Antipsychotic drugs limitations

Medications may be necessary for patients with delirium especially in patients with severe behavioural disturbances and agitation. Any medications used may however be hazardous and actually lengthen the condition. A continuous reassessment of the need for theses kind of drugs should be done. Antipsychotic drugs may be needed especially if vision hallucinations and agitated behaviour are predominant. Short-acting benzodiazepines may be used for a limited time. There is no... 

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). 

Tardive dyskinesia is a late-occurring syndrome of abnormal movements of the face and tongue with widespread choreoathetosis. It is the most serious adverse effect of the antipsychotic drugs. It can be expected to occur in 20 to 40% of chronically treated patients there is no established treatment, and reversibility may be limited. These reactions are more frequent and severe in the elderly. 

Deposits in the anterior portions of the eye (cornea and lens) are a common complication of chlorpromazine therapy. They may accentuate the normal processes of aging of the lens. Thioridazine is the only antipsychotic drug that causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa. The deposits are usually associated with "browning" of vision. The maximum daily dose of thioridazine has been limited to 800 mg/d to reduce the possibility of this complication. 

Various neuroleptics are also used for nonpsychiatric purposes, usually in smaller doses for shorter durations. However, severe effects can sometimes develop from these limited uses. Reserpine (Serpasil) is a neuroleptic that is more often used to suppress the symptoms of tardive dyskinesia (chapter 4). Prochlorperazine (Compazine) is used as an antiemetic and rarely as a neuroleptic. If given in sufficient doses to manifest psychoactive effects, these drugs produce the same emotional indifference as the other antipsychotic drugs. 

Ziprasidone is apparently well tolerated, with a limited potential to cause extrapyramidal adverse effects or weight gain (4). Out-patients who partly respond to conventional antipsychotic drugs, risperidone, or olanzapine may have improved control of psychotic symptoms after switching to ziprasidone, according to the results of a reanalysis of 6-week, multicenter, randomized, open, parallel-group studies in patients with schizophrenia who had previously taken conventional antipsychotic drugs (n = 108), olanzapine (n = 104), or risperidone (n = 58) these results have been published in two different journals (5, 6). 

Newer antipsychotic agents may also be helpful with regard to these concerns. The atypical antipsychotic clozapine was the first of the atypical antipsychotics, which offer significant advantages over typical antipsychotics (Kane et al. 1988). Clozapine is effective in many patients unresponsive to treatment with typical antipsychotics. It also seems to be associated with few extrapyra-midal symptoms (EPS) and a lower risk for TD. However, other features of the drug limit its use by African Americans. 

Activity at the 5HT-2 receptor is an important feature of many atypical antipsychotic drugs (e.g., risperidone, olanzapine, sertindole), but the body of knowledge on 5HT-2 ligands in anxiety is more limited (173). Nonselective 5HT-2 antagonists, such as ritanserin (112), mianserin (113), and ketanserin (114), have been shown to produce anxiolytic effects in less than half of the preclinical studies conducted (202). The clinical data for ritanserin in human subjects are likewise inconclusive (458, 459). The mixed results obtained with... 

Unfortunately, potentially fatal agranulocytosis appears in 1-2% of patients treated with clozapine (7). This necessitates frequent blood monitoring, which can be inconvenient and expensive. Furthermore, despite its low potential for causing EPS and TD, clozapine causes other, dose-related side effects that can limit its effectiveness in some patients. The precise pharmacological actions of clozapine responsible for its clinical effectiveness are still being debated. Attempts to duplicate elements cf its complex pharmacological profile have led to the discovery of several new atypical antipsychotic drugs that have been approved in the United States for the treatment of schizophrenia. 

In summary, existing drug treatments for schizophrenia are of limited efficacy and have substantial side effects. New treatment can arise only on the basis of a new hypothesis. The phospholipid hypothesis of schizophrenia provides the theoretical basis for treatment with PUPA supplementation. Pre vlous studies using n-6 supplementation have had mixed results. We now have evidence from a double-blind, placebo-controlled trial that EPA, but not DHA, is effective in reducing the symptoms of schizophrenia. It is possible that the response to EPA is impaired by concomitant treatment with antipsychotic drugs that damage membrane phospholipids. The best treatment effects of EPA have been seen in patients who are otherwise unmedicated or who are currently taking clozapine. This remains to be explored further. 

The beneficial effects of antipsychotic drugs are not limited to schizophrenia. They also are employed in disorders ranging from postsurgical delirium and amphetamine intoxication to paranoia, mania, psychotic depression, and the agitation of Alzheimer s dementia (although their efficacy in this disorder in not proven). They are especially useful in severe depression and possibly in other conditions marked by severe turmoil or agitation. 

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