Neuroleptic Drug Development

The introduction of the phenothiazinc neuroleptic drug chlorpromazine in the treatment of schizophrenia is regarded by many as the most important event in 20th century psychiatry (Table 5.1 Swazey, 1974). Prior to chlorpromazine most schizophrenics could look forward to a lifetime in a state mental hospital. Though chlorpromazine and its successor neuroleptic drugs do not cure the disease, they favorably influence the fundamental symptoms so much that most patients can function reasonably well. Together with the advent of the community mental health move- 

1950 Promethazine employed as a preanesthetic calming drug by Laborit. 

1950 Synthesis of chlorpromazine, a very sedating phenothiazine antihistamine.  

1951 Laborit replaces promethazine with chlorpromazine for pre-surgical anesthesia. 

1952 Delay and Deniker observe antipsychotic actions of chlorpromazine. 

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A 55-year-old man with a 15-year history of schizophrenia treated with various neuroleptic drugs developed a tremor and was given tetrabenazine 75 mg/day, with complete regression of the tremor. Three months later he developed depression, a known adverse effect of tetrabenazine, which was discontinued, with subsequent partial improvement of his depressive symptoms but reappearance of the tardive tremor. Clozapine 25 mg/day was started and increased to 75 mg/day his tardive tremor again disappeared. 

Extrapyramidal disorders which develop soon after initiating treatment with neuroleptic drugs are likely to be transient. A dosage of 1 to 2 mg orally 2 or 3 times a day usually provides relief within 1 or 2 days. After 1 or 2 weeks, withdraw drug to determine its continued need. If such disorders recur, reinstitute benztropine. 

Chronic stimulant abuse alters the personality of the abuser. These and related changes are the result of neurotoxicity and are not characterized as either acute drug effects or withdrawal signs. Individuals have delusions of being pursued or persecuted and therefore become suspicious and paranoid. They become self-occupied and hostile toward others. Long-term abuse can produce toxic psychosis that closely resembles schizophrenia and must be treated with neuroleptic drugs (haloperidol, chlorpromazine). This psychosis can develop even within 1 to 2 weeks if the person is on a run of very high doses of stimulants. 

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... 

The neuroleptics show variable absorption after oral administration. These agents readily pass into the brain, have a large volume of distribution, bind well to plasma proteins, and are metabolized to many different substances by the P-450 system in the liver. Fluphenazine decanoate and haloperidol decanoate are slow release (up to 3 weeks) formulations of neuroleptics, administered by intramuscular injection. These drugs are increasingly used in treating outpatients and individuals who are noncompliant. However, about 30% of these patients develop extrapyramidal symptoms. The neuroleptic drugs produce some tolerance but little physical dependence. 

Fig. 3.1 Morphine 1 has been the lead structure for the development of the major analgesic fentanyl 2, the antitussive drug dextromethorphan 3, the constipating drug loperamide 4, and the neuroleptic drug haloperidol 5.

More than a dozen drugs, almost all of them in use for many years, can be classified as neuroleptics. The phenothiazine derivatives were originally the most commonly used class of neuroleptic drugs. Chlorproma-zine is the prototype, developed in France and introduced into North America in 1953 by Heinz Lehmann. Its brand name in Canada and England is Largactil, and in the United tates, Thorazine. The antidepressant amoxapine (Asendin) is metabolized into a neuroleptic and has similar effects and, more important, adverse effects, such as tardive dyskinesia. All the classic neuroleptics block dopamine, but all of them also affect other neurotransmitter systems. 

NMS is a potentially fatal reaction to neuroleptic drugs such as Haldol, Prolixin, Risperdal, Zyprexa, Seroquel, and Abilify. It occurs at a relatively high rate, developing in somewhere from 1.4% to 2.4% of patients exposed to the older neuroleptics and at significant rates to patients exposed to the newer ones (chapter 4). By contrast, a reaction that occurs 1% of the time is considered common or frequent by FDA standards. This particular reaction is extremely dramatic and therefore not easily overlooked. Yet NMS was entirely missed in one study after another conducted by drug companies when applying for FDA approval of neuroleptic drugs. 

Two Scandinavian patients taking combinations of neuroleptic drugs and tricyclic antidepressants developed epileptic seizures (194). The risk of seizures is greater in patients with brain damage or epilepsy and with high dosages, sudden increases in dosage, or shortly after the introduction of a second compound. 

Of 86 439 patients who had been exposed to neuroleptic drugs, 59 developed a cardiovascular adverse effect (116). Among the commonly used neuroleptic drugs, the highest rate of cardiovascular adverse effects was found for... 

Patients with AIDS are sensitive to the extrapyramidal adverse effects of neuroleptic drugs and have evidence of depletion of dopamine in the cerebrospinal fluid (SEDA-22, 52). Of 115 consecutive HIV-infected patients, six developed parkinsonism and three of the cases were precipitated by the use of neuroleptic drugs (165). 

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