Development antipsychotics

Two different aspects have to be considered in the answer economic and scientific. An economic interest to have a variety of products in the market exists on the part of those pharmaceutical companies that have developed and marketed or are developing antipsychotics. Consequently, their advertising places the emphasis on the special features and advantages of individual medications, even though the differences between many products are not always very relevant clinically. Nevertheless, the differences that actually exist between products with regard to their pharmacokinetic and pharmacodynamic properties are of scientific interest, especially those related to the effects of atypical versus typical antipsychotics ... 

CJ-Receptors are localized ia the brain stem and limbic stmcture, regions associated with endocrine function (76). In the periphery, CJ-receptors are found in the Hver, heart, ileum, vas deferens, and on lymphocytes and thymocytes. Although there is insufficient evidence to clearly define the functional role of CNS CJ-sites, based on the effects of PCP and the interaction of haloperidol with CJ-sites, CJ-receptor ligands may be antipsychotics or used for the treatment of substance abuse. Several CJ-receptor ligands have shown neuroprotective effects in vivo. Ifenprodil (315) and CNS 1102 (316) are being developed for treatment of stroke (Table 18). 

The antipsychotic activity of neuroleptics (D2-like receptor antagonists) has led to the development of many different ligands for the D2 receptor. These drugs... 

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

It is not surprising that a DA antagonist (especially those acting primarily on Di receptors) should produce the symptoms of Parkinsonism, a disorder caused by inadequate DA function (see Chapter 15), nor that its intensity or rate of onset over some weeks or months should increase with Dj antagonistic potency. Tolerance to this adverse effect can develop without affecting antipsychotic activity but the speed with which Parkinsonism resolves after stopping therapy may be from 3 to 12 months and can persist indefinitely in some cases. 

Compared to the older antipsychotics (first-generation antipsychotics), the more recently developed second-generation antipsychotics are associated with a lower risk of motor side effects (tremor, stiffness, restlessness, and dyskinesia) may offer greater benefits for affective, negative, and cognitive symptoms and may prolong the time to psychotic relapse. 

Psychotic symptoms in late life (greater than 65 years of age) are generally a result of an ongoing chronic illness carried over from younger life however, a small percentage of patients develop psychotic symptoms de novo, defined as late-life schizophrenia. The 6-month prevalence rate of schizophrenia in the elderly is around 1%. However, other illnesses presenting with psychotic symptoms are common in this population, as approximately one-third of patients with Alzheimer s disease, Parkinson s disease, and vascular dementia experience psychotic symptoms. The majority of data for antipsychotic use in the elderly comes from experience treating these other disease states. 

From American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004 27 596-601, with permission. 

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Tardive dyskinesia A chronic disorder of the nervous system characterized by involuntary jerky or writhing movements of the face, tongue, jaws, trunk, and limbs, usually developing as a late side effect of prolonged treatment with antipsychotic drugs. 

However, taken as a whole, the findings from these early studies did point the way to considering ethnicity as an important variable in psychopharmacological response to antipsychotics. It is unfortunate that despite the rapid increase in the development of SGAs, and the voluminous literature accompanying them, specific clinical studies of the influence of ethnicity remain uncommon. 

Udomratn, P., Vasiknanonte, S., Lambert, T., Ng, C. 8cFreeman, N. (2004). Pattern ofprescribing antipsychotic drugs in a developing country a report from Thailand. European Psychiatry, 19(suppl 1), 194S. 

Examples abound regarding the role of serendipity in the discovery of new therapeutic approaches, which on closer examination usually turned out to be the result of clinicians paying attention to unexpected clinical effects rather than discounting them. For example, lithium was tried first for hypertension, chlorpro-mazine was initially developed as an anesthetic, and imipramine was originally regarded as an antihistamine and an antipsychotic agent. Without astute clinical observations, these drugs would not have found their niche, nor would clozapine have been revived for the benefit of millions of the most difficult to treat schizophrenic patients. Other examples include the expanded indications of newer... 

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