Antagonist psychiatric disorders

The short-acting clomethia2ole [533-45-9] (1), sometimes used as therapy for sleep disorders ia older patients, shares with barbiturates a risk of overdose and dependence. Antihistamines, such as hydroxy2iae [68-88-2] (2), are also sometimes used as mild sedatives (see HiSTAMlNES AND HISTAMINE antagonists). Antidepressants and antipsychotics which have sedative effects are used to treat insomnia when the sleep disorder is a symptom of some underlyiag psychiatric disorder. 

Eplivanserin (39) is a 5-HT2A antagonist initially developed for a broader spectrum of psychiatric disorders but that has been tested recently for insomnia. Within this latter indication, phase II studies showed benefits in sleep maintenance, but not in induction [9]. Compound 39 is currently in phase III, to assess the efficacy for the treatment of sleep maintenance insomnia, evaluating both sleep and daytime functioning [96]. 

The early suggestion by Fozard [54] that 5-HT3 receptor antagonists may be useful in the treatment of migraine has yet to be established, although MDL 72222 appeared to be effective in limited clinical trials [94, 95]. There are exciting prospects for other clinical applications of 5-HT3 antagonists in psychiatric disorders which have been predicted from behavioural studies in rodents and primates, and several clinical trials are underway in psychiatric patients. 

The part played by endogenous opioid systems in the regulation of these various physiological and behavioral functions has led to the experimental application of opiate antagonists in psychiatric disorders. This chapter focuses on autism and self-injury, which are two potential indications for opiate antagonists in pediatric populations. In adults, treatment with opiate antagonists has shown to be useful in the relapse prevention of alcoholism as part of a comprehensive treatment approach (Anton et ah, 1999, 2001). 

Dopamine is a major neurotransmitter which acts on multiple receptors. It can activate both a and 3 adrenoceptors in addition to acting on specific dopamine receptors. These are widely distributed throughout the CNS and are also present in the renal tubules and renal and mesentric blood vessels, and many dopaminergic drugs are used in the treatment of Parkinson s disease, psychiatric disorders, as antiemetics, and for renal protection. Neuroleptic drugs, such as haloperidol and droperidol, are dopamine receptor antagonists. 

If serum Na+ is not monitored closely, ADH antagonists can cause severe hypernatremia and nephrogenic diabetes insipidus. If lithium is being used for a psychiatric disorder, nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride. 

Pyridazino[4,5-A]oxazepines 295 are 5-HTia receptor ligands <1997BML2857>. The 5-HT1A receptor plays a role in psychiatric disorders such as anxiety and depression. 1,4-Benzoxazepine 296 is a 5-HT1A antagonist and exhibits highly potent anti-ischemic effects <2001BML595>. 

Psychiatric Disorders. The main indications for DA antagonists are the treatment of adult schizophrenia, and childhood psychosis. Haloperidol and chlorpromazine are the most frequently employed. 

The 5-HT3 receptors are found in both the peripheral nervous system and central nervous system (CNS), where they mediate last synaptic transmission at synapses (3). In the CNS, they are located predominantly at intemeurones, where they modulate the release of a range of neurotransmitters (4-9). There is some evidence that 5-HT3 receptors play roles in brain reward mechanisms and in neurological phenomena such as anxiety, psychosis, nociception, and cognitive function (10,11), and in the first few years following the discovery of these receptors, there was also much interest in the therapeutic potential of 5-HT3 receptor antagonists for antipsychotic, antinociceptive, and other psychiatric disorders (12-15). This potential has not yet been realized, but there is still active research in this area (16), and their current major therapeutic target is against emesis in cancer chemotherapy and irritable bowel syndrome (17,18). 

Antipsychotics have been used to promote sleep in resistant insomnia occurring as part of another psychiatric disorder, probably due to a combination of 5HT2-receptor, -adrenoceptor and histanaine Hj-receptor antagonism, in addition to their primary dopamine antagonist effects. Their long action leads to daytime sedation and extrap5n a-midal movement disorders may result from dopamine receptor blockade (see p. 380, Antipsychotics). Nevertheless, modern antipsychotics, e.g. quetia-pine, have been occasionally used for intractable insonmia. 

The systemic effects exerted by eye-drops are most pronounced in the case of agonists and antagonists in the autonomic nervous system. For example, beta-blockers in eye-drops can cause bronchospasm, heart failure, syncope, and psychiatric disorders (4-6), especially at high doses and with non-selective beta-blockers, although these adverse reactions are usually related to failure to observe prescribing precautions (1). 

M. H.Eader, The Role of Ondansetron, a Novel 5HT3 Antagonist, in the Treatment of Psychiatric Disorders (Satellite Symposium 5th World Congress Biological Psychiatry), 1991, pp. 17-19. 

HT2-type receptors have been a focus for investigations into its putative clinical importance for treatment of psychiatric disorders. h-HTg-type receptors have been implicated in several disorders like anxiety, depression and psychosis. As we are presently in the dark with respect to the mechanisms underlying the development of these disorders, future pharmacotherapy largely aims at alleviating symptoms. To that end various compounds, which have antagonistic properties on S-HTj-type receptors, are currently tested in clinical studies. 

---