Antipsychotic clozapine

Agranulocytosis A severe form of neutropenia where the number of neutrophils (the major type of leucocyte or white blood cell) is very low, so reducing an individual s ability to fight infection. It is a potentially serious side effect of the atypical antipsychotic clozapine. 

Schechter MD, Rosecrans JA (1972) Nicotine as a discriminative cue in rats depleted of norepinephrine or 5-hydroxytryptamine, Psychopharmacologia 24 417 29 Schreiber R, Brocco M, MiUan Ml (1994) Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the atypical antipsychotics, clozapine and risperidone, Eur J Pharmacol 264 99-102... 

The seeds of this transformation were sown some years ago. The first so-called atypical antipsychotic, clozapine (Clozaril), was devised in the 1960s. Clozapine was used widely in Europe until a series of deaths from a toxic hematological (blood) side effect called agranulocytosis occurred in the mid-1970s. Clozapine resurfaced in the 1980s and was approved for use (under strict guidelines) in the United States in 1990. Since that time, several other atypical antipsychotics have been approved, and others loom on the horizon. 

Of all these treatments, the only consistent improvement is seen with the atypical antipsychotic clozapine (Clozaril). Treatment-resistant TD is in fact one generally accepted indication for nsing clozapine. However, becanse of the expense of this drug, the risk for granulocytopenia, and the reqnirement for biweekly blood draws, other measures should hrst be tried. 

Antidepressants tricyclics, mirtazepine, fluoxetine Antipsychotics clozapine, haloperidol, olanzapine, phenothiazines... 

Of the atypical antipsychotics, clozapine, olanzapine, and risperidone have been studied the most. Clozapine was used to treat 10 treatment refractory acutely manic patients and 15 schizomanic patients. Using reduction in the YMRS score as the outcome measure, 72% improved (non-rapid cycling, bipolar patients). Comparison of olanzapine (5-20 mg) with placebo showed significant reduction of the YMRS in 49% vs. 24% of subjects by 3 weeks, with significant change evident by the first week. In a trial comparing risperidone at 6 mg with haloperidol at 10 mg and low-dose lithium (800-1200 mg/day) efficacy was similar over the 28 days of the trial. 

Most conventional antipsychotics are associated with a dose-depen-dent risk of a lowered seizure threshold, although the incidence of seizures with most of these drugs is quite small (Devinsky et al. 1991). Of all the conventional antipsychotics, molindone and fluphenazine have been shown most consistently to have the lowest potential for this side effect (ltd and Soldatos 1980 Ohver et al. 1982). The atypical antipsychotic clozapine is associated with a dose-dependent risk of seizure. 

Atypical antipsychotics cause fewer EPS than do conventional antipsychotics. Clozapine and quetiapine are the least likely to cause EPS and are therefore recommended for treatment of psychosis in patients with Parkinson s disease. With the notable exception of risperidone, atypical antipsychotics cause substantially less hyperprolactinemia than do conventional antipsychotics. Weight gain is a side effect of all atypical antipsychotics except ziprasidone and aripiprazole. Concerns about cardiac conduction delay with ziprasidone therapy exist and warrant consideration in patients who have... 

The availability of the more recent, so-called atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone see Table 1.2) makes it prudent... 

Of the atypical antipsychotics, clozapine produced tiredness and a desire to sleep in healthy volunteers at very low single doses of 5 and 10 mg a dose of... 

More recent variants of the dopamine hypothesis have been derived mostly from the profile of actions of the atypical antipsychotic clozapine and seek to relate pharmacological findings to the clinical actions of this product. At the same time the pharmacological profile of clozapine is being used as a starting point for obtaining safer and more effective antipsychotics. Comparison of the major clinical and pharmacological effects of clozapine provides the picture shown in Table 4.1. 

Sedation, ataxia, and cognitive impairment occur more frequently with high BZD dosages. Other adverse effects reported when BZDs were used to treat schizophrenia include behavioral disinhibition, exacerbation of psychosis, and increase in anxiety and depression ( 163, 188, 189,190, 191,192, 193,194 and 195, 351). Concomitant use of a BZD and the atypical antipsychotic clozapine may increase the risk of sedation, dizziness and collapse with loss of consciousness ( 196). Respiratory compromise has also been reported with this combination (395, 396). 

Van Tol HHM, Bunzow JB, Guan H-C, et al. Cloning of the gene fora human dopamine D receptor with high affinity for the antipsychotic clozapine [Letter], Nature 1991 350 610-614. 

Among the atypical antipsychotics, clozapine has the most convincing evidence of efficacy in children and adolescents with schizophrenia ( 166,167, 170). Kumar and colleagues (171) conducted a double-blind, randomized trial of clozapine versus haloperidol in 21 children and adolescents (mean age = 14 years) whose psychosis had been previously unresponsive to typical antipsychotics. Clozapine at a mean dose of 176 mg per day was superior to haloperidol for both positive and negative symptoms. These results are consistent with an open-label study by Remschmidt and colleagues (172). This group found that clozapine at a mean dose of 154 mg per day produced notable improvement in 27 of 36 (75%) adolescents with schizophrenia previously unresponsive to at least two trials of typical antipsychotics. 

The discovery of the atypical antipsychotic clozapine opened a new era and set new standards in the drug treatment of schizophrenia. Modifications of the diben-zoazepine structure in clozapine resulted in olanzapine and quetiapine, which are among the most frequently used antipsychotic drugs. From a chemical viewpoint, clozapine, olanzapine and quetiapine can be considered as structural analogues. Although they share some common features in their molecular mechanism of action, the three compounds show significant differences in their clinical efficacy and adverse event profile. 

SPECT imaging has also been used to study the in vivo effects of antipsychotics on mAChRs. Using SPECT imaging, decreased mAChR availability was shown in schizophrenic subjects under treatment with the antipsychotics clozapine (Raedler et al., 2003a) and olanzapine (Raedler et al., 2000 Lavalaye et al., 2001) with a stronger reduction of mAChR availability under treatment with clozapine (Raedler et al., 2007). 

ANTIPSYCHOTICS-CLOZAPINE PROTON PUMP INHIBITORS -OMEPRAZOLE Possible 1 efficacy of clozapine t metabolism via CYP1A2 Clinical significance unclear monitor more closely... 

ALL ANTIPSYCHOTICS -CLOZAPINE t risk of bone marrow toxicity Additive effect Avoid co-administration... 

IMATINIB 1. ANTIARRHYTHMICS -flecainide, mexiletine, propafenone 2. ANTIDEPRESSANTS - fluoxetine, paroxetine, TCAs, trazodone, venlafaxine 3. ANTIPSYCHOTICS -clozapine, haloperidol, perphenazine, risperidone, thioridazine 4. BETA-BLOCKERS - metoprolol, propanolol, timolol 5. DONEPEZIL 6. METHAMPHETAMINE Imatinib may cause t plasma concentrations of these drugs, with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

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