Major depressive disorder mechanisms

Stahl, S.M., Kaiser, L., Roeschen, J., Keppel Hesselink, J.M. and Orazem, J. (1998) Effectiveness of ipsapirone, a 5-HT-1A partial agonist, in major depressive disorder support for the role of 5-HT-1A receptors in the mechanism of action of serotonergic antidepressants. International Journal of Neuropsychopharmacology, 1, 11-18. 

The treatment of the major depressive disorders such as unipolar and bipolar depressions was initially considered to be uniform, ffowever, with psychopharmacological advances, it has been demonstrated that the patients with bipolar depression may be partially responsive, at least prophylactically responsive, to lithium therapy, whereas the patients with unipolar depression are not as responsive (Abou-Saleh 1992). In addition, the treatment of depression may contribute through serendipity to the confirmation of a subgroup of patients with a bipolar disorder referred to as bipolar II. These patients, following treatment with antidepressants, will switch over to a hypomanic or fully manic phase resulting from pharmacological mechanisms. Thus, another subgroup of the bipolar disorder may be identified in the future. 

The overall efficacy among the SSRIs for major depressive disorder is remarkably similar, consistent with the hypothesis that they have the same mechanism of action (i.e., serotonin uptake inhibition). 

Although a number of theories have been proposed, the mechanism of action of this form of treatment is essentially unknown. The main indication for ECT is major depressive disorder, particularly in the presence of certain clinical characteristics. Mania and schizophrenia in some situations also constitute indications for ECT (see Tables 3.18 and 3.19). 

Acute mania as part of bipolar I disorder is supposed to result from overexcitation of limbic neurons. This can arise either from loss of inhibitory tonic orbitofrontal control of limbic neurons or from various intra- and intercellular alterations (the full mechanism is unknown as yet). Manic episodes are often classified into euphoric (classical), dysphoric, mixed (along with clinical manifestations of major depressive disorder), mania with psychotic/catatonic features, and mania with a rapid cycling course of the disease. 

Supposed mechanism of action of iight therapy in major depressive disorder as part of MDDSP... 

Reboxetine is a nontricyclic SNRI in which the propylamine side chain of the TCAs is constrained into a morpholine ring (Fig. 21.8). It is a potent and selective ligand for the NET, with a mechanism of action is similar to that of desipramine. Reboxetine is used for the treatment of major depressive disorders. It is a chiral compound that is marketed as a racemic mixture of R,R- and S,S-reboxetine. The antidepressant activity for reboxetine appears to reside with the S,S-(+)-enantiomer, which has approximately twofold the inhibition potency of the R,R-enantiomer (42). It is well tolerated, with different adverse-event profiles, and it appears to be at least as effective as the SSRIs in the treatment of depressive illness. Currently, it is available only in Europe and is under U.S. FDA review. It preferentially inhibits the reuptake of NE (5-FIT NE ratio, 8). Reboxetine is not metabolized by the polymorphic isoforms, CYP2D6 or CYP2C19, and may offer a valuable alternative to the secondary amine TCAs in the treatment of major depression. Reboxetine is likely to become a promising alternative for patients who have failed treatment with or do not tolerate serotonergic antidepressants. Reboxetine has been shown to be effective and well tolerated in the treatment of panic... 

The serotonergic system has long been thought to play a role in major depression and bipolar disorders, although the exact mechanisms are yet to be determined 889... 

The treatment of major depression in psychiatry is analogous to the treatment of many conditions in general medicine. Thus, patients with these various disorders can benefit from several classes of medications with different mechanisms of action and adverse effects. The development of newer agents with unique spectra of activity requires the parallel development of specific strategies for their optimal use. Later, after a review of the efficacy literature, we suggest such a model to manage the depressed patient. 

In this review we discuss the relationships between serum lipid profile levels, major depression, and suicide attempts, as well as the interactions between lipid profiles, stress, HPA axis, and inflammation/immunity in depressive disorders. The conclusion emphasizes the importance of integrated data between clinical phenotypes and molecular mechanisms in depressive disorders. 

For further progress towards mechanisms based models, such phenomenological descriptions shall also be examined in context with disease-related disturbances of autonomous functions. This mainly concerns disturbances of sleep-wake cycles and cortisol release which are the most reliable biological markers of mental diseases, especially major depression, and can provide objective and quantifiable parameters (e.g. EEG frequency components, cortisol blood level) for the estimation of an otherwise mainly subjective and only behaviorally manifested illness. Moreover, there is a manifold of data which interlink the alterations of the autonomous system parameters (sleep states, cortisol release) with alterations of neural dynamics. Therefore, the most promising approach also to understand the interrelations between neural dynamics and affective disorders probably goes via the analysis of mood related disturbances of autonomous functions. 

Major depression is a complex disorder with a highly variable course and an inconsistent response to treatment—and no established biogenic or psychogenic mechanism.55 We really don t understand it, we don t know how to treat it in all cases, and we don t know what causes it. We have only some intriguing correlations. 

Desipramine is a tricyclic antidepressant, inhibits reuptake of norepinephrine and serotonin in CNS, and is indicated in relief of symptoms of depression. Desipramine (75 to 150 mg p.o./day in divided doses) is indicated in endogenous depression major depression with melancholia or psychotic symptoms depression associated with organic brain disease, alcoholism, schizophrenia, or mental retardation and the depressive phase of manic-depressive disorder. Desipramine is absorbed rapidly from the GI tract, distributed widely in the body, and appears also in breast miUc. It is bound to plasma proteins to the extent of 90%, undergoes extensive first-pass metabolism, and its metabolites are excreted in urine. Desipramine strongly blocks the norepinephrine uptake mechanism and has no effect on the uptake of serotonin. Desipramine has weak alpha -adrenergic and... 

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