipsychotics such as haloperidol. Risperidone and ziprasidone have similar D2 receptor affinities to haloperidol and yet they too are 'atypical'. It has been hypothesized that very high affinity for the serotonin-2A receptor, (5-HT2A), may underlie the atypicality of ziprasidone and risperidone. Indeed this may be important for 'atypicality' perse, as all of the newer medications have a higher affinity for the 5-HT2A than for the D2 receptor. Amisulpride, by contrast to the medications in this figure, only has appreciable affinity for D2 and D3 receptors and has high equipotent affinity for both receptors, as can be seen in Table 4.3. Data from reference 45

Figure 4.18 Comparison of efficacy of clozapine versus chlorpromazine in treatment-resistant schizophrenia. Figure reproduced with permission from Kane J, Honigfeld G, Singer J, Meitzer H. Clozapine for the treatment-resistant schizophrenic: a double blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789-96

CLOZAPINE vs. CHLORPROMAZINE IN TREATMENT-RESISTANT SCHIZOPHRENIA

Figure 4.18 Comparison of efficacy of clozapine versus chlorpromazine in treatment-resistant schizophrenia. Figure reproduced with permission from Kane J, Honigfeld G, Singer J, Meitzer H. Clozapine for the treatment-resistant schizophrenic: a double blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789-96

Clozapine Chlorpromazine

Clozapine Chlorpromazine receptors. It is postulated that it is the balance between the blockade of these receptors that underlies clozapine's clinical efficacy in improving positive and negative symptomatology. Clozapine is an antagonist at the a1 receptor but less so at the a2 receptor, resulting in sedation and hypotension. Clozapine's antagonism at the histamine H1 receptor adds to the sedative effects and may be, in part, responsible for weight gain. Other side-effects include hypersalivation, tachycardia, sedation and hypotension. More rarely, clozapine can produce seizures (approximately 1%) and blood dyscrasias (< 1-2%). The risk of neutropenia is 1-2%, and in most cases is reversible. The majority of cases (83%) occur within the first 20 weeks of treatment. Risk of agranulocytosis decreases to 0.07% after the first year of treatment. Agranulo-cytosis probably results from toxic and immuno-logical factors (reviewed in reference 46). It is this last potentially fatal side-effect that has led to the limits on the use of clozapine and the requirement for blood monitoring in patients receiving cloza-pine. Interestingly, clozapine does not increase serum prolactin.

Clozapine is the most effective treatment for schizophrenic patients refractory to other therapies, and improves both positive and negative symptoms. In non-comparative studies, clozapine has led to > 15% improvement in baseline ratings in 30-70% of previously treatment-refractory patients after 2-6 months of treatment (reviewed in reference 46). In comparison to chlorpromazine47-49 (Figure 4.18), haloperidol50 or fluphen-azine51, clozapine shows a 30-100% response rate, versus a 4-17% rate for the comparator, when administered to patients resistant to previous treatment with classical antipsychotics.

Clozapine has been investigated in few randomized controlled trials of maintenance therapy. This is due to the restrictions imposed on its use. In one of the few studies published, Essock and co-workers52 followed up a sample of 227 patients randomized to either clozapine or treatment as usual. They reported that those treated with clozapine had significantly greater reductions in side-effects, disruptiveness, hospitalization and readmission after discharge. Furthermore, the clinical efficacy of clozapine in relapse prevention is well established, naturalistically, at 1-2 years of treatment and there have been reports of good maintenance efficacy for up to 17 years of treatment (for review see reference 46).

Risperidone

This drug has high affinity for the 5-HT2A receptor, with a similar affinity at the D2 receptor to most typical antipsychotics. In the acute phase of treatment, risperidone appears as effective as haloperidol in terms of improvement in positive and secondary negative symptom scores53.

The optimal dose of risperidone appears to be between 4 and 6 mg/day. At doses higher than 8-12mg/day risperidone can cause extrapyramidal side-effects of tremor, rigidity and restlessness, with a similar frequency to typical antipsychotics. Risperidone can increase serum prolactin which may lead to sexual dysfunction.

Risperidone has been assessed for long-term efficacy and safety in a number of long-term open-label studies. Earlier data suggested that long-term therapy with risperidone was associated with a meaningful reduction in psychopathology, amelioration of extrapyrimidal side-effects (EPS) and improved social functioning from baseline measures or against placebo.

More recently a meta-analysis of eleven of the risperidone/conventional antipsychotic comparator randomized controlled trials was performed54. The author reported that slightly but significantly more patients on risperidone showed clinical improvement than with comparison antipsych-otics (57% vs. 52%) and used significantly less medication for EPS (29.1% vs. 33.9%).

Olanzapine

A more broad-spectrum atypical antipsychotic, olanzapine has a side-effect profile similar to that of clozapine but with a higher incidence of extra-pyrimidal side-effects at doses above 20 mg/day. Olanzapine also demonstrates antagonistic effects at a wide range of receptors, but has a higher affinity for D2 and 5-HT2a receptors than clozapine and a lower affinity at the D1 receptor subtype. In acute-phase studies, olanzapine is efficacious for positive and secondary negative symptoms and was superior to haloperidol on overall improvement according to the Brief Psychiatric Rating Scale (BPRS)55 and every other secondary measure.

Standard-dose olanzapine (5-15 mg/day) has been shown to be an effective maintenance treatment for schizophrenia in comparison with placebo56. The estimated 1-year risk of relapse with olanzapine was 19.6-28.6% for standarddose olanzapine in comparison with a 69.9% risk of relapse with placebo. Initial data from a meta-analysis of three studies using haloperidol-treated patients as a test group, indicated that 80.3% of patients receiving olanzapine maintained their response at 1 year in comparison with 72% for haloperidol-treated patients57.

Quetiapine

Another broader-spectrum atypical, quetiapine has a similar receptor binding profile to clozapine, but with relatively lower affinity for all receptors and virtually no affinity for muscarinic receptors. Quetiapine is effective in acute phase studies for the treatment of positive and secondary negative symptoms. Initial randomized controlled trials indicated that quetiapine (250-750mg, n =96) was more effective than placebo (n =96) and that this efficacy was not seen at doses of less than 250 mg/day of quetiapine58. In comparison with chlor-promazine, response rates to quetiapine were similar across all symptom domains59. Response rates between haloperidol- and quetiapine-treated groups are also similar60.

In all of these studies, the rates of EPS with quetiapine were similar to those seen in placebo-treated groups and significantly lower than in conventional antipsychotic comparator groups. Most common side-effects are somnolence and dry mouth. Quetiapine demonstrates a lower potential to cause weight gain than clozapine and olanzapine, and does not increase serum prolactin61.

In long-term studies, quetiapine was well tolerated with up to 75% of respondents to a questionnaire denying any side-effects from quetiapine62.

Amisulpride

In contrast to all the other newer antipsychotics, amisulpride only has effects on the dopamine D2 and D3 receptors, where it is a potent antagonist. In animal models at lower doses, amisulpride appears to bind preferentially to presynaptic D2 receptors64, and at projected therapeutic levels it also appears to be selective, in a neurochemical imaging study in humans, for limbic D2 and D3 receptors63. It has a similar efficacy to haloperidol for positive symptoms in acute exacerbations of schizophrenia64-67, with a projected optimum dose in this group of between 400 and 800 mg/day66. Some studies at this dose range have reported a significantly greater efficacy for amisul-pride in comparison with placebo for treating the negative symptoms of schizophrenia65,66.

In all of the studies above, amisulpride has a significantly lower incidence of extrapyrimidal side-effects, at doses below 1200 mg/day, than haloperidol. Amisulpride may cause less weight gain than other atypical antipsychotics but it does increase plasma prolactin68,69.

In a 12-month trial of amisulpride 200-800 mg/day versus haloperidol 5-20 mg/day, amisulpride showed enhanced efficacy for positive and negative symptoms in comparison with halo-peridol. Those treated with amisulpride had significantly greater improvement in quality of life and significantly fewer extrapyrimidal side-effects. Long-term efficacy and relapse prevention were similar in the amisulpride- and haloperidol-treated

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