The TRH-test in depression: a review

This paper reviews the literature on the thyrotropin releasing hormone (TRH)-test in depressive patients. The TRH-test appears to exhibit some use as an external validating criterion for the clinical diagnosis of major depression and, in particular melancholia versus minor depression once the clinical diagnosis depression is made. However, the clinical use of this test is hampered by the low sensitivity (±50%) and by the fact that abnormal tests occur in non-depressive states such as borderline personality disorder, schizophrenia, and anxiety disorders. The TRH-test may be used as a predictor for a positive response to biological therapies. In addition, the test has some value for the outcome of a depressive episode. The pathophysiology underpinning an abnormal TRH-test may be determined by noradrenergic (central and peripheric) or serotonergic (central) dysfunctions, thyroid hormone and cortisol hypersecretion, phenomena that are pertinent to severe depression. Recently, it has been established that an abnormal depression-linked TRH-test reflects lower basal thyroid secreting hormone (TSH) secretion. The determination of basal TSH may, in the future, replace TRH-testing.

Over the past 25 years much effort has been put into the research of the relationship between neuropsychiatric disorders and the concentrations of CSF-monoamine metabolites. Most of this research has beenfocused on the relation between CSF-concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) and specific symptomatological entities, particularly schizophrenia, Alzheimer's dementia and endogenous depression. It appeared that specific relations between diseases and CSF-concentrations of monoamine metabolites cannot be longer maintained and that a more functional psychopathology should be considered as the future research strategy.

Neuropeptides are endogenous substances present in nerve cells and involved in nervous system functions. Neuropeptides are synthetized in large precursor proteins and several are formed in the same precursor. Neuropeptides affect learning and memory processes, social, sexual and maternal behavior, pain and addiction, body temperature, food and water intake e.a. In addition, neuropeptides possess trophic influences on the nervous system, neuroleptic-like andpsychostimulant-like activities. Disturbances in classical neurotransmitter activity as found in Parkinson's disease, psychoses, and dementia, may also be caused by disturbances in neuropeptide activity. In fact, alterations in the concentration of a number of neuropeptides in schizophrenia, depression, and dementia have been found.

Much work has been done during the last decade on the influence of neuropeptides in schizophrenia, autism, depression, and in various disorders associated with memory disturbances. These studies concern neuropeptides related to adrenocorticotropic hormone (ACTH) and melanocyte stimulating hormone (MSH), vasopressin- and endorphin-type neuropeptides, thyrotropic releasing hormone (TRH), and the C-terminal part of oxytocin Pro-Leu-Gly-NH2 (PLG). Several of these exert positive effects but in not more than 25% the response is clinically relevant. This may have to do with the severity of the disease and its chronicity. The modest effects may also be caused by the poor bioavailability of peptides and insufficient pharmacotherapeutic experience regarding dose, and duration of treatment.

In this review article four neuropeptides: adrenocorticotrope hormone (ACTH), corticotrope releasing hormone (CRH), neuropeptide- Y(NPY) and cholecystokinin (CCK) are discussed with respect to their possible role in the pathogenesis of anxiety disorders. First the presumable working mechanism of these peptides in the brain is mentioned. In addition, the relationship of these peptides and anxiety is outlined using neuroanatomical and electrophysiological research data. Subsequently, animal experiments and human research findings are discussed. Most of the research findings so far are obtained from animal data. Only with respect to CCK, there is increasing evidence, also from human studies, that this peptide might play a role in the pathogenesis of anxiety disorders. The putative role of the other peptides remains to be estab lished in future research.

Within the framework of interactional theories of depression it was examined whether the interaction of 31 severely depressed patients and a psychiatrist was related to the course of depression during hospitalization. Interactional processes were defined on the basis of directly observed behaviour displayed during an interview and by the use of ethological methods. The behavioural structure of such interaction could be described by 6-7 factors. Some of these factors could predict the clinical course of depression, over an interval of tien weeks. The patients who would not improve displayed before treatment (just after admission) more involvement (i.e., looking, gesticulating) coinciding with more general activation (leg and hand movements) than the patients who would improve. The psychiatrist displayed relatively high levels of involvement (encouragement: hm, hm, yes, yes, and yes-nodding) and low levels of general activation (hand movements) in his interaction with patients who would not improve. The results provide support for interactional theories of depression.

After a description of the harmful effects of psychotropic drugs as well as of the moments of vulnerability to any teratogenic effect, this paper reviews prospective, retrospective and epidemiological studies of the teratogenic effects of anticonvulsants (phenytoin, valproic acid, carbamazepine and barbiturates), lithium, anti-psychotics, benzodiazepines and anti-depressive agents. It is found that the results of these studies are not unequivocal. Only lithium and valproic acid are shown to be teratogenic. In cases where malformations of the fetus are observed, the treatment often consisted in a combination of various psychotropic drugs.

The review is completed with data on the psychopharmacological problems during delivery and their side-effects on the newborn.

This paper addresses the issue of (recurrent) mania in relation to an increased T4-value, whether or not influenced by lithium. Lithium has an anti-TSH-effect on the thyroid gland by inhibiting the intracellular enzyme adenylate cyclase. This might cause hypothyroidism. Moreover, lithium is also known to have a direct stabilizing effect on (behavioral manifestations) of dopamine receptor supersensitivity.

The hypothesis regarding the relation between thyroid function and affective disturbances is that the altered thyroid function may cause a change in the availability of the central dopamine receptors. Dopamine is known to be able to cause a manic state. TSH and TRH are also involved in this mechanism. It is, therefore, very likely that an increased thyroid function, whether or not caused by discontinuation of lithium-therapy, could induce a (recurrent) mania.

A review is given of the neuropsychological conceptualizations of aphasia and apraxia in SDAT. In the beginning of this century localisationism was prevailing. Later, developmental and cognitive psychology gave an important impetus to reconsider these symptoms in an holistic framework. More recently, since the application of new brain imaging techniques, there is a revival of localizing conceptualizations.

Food and Drug Administration, World Health Organisation and Committee on Proprietary Medicinal Products have published guidelines with recommendations how to conduct clinical trials. The guidelines for the clinical evaluation of antidepressant drugs contain a great variety of recommendations how to design phase I, phase II and phase III trials. Especially the pharmaceutical industry will follow these guidelines as much as possible to make the chances to register a new chemical entity as optimal as possible. While FDA and CPMP guidelines are primarily meant to be read by representatives from the pharmaceutical industries, the WHO guidelines give mainly information for clinicians. For the psychiatrist with interest in clinical research on antidepressants it is mandatory to know about the existence of these different guidelines. Fundamental differences between the guidelines do not exist; the methodological and ethical problems concerning placebo-use and relapse-recurrence problems are especially emphasized in the CPMP-guidelines.

Dystonie reactions and hallucinations: a rare adverse-effect? One of the intriguing side-effects of neuroleptics is the acute dystonie reaction like oculogyric crises. It is seldom mentioned that the dystonie reaction may be combined with hallucinations. This combination of acute dystonia with hallucinations may be explained by overstimulation of dopamine-receptors in the striatal neurons. Awareness of these hallucinations as a complication of neuroleptics is essential to prevent that neuroleptic dose will be increased; instead it must be lowered. Prevention of the dystonia is critical. These side effects may be suppressed with anti-parkinsonian drugs. Information to the patient in due time may prevent anxiety about the side effects.