Neuroleptic drugs clozapine

A 17-year-old boy with severe clozapine-induced neutropenia had a negative rechallenge because he had had an unsatisfactory response to traditional neuroleptic drugs, clozapine was continued despite a fall in white blood cell count, since concomitant treatment with granulocyte colony-stimulating factor was followed by rapid normalization of the white blood cell count (152). 

There is some evidence that the atypical neuroleptic drug clozapine can alleviate levodopa-induced dyskinesia while itself providing additional relief in Parkinson s disease (SEDA-18, 159) clozapine may also relieve levodopa-induced psychosis (SEDA-17,166). 

Some neuroleptics, including clozapine, are potent 5-HT-receptor antagonists and the possible role of 5-HT in the action of neuroleptics and the development of schizophrenia has recently generated much interest (Busatto and Kerwin 1997). This has centred primarily on 5-HT2A receptors found in the limbic cortex, which are linked to neuronal excitation and believed to mediate the hallucinogenic effects of drugs such as lysergic acid diethylamide (LSD). 

Despite their importance in psychiatry, the neuroleptics are by no means cure-alls. Even patients that respond extremely well to neuroleptics remain disturbed. Specifically, though their florid hallucinations and delusions, the positive symptoms of schizophrenia, are alleviated, patients remain emotionally detached from the environment. This wallflower syndrome and related symptoms are commonly designated the negative symptoms of schizophrenia and often are the most disabling ones. The first glimmer of effective treatment of such negative symptoms came with the drug clozapine. 

Clozapine and olanzapine are atypical antipsychotic drugs used in the treatment of schizophrenia. Their strnctnres are depicted in Scheme 2.36. The use of clozapine and olanzapine, which are more effective than standard neuroleptic drugs in the treatment of refractory schizophrenia, is, however, limited becanse of their adverse effects. These adverse effects are ascribed to the formation of the corresponding cation-radicals in living organisms under oxidation by bone marrow cells. These cation-radicals eliminate protons from the NH fragments and generate their nitrenium cations. The nitreninm cations are covalently bonnd to the life-important proteins. This results in the toxic effects of clozapine and olanzapine (Sikora et al. 2007). 

In most cases, SSRIs are the first choice for drugs to combat OCD. Clomipramine, fluvoxamine, fluoxetine, paroxetine, sertraline, and citalopram are all SSRIs that have been proven effective in reducing OCD symptoms. However, in about 40 to 60% of patients, these drugs do not completely alleviate all the symptoms. When this is the case, a second type of drug called a neuroleptic is often added. Neuroleptic drugs, such as haloperidol, clozapine, risperidone, and chlorpromazine... 

Risperidone and olanzapine are more effective than neuroleptics and safer than neuroleptics and clozapine, so they represent first-line choices. Quetiapine and ziprasidone are safer but may only be equal in efficacy to neuroleptics. The timing for clozapine is less certain with arguments put forth for earlier versus later introduction based on efficacy and safety issues, respectively. Clozapine is an important drug for the patients who have not fully remitted with first line drugs. 

Meltzer HY, Lee MA, Ranjan R, et al. Relapse following clozapine withdrawal effect of neuroleptic drugs and cyproheptadine. Psychopharmacoiogy 1996 124 176-187. 

Diabetes was also more common in 63 patients taking clozapine than in 67 receiving typical depot neuroleptic drugs (299). The percentages of type 2 diabetes mellitus were 12% and 6% respectively. Nevertheless, the mechanism is not known. In six patients with schizophrenia, clozapine increased mean concentrations of blood glucose, insulin, and C peptide (300). The authors concluded that the glucose intolerance was due to increased insulin resistance. 

Some patients who take clozapine take another neuroleptic drug, and the consequences of this practice in terms of prolactin have been studied in five patients (758). After the addition of haloperidol (4 mg/day) to clozapine the mean prolactin concentration increased from 9.7 ng/ml to 16 ng/ml at week 4 and 19 ng/ml at week 6. Each subject had an increase in the percentage of D2 receptor occupancy, and the group mean increased from 55% at baseline to 79% at week 4 the increased prolactin concentrations correlated with receptor occupancy. 

Several cases of de novo onset or exacerbation of existing diabetes mellitus in patients treated with neuroleptic drugs have been reported and were not significantly related to weight gain. These included eight patients treated with clozapine (767,768) and two patients treated with olanzapine (768). 

In 48 patients with schizophrenia taking clozapine, olanzapine, risperidone, or typical neuroleptic drugs, and 31 untreated healthy control subjects newer neuroleptic drugs, such as clozapine and olanzapine, compared with typical agents, were associated with adverse effects on blood glucose regulation (774). 

The hormone leptin is synthesized by adipocytes and is important in controlling body weight plasma leptin concentrations correlate with fat mass and insulin resistance. Leptin could be a link between obesity, insulin resistance syndrome, and treatment with some neuroleptic drugs. Plasma leptin concentrations are raised, regardless of weight, in patients taking clozapine (793). 

Weight gain related to the use of atypical neuroleptic drugs in children and adolescents, in whom this adverse effect is of particular concern, has been reviewed (804). The published data suggest that clozapine and olanzapine... 

There has been one comprehensive meta-analysis including over 80 studies and over 30 000 patients (814). A meta-analysis of trials of neuroleptic drugs showed the following mean weight gains in kg after 10 weeks of treatment clozapine, 4.5 olanzapine, 4.2 thioridazine, 3.2 sertindole, 2.9 chlorpromazine, 2.6 risperidone, 2.1 haloperidol, 1.1 fluphenazine, 0.43 ziprasidone 0.04 molindone, —0.39 placebo, —0.74... 

This neuroleptic drug 223313,314 has been labelled with carbon-14 in the 11-position315 (equation 150) and with C3H3 in the methyl group of the 4-methylpiperazine ring315 (equation 151) by reacting des-methyl clozapine 225 (obtained from lactam 226316) with tritiat-ed methyl iodide. 

The concept of treatment-resistant schizophrenia, which was developed to delineate a market for the relaunch of clozapine, has lead to public acknowledgment of the extent of non-response to treatment with other neuroleptic drugs. It is now widely admitted that at least 25% of patients do not show any significant clinical improvement with drug treatment. A recent comparison of two of the newer neuroleptic drugs, risperidone and olanzapine, found that 46% and 56% of patients, respectively, did not respond after four months of treatment (Robinson et al. 2006). In addition, the majority of inpatients with psychosis are treated with other sedative drugs in addition to... 

Clozapine differs from typical neuroleptic drugs in having a similar affinity for both Dj and D2 dopaminergic receptors. 

Amenorrhea and infertility were consequences of the effects of typical neuroleptic drugs and of risperidone. Clinicians should be aware that patients changed from these agents to drugs like olanzapine, quetiapine, or clozapine are therefore at risk of pregnancy (6). 

---