Mood disorders systems

Glassification of Substance-Related Disorders. The DSM-IV classification system (1) divides substance-related disorders into two categories (/) substance use disorders, ie, abuse and dependence and (2) substance-induced disorders, intoxication, withdrawal, delirium, persisting dementia, persisting amnestic disorder, psychotic disorder, mood disorder, anxiety disorder, sexual dysfunction, and sleep disorder. The different classes of substances addressed herein are alcohol, amphetamines, caffeine, caimabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics, polysubstance, and others. On the basis of their significant socioeconomic impact, alcohol, nicotine, cocaine, and opioids have been selected for discussion herein. 

There is evidence for the contribution of serotonin dysfunction to mania, and in the mechanism of action of mood stabilizers [19], however, specific data on the serotonergic system and mania are fewer and variable. Moreover, altered functioning of other neurotransmitters in mania such as norepinephrine, dopamine, acetylcholine, and GABA, and their interaction with serotonin, are also likely to be involved in the pathogenesis of mood disorders. Differences in these neurotransmitter systems possibly underlie differences in the pathogenesis of depressive and manic episodes. 

There is ample support for the hypothesis of noradrenergic system dysfunction in depression however, the inconsistencies in findings rule out any simple model of increased or decreased noradrenergic activity. It is important to determine which noradrenergic system abnormalities relate specifically to the pathogenesis of mood disorders, and which are related to nonspecific effects of stress, homeostatic mechanisms, or comorbid psychopathology. More work is needed on the mood-state-depen-dence of noradrenergic function. 

Neuropsychological impairments in mood disorders, particularly those of working memory and executive function, are the most convincing and objective demonstrations of an impairment of consciousness. Since these impairments do not correlate with the severity of the mood disturbance and persist upon recovery they are not simply epiphenomena of the mood disturbance but rather may index trait pathology in susceptible individuals. It has previously been argued that mood disturbance and neuropsychological impairment may result from disturbances in two different neurochemical systems, the serotonin (5-HT) system and the hypothalamic-pituitary-adrenal (HPA) axis, between which there is a close interaction (McAllister-Williams et al., 1998). 

Tryptophan depletion in healthy volunteers impairs the retrieval of learnt material (Park et al., 1994), an effect probably mediated through a selective impairment of episodic memory consolidation (Riedel et al., 1999 Schmitt et al., 2000). However, tryptophan depletion appears to have no effect on working memory (Riedel et al., 1999) and either no effect or an enhancement of tests of executive function (Park et al., 1994 Schmitt et al., 2000). Thus the abnormality in episodic memory in mood disorders could conceivably be related to an impairment in the 5-HT system, but such an impairment is unlikely to account for the abnormalities in working memory and executive function. Clearly then, changes in consciousness occurring in affective disorders are unlikely to be explainable on the basis of an abnormality in a single neurochemical system. 

The nature of the neurochemical impairment underlying depressive illness remains elusive. There is a great deal of evidence supporting roles for the 5-HT system and the HPA axis. However the evidence is less clear that an abnormality in one system alone can explain the full extent of the clinical features of depressive illness. Subtle abnormalities in the interactions between the HPA axis and the serotonergic system may lead to profound alterations in the functioning of both systems, and it may be this that results in the range of symptoms found in mood disorders. 

Schatzherg, A.E and Schildraut, J.J. (1995) Recent studies on norepinephrine systems in mood disorders. In Bloom, EE. and Kupfer, D.J., eds. Psychopharmacology The Fourth Generation of Progress. New York Raven Press, pp. 911-920. 

Donovan et al. (1996, 1997) completed an open study evaluating the use of valproic acid (Depakote) in adolescent outpatients with marijuana abuse or dependence and explosive mood disorder (mood symptoms were not classified using the DSM FV Diagnostic System). Eight subjects were prescribed 1000 mg of valproic acid (Depakote) for 5 weeks, in addition to regular therapy sessions, but did not receive any other psychotropic medications. All subjects showed a significant improvement in their marijuana use (p <0.007) and their affective symptoms (p < 0.001), although both outcomes were measured only by self-report. The most common adverse events were nausea and sedation. No subjects discontinued because of these side effects, nor were there any reported interactions between the valproic acid (Depakote) and substances of abuse. 

In summary, these clinical and preclinical findings support the view that mood disorders can be seen as stress system disorders, in which impairment of GR and MR action plays a causal role. The impairments may be genetically determined or acquired through a variety of early stressors, or both. It is possible that antidepressants exert their clinical efficacy through reinstatement of complete corticosteroid receptor function. Of course, other important actions of these drugs also need careful consideration. 

These data and findings from serotonin depletion studies show that, in patients treated successfully, NA and serotonin systems are involved in maintenance of drug-induced remission. However, the absence of an increased severity in depressive symptoms in drug-free patients with depression suggests that alterations in serotonin and catecholamine release may not be causally involved in the pathophysiology of mood disorders. 

In my admittedly biased view, the most coherent approach is that of a profoundly disturbed stress system that under specific conditions paves the way to development of mood disorders. These stress-system alterations can be genetic or acquired through trauma in early life or even in utero. Consistent with this neuroendocrine hypothesis are findings that centrally released neuropeptides that drive the HPA system also have behavioral effects that are similar to affective symptoms. This view is further supported by the documented ability of various antidepressants to enhance corticosteroid receptor synthesis and efficacy. Moreover, the stress system, particularly the corticosteroids and their receptors, interferes with all of the neurotransmitter receptor systems, including intracellular signaling, that have been considered in the context of mood disorders. New drugs targeted directly to various elements of the stress system will constitute a major step forward. 

What then, is the current evidence to support a role of norepinephrine in depression, such that manipulation of noradrenergic activity bears particular relevance to the successful treatment of mood disorders Interpretation of studies depends on the continually evolving conceptualizations of the roles of brain noradrenergic systems. A potentially useful way of thinking about the function of the norepinephrine in the brain can be derived from examining the neuroanatomy of the noradrenergic system. A summary of findings [primarily from rodents and primates) is as follows. 

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