Oxytocinergic regulation of endogenous as well as drug-induced mood.

The interconnections between the serotonin and oxytocin pathways in the brain suggest that changes in oxytocin levels - arising from natural or drug-induced stimuli - lead to measureable changes in mood. In this paper, we review our findings in the context of what is known about the roles of oxytocin and vasopressin in the expression of a range of behaviours. In our first set of studies we investigated whether stimulation of oxytocin and vasopressin receptors, via central or systemic drug administration, would produce behavioural changes indicative of anti-depressant or anxiolytic activity. In our second study we investigated whether oxytocin receptor activation might be implicated in the interoceptive effects experienced with the popular party drug, MDMA ('ecstasy'). Our first study demonstrated that carbetocin, an oxytocin analogue, had anti-depressant actions following systemic and central administration, effects which were blocked by the oxytocin and vasopressin 1A receptor antagonist, atosiban. Carbetocin also had anxiolytic effects in the elevated plus maze. In an evaluation of the complementary nature of oxytocin and vasopressin, we found that systemic administration of desmopressin, a vasopressin analogue, was anxiogenic; its effects blocked by atosiban which on its own produced robust anxiolytic behavioural changes. In our second study, we evaluated MDMA's interoceptive effects using a drug discrimination paradigm. Carbetocin partially substituted for MDMA, while atosiban interfered with MDMA discrimination, suggesting that oxytocin receptor activation contributes to MDMA-related interoceptive cues. The results of these and other clinical and preclinical studies suggest that oxytocin, as well as its closely related counterpart vasopressin, may provide alternative therapeutic targets for the treatment of mood disorders such as anxiety and depression. The possibility that oxytocin release may contribute to the perception of and processes underlying natural and drug-induced behavioural reinforcement offers exciting prospects for future study.

A placebo-controlled, double-blind study of fluoxetine in severe alcohol dependence: adjunctive pharmacotherapy during and after inpatient treatment.

Twenty-eight male patients with severe alcohol dependence (mean pretreatment consumption of 18.6 standard drinks per day) completed a placebo-controlled, double-blind clinical trial of fluoxetine (60 mg/day). They were assigned to medication group in the second of 4 weeks on a voluntary inpatient chemical dependency ward and continued medication during a 12-week follow-up phase. Fluoxetine did not reduce clinically significant relapse rates; only 8 of 15 (53%) of fluoxetine subjects remained sober at 12 weeks, compared with 9 of 13 (69%) of the placebo group (Fisher's exact test, p = 0.46). Subjects with comorbid cocaine dependence relapsed more than twice as often (3 of 4, 75%) as those with alcohol dependence alone (8 of 24, 33%), although this trend did not reach statistical significance because of the small number of dually dependent subjects (Mann Whitney U test = 68, p = 0.13). Supportive living arrangements after hospital discharge did reduce relapse rates: 8 of 9 subjects (89%) discharged to a Veterans Affairs domiciliary were sober at 12 weeks, compared with 9 of 19 (47%) subjects discharged back to the community (Mann-Whitney U test = 125, p = 0.02). Fluoxetine-treated subjects who remained sober at 12 weeks reported a significant decrease in mean subjective alcohol craving scores from 2.9 to 0.7 on a 10-point scale (t = 2.828, p = 0.02). In summary, fluoxetine did not reduce clinical relapse rates in this sample of male severe alcoholics without other axis I disorders who completed 4 weeks of inpatient alcoholism treatment.

Valproate as an antidepressant in major depressive disorder.

Thirty-three outpatients who met DSM-IV criteria for major depressive disorder (MDD) with no history of manic or hypomanic symptomatology were enrolled in an 8-week open trial of valproate. By Week 4, 15 of the 28 completers (54%) demonstrated a significant clinical response as defined by a score reduction of 50 percent or more or a total score of 9 or lower on the Hamilton Rating Scale for Depression (HRSD). Mean HRSD scores of the completers decreased 48.8 percent at Week 4 (p < .0001). At Week 8, 19 of the 22 completers (86%) showed a significant response. Mean HRSD scores decreased from 22 +/- 5 at baseline to 7 +/- 4 at Week 8 (p < .0001). With the intent-to-treat analysis at Week 8, 66 percent were responders, and total group mean HRSD scores decreased 55 percent (p < .0001). The data suggest that valproate may be an effective treatment for MDD. Double-blind, placebo-controlled trials are needed to further document its efficacy in the treatment of MDD.

Serotonin dysfunction disorders: a behavioral neurochemistry perspective.

The spectrum of efficacy of the serotonin selective reuptake inhibitor (SSRI) antidepressant drugs continues to expand. In fact, no psychiatric syndrome seems to worsen with these agents, and few studies fail to demonstrate clinical improvement in some patients, regardless of any nosologic nicety, such as precise DSM diagnosis. This suggests that the biological rubric of psychopathology is dimensional rather than categorical. New research using in vivo microdialysis shows differences in neurochemistry among SSRIs, wherein fluoxetine blocks reuptake of dopamine and norepinephrine, as well as serotonin, in medial prefrontal cortex, and fluvoxamine has a relatively more selective neurochemical profile. In the animal model of learned helplessness, which is a biobehavioral model for stress-induced anxiety causing depression, the SSRIs including fluvoxamine prevent helplessness. From these and other data, a neurotransmitter balance theory of biopsychopathology is formulated. In this hypothetical construct, dopamine, norepinephrine, and GABA modulate thought, anxiety, and mood, respectively. Serotonin is a stabilizing agent, which assists in returning the mind to its homeostatic setpoint.