Mood disorders serotonin

Serretti, A., Lorenzi, C., Lilli, R. Smeraldi, E. (2000). Serotonin receptor 2A, 2C, 1A genes and response to lithium prophylaxis in mood disorders. /. Psychiatr. Res., 34, 89-98. 

Serretti, A., Malitas, R N., Mandelli, L. etal. (2004). Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders. Pharmacoge-nomics /., 4(4), 267-73. 

Smeraldi, E., Benedetti, F. Zanardi, R. (2002). Serotonin transporter promoter genotype and illness recurrence in mood disorders. Eur. Neuropsychopharmacol. 12, 73-5. 

Since the introduction of fluoxetine (3) in 1987, a series of selective serotonin reuptake inhibitors (SSRIs) have been discovered that have seen broad application in many facets of mood disorders. These compounds include fluvoxamine (4) which contains a trifluoromethyl group and paroxetine (5) and citalopram (6) which contain 4-fluorophenyl groups [5,6]. 

Non-motor signs of the disorder are also treatable with symptomatic medications. The frequent mood disorder can be treated with standard antidepressants, including tricyclics (such as amitryptiline) or serotonin reuptake inhibitors (SSRIs, such as fluoxetine or sertraline). This treatment is not without risks in these patients, as it may trigger manic episodes or may even precipitate suicide. Anxiety responds to benzodiazepines, as well as to effective treatment of depression. Long-acting benzodiazepines are favored over short-acting ones because of the lesser abuse potential. Some of the behavioral abnormalities may respond to treatment with the neuroleptics as well. The use of atypical neuroleptics, such as clozapine is preferred over the typical neuroleptics as they may help to control dyskinesias with relatively few extrapyramidal side-effects (Ch. 54). 

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. 

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). 

Ryan, N.D. and Varma, D. (1998) Child and adolescent mood disorders—experience with serotonin-based therapies. Biol Psychiatry 44 336-340. 

As outlined previously, initial biological hypotheses of mood disorders were derived from the pharmacological actions of antidepressant drugs, which increase synaptic concentrations of noradrenaline (NA] and/or serotonin. Consequently, the biogenic amine hypothesis was formulated, but it lacks consistent proof that NA and/or serotonin release is indeed diminished. This failure is in part a result of the limited access to relevant brain areas. Measurements of NA and serotonin and their metabolites in blood, urine, and CSF... 

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. 

This case report (Figures 6-4Ato 6-4C) (McDermut et al. 1995) of selective response to dihydropyridine CCBs but not a phenylalkylamine CCB is of considerable interest in relationship to the patient s history of nonre-sponsivity to multiple tricyclic antidepressants, the selective serotonin reuptake inhibitors, lithium, carbamazepine (the patient developed drug-induced hepatitis on carbamazepine and was unable to be evaluated), alprazolam, trazodone, and phenelzine. This suggests that patients with refractory mood disorders may have differential responses to various CCBs and that nonresponse to one CCB does not preclude response to another CCB, particularly if the other CCB is from a different category (Table 6-3). 

Sprouse JS, Wilkinson LO Innovative therapeutic actions by targeting serotonin lA receptors selectively. International Review of Psychiatry 7 5-15, 1995 Squillace K, Post R, Savard R, et al Life charting of the longitudinal course of recurrent affective illness, in Neurobiology of Mood Disorders, Vol 1. Edited by Post RM, Ballenger JC. Baltimore, MD, Williams Wilkins, 1984, pp 38-59 Squires RF, Braestrup C Benzodiazepine receptors in rat brain. Nature 266 732-734, 1977... 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

In the mid-1960 s, Schiidkraut and Bunney and Davis, independently developed the monoamine hypothesis of mood disorders. To date, a great wealth of data has been generated to test this theory (see also the section Mechanism of Action in Chapter 7) (21, 22). Because the early development of psychotropic agents was based on the concept that altering norepinephrine (NE) or serotonin activity could benefit depression or mania, it is not surprising that the action of these drugs... 

Some studies have shown increased risks of violent death and depression in subjects with reduced serum cholesterol concentrations. Serum and membrane cholesterol concentrations, the microviscosity of erythrocyte membranes, and platelet serotonin uptake have been determined in 17 patients with hypercholesterolemia (21). There was a significant increase in serotonin transporter activity only during the first month of simvastatin therapy. This suggests that within this period some patients could be vulnerable to depression, violence, or suicide. This is an important paper, in that it explains why mood disorders are not regularly seen in clinical trials with statins, as has been summarized in a recent review (3). 

If the patient has a pre-existing mood disorder, such as depression or anxiety disorder, antidepressant medication may also be prescribed. Studies have shown that the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) and sertraline (Zoloft) are effective in people with bulimia and anorexia. These medications reduce depression by increasing levels of serotonin, a neurotransmitter. 

Serotonin Firing Activity as a Marker for Mood Disorders Lessons from Knockout Mice Gabriella Gobbi... 

Tsai SJ, et al. Serotonin-2A receptor polymorphism (102T/C) in mood disorders. Psychiatry Res 1999 87(2-3) 233-237. 

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