Mood axis

In depressed patients, cortical-hypothalamic-pituitary-adrenal axis hyperactivity can be explained by the hypersecretion of CRF, and secondary pituitary and adrenal gland hypertrophy. Impaired negative feedback at various CNS sites, including the hippocampus and pituitary are also likely to contribute. Downregulation of hippocampal mineralocorticoid receptors and expression is reported in depressed suicides [50]. In bipolar disorder, hyperactivity of the cortical-hypothalamic-pituitary-adrenal axis has been observed [51]. This increase in cortical-hypothalamic-pituitary-adrenal axis activity has also been observed in mixed mood states, mania and in depression in rapidcycling patients. Partial reversal of HPA overactivity is associated with treatment and recovery from depression. 

Growth hormone. Mood disorders have been related to alterations in the activity of the growth-hormone axis. A blunted growth-hormone response to clonidine, an a2 receptor agonist, has been consistently found in depression. Increased growth-hormone secretion during the day and decreased nocturnal growth-hormone secretion have also been observed in depressed patients. Depressed patients have lower CSF concentrations of somatostatin, compared to those with schizophrenia and normal controls. While lower CSF somatostatin is a state-dependent marker of depression, it occurs in a number of unrelated nonpsychiatric conditions, and thus appears to be relatively nonspecific. 

The potential hyperactivation of the HPA axis in mood disorders has been revisited in recent years, in large part due to the growing recognition of the specific brain areas in which atrophy (loss), a neuroplastic event, may be present in many patients. To what extent these findings of atrophy represent the sequelae of the biochemical changes (for example, in glucocorticoid levels) accompanying repeated affective episodes, remains to be fully elucidated. 

These patients will often present with complaints of depressed mood or anxiety. The depression frequently takes the form of dysthymic disorder although these patients are at increased risk for major depressive disorder as well. Anxiety is often a symptom of the personality disorder itself, though comorbid Axis 1 anxiety disorders are occasionally present. Similar to the other personality disorders, there is a differential diagnosis that should be considered in patients who have a Cluster C personality disorder. 

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). 

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. 

One hypothesis is that an impairment ofserotonergic transmission through hippocampal 5-HTia receptors may underlie the low mood seen in depression. In addition, the reduced activation of hippocampal 5-HTia receptors may decrease the inhibitory control of the HPA axis mediated by the hippocampus leading to hypercortisolaemia and a neuropsychological impairment. An alternative hypothesis is that the primary neurobiological disturbance in depression is an abnormality of GRs leading to an impaired feedback control of the HPA axis and hypercortisolaemia. This in turn may lead to neuropsychological dysfunction. Reduced functional activity of GRs may increase the autoinhibitory action of somatodendritic 5-HTja receptors, decrease 5-HTia receptor num-... 

Prange AJ Jr, Loosen PT, Wilson IC, et al The therapeutic use of hormones of the thyroid axis in depression, in Neurobiology of Mood Disorders (Frontiers of Clinical Neuroscience, Vol 1). Edited by Post RM, Ballenger JC. Baltimore, MD, Williams Wilkins, 1984, p 311... 

The most commonly used semi-structured diagnostic scale is the Structured Clinical Interview for DSM-IV Axis I Disorders (SCI I) First et al., 1997). A clinical version of the SCID (SCID-CV) is designed for use in clinical settings and covers the most commonly seen diagnoses according to DSM-IV. The research version of the SCID includes ratings for different subtypes, severity and course specifiers of mental disorders. The SCLD-CV contains six modules (A) Mood Episodes (B) Psychotic Symptoms (C) Psychotic Disorders (D) Mood Disorders (E) Substance Use Disorders fF) Anxiety and Other Disorders. 

Mental disorders, also called affective disorders, are multi-level, multi-scale and multiple-system diseases (Fig. 7.1). Mental disturbances generally go along with disturbances of autonomous functions. These essentially are (1) sleep disturbances, both sleep duration and sleep pattern, and (2) disturbances of the hypothalamic-pituitary-adrenal (HPA) axis, the so-called stress axis with elevated cortisol levels. It can be expected that disturbances of autonomous control systems as well as mood are caused by neuronal malfunctioning which may concern practically all neuronal levels systemic interactions, neuronal network connections, single neuron dynamics, synaptic transmitters and/or receptors, ion channels, second messengers, and gene expression (Fig. 7.1a). Nevertheless, despite a manifold of data, there are only vague ideas so far about the differences in neuronal dynamics in the brain of a chronically depressed person compared with a person with a sensitive but balanced mood. 

Mood Related Disturbances of Circadian Rhythms.Sleep-Wake Cycles and HPA Axis 207... 

A vast amount of literature indicates a relationship between stress and depression, and in this regard it is interesting that the HPA axis, which is involved in the coordination of neuroendocrine responses to stress, has been shown to be hyperactive in many depressed patients (57, 58). In their diathesis-stress hypothesis of mood disorders. Stout et al. (58) propose that the HPA axis is the principal site where genetic and environmental influences converge to cause mood disorders. 

Several studies have show n increased plasma levels of IL-6 in patients with MDD. In a more extensive study, Alesci and colleagues found that IL-6 levels were increased in MDD patients throughout the circadian cycle (Alesci et al., 2005). There was a 12-hour shift in the circadian rhythm of IL-6 plasma levels and its complexity was reduced. Even though IL-6 is a known activator of the HPA axis, cortisol levels were not consistendy changed in MDD padents compared to controls. Addidonally, it v as found that IL-6 levels, with their altered rhythm, correlated significandy with mood radngs. IL-6 also induces a sickness behavior very similar to depression. These data suggest a direct reladonship betw een IL-6 and depression. 

Esposito S. The thyroid axis and mood disorders Overview and future prospects. Psychopharmacol Bull 1997 33 205-17. 

In addition, it exerts beneficial effects in many disorders as an adjuvant to other treatment modalities. Such effects are apparent only if it is administered to an already pharmacologically treated patient. For example, in unresponsive major depressive disorder, the co-administration of lithium to an ongoing antidepressant treatment increases the response rate by up to 50%. In most cases, the response to lithium augmentation is either considerable or not at all ( all-or-none phenomenon). Some (currently not convincing) results have also been reported in unipolar depression, bulimia nervosa, and attention deficit hyperactivity disorder (ADHD). Lithium also exerts antiaggressive effects in conduct disorder, independent of any mood disorder, and can reduce behavioral dyscontrol and self-mutilation in mentally retarded patients. One of the most striking effects of lithium is its antisuicidal effect in patients who suffer from bipolar and unipolar depressive disorder irrespective of comorbid axis I disorder. ... 

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