Angela Cappiello

Antidepressant effects of ketamine in depressed patients

BACKGROUND A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. METHODS Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. RESULTS Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). CONCLUSIONS These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.

SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder

BACKGROUND Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects. METHODS A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96). RESULTS A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex. CONCLUSIONS Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.

The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial

BACKGROUND Preliminary reports have suggested that concomitant institution of pindolol and serotonin reuptake inhibitors robustly hastens clinical response; however, contradictory evidence from a randomized double-blind, controlled trial was recently reported by this group in a population of depressed patients who were prescribed fluoxetine and pindolol. Herein, we report final results from an extended sample size. METHODS Drug-free outpatients with a major depressive episode were randomized in a double-blind manner to one of two treatment conditions: fluoxetine (20 mg daily) with pindolol (7.5 to 10 mg daily) or fluoxetine (20 mg daily) with placebo. After 6 weeks, patients were followed for 3 more weeks in a single-blind manner, on fluoxetine and placebo pindolol. RESULTS Eighty-six patients completed at least 1 or more weeks on protocol, with 45 and 41 patients randomized to the pindolol and placebo groups respectively. After 2 weeks on protocol, partial remission (i.e., at least 50% decrease in depression rating scores from baseline) rates for pindolol (16%) and placebo (19%) groups were comparable. By the studys end, a partial remission was achieved, at least transiently, for 67% of the pindolol group and 80% of the placebo group. Pindolol treatment was associated with statistically significant reduction in blood pressure and pulse as compared to the control group. The two groups did not have overall differences in rates of attrition, time to response, and side effects. CONCLUSIONS In accord with our previously published findings, these extended results do not support the efficacy of pindolol in hastening clinical response to fluoxetine in a patient population with predominantly chronic and recurrent depression.

Addition of the α2-Antagonist Yohimbine to Fluoxetine: Effects on Rate of Antidepressant Response

Electrophysiological studies suggest that α2-adrenoceptors profoundly affect monoaminergic neurotransmission by enhancing noradrenergic tone and serotonergic firing rates. Recent reports suggest that α2-antagonism may hasten and improve the response to antidepressant medications. To test this hypothesis, a randomized double-blind controlled trial was undertaken to determine if the combination of an α2-antagonist (yohimbine) with a selective serotonin reuptake agent (SSRI) (fluoxetine) results in more rapid onset of antidepressant action than an SSRI agent alone. In all, 50 subjects with a DSM-IV diagnosis of major depressive disorder confirmed by SCID interview were randomly assigned to receive either fluoxetine 20 mg plus placebo (F/P) or fluxetine 20 mg plus a titrated dose of yohimbine (F/Y). The yohimbine dose was titrated based on blood pressure changes over the treatment period, in a blind-preserving manner. Hamilton depression scale ratings (HDRS) and clinical global impression (CGI) ratings were obtained weekly over a period of 6 weeks. The rate of achieving categorical positive responses was significantly more rapid in the F/Y group compared to the F/P group using both the HDRS and the CGI scales as outcome measures in a survival analysis using a log-rank test (χ2(1)=5.86, p=0.016 and χ2(1)=5.29, p=0.021, respectively). At the last observed visit, 18 (69%) of the 26 F/Y subjects met the response criteria for CGI compared to 10 (42%) of 24 F/P subjects. Using the HDRS criteria, 17 (65%) of 26 F/Y subject vs 10 (42%) of 24 F/P subjects were responders. The addition of the α2-antagonist yohimbine to fluoxetine appears to hasten the antidepressant response. There is also a trend suggesting an increased percentage of responders to the combined treatment at the end of the 6-week trial.

Estradiol and Tryptophan Depletion Interact to Modulate Cognition in Menopausal Women

Despite an abundance of data in animals, there is little research in humans regarding how estrogen and serotonin (5-HT) may interact to influence cognition. Through the use of estrogen treatment (ET) and tryptophan depletion (TRP-D) in a within-subject design involving healthy menopausal women, we have manipulated both estrogen and 5-HT in order to evaluate their individual and joint effects. Although neither manipulation influenced visuospatial learning, a significant interaction suggested that estrogen exerted a protective effect on verbal memory, such that TRP-D impaired performance to a greater extent before the administration of ET. In consonance with this finding, ET was associated with a small, but positive mood effect on the day following active TRP-D. In addition, ET significantly improved letter-cued verbal fluency with and without TRP-D. Finally, time since last menstrual period was significantly associated with verbal memory scores, such that longer length of hypogonadism resulted in decreased verbal memory performance. These data support the interaction of estrogen and 5-HT in nonreproductive behavior in humans as well as highlight the role of ovarian steroids in cognition.

Effect of catecholamine depletion on lithium-induced long-term remission of bipolar disorder

BACKGROUND This study investigated the effects of catecholamine depletion with alpha-methylparatyrosine (AMPT) on mood indices in patients with bipolar disorder who were in long-term remission with lithium therapy. METHODS Eight subjects with DSM-IV bipolar disorder currently in remission for > 3 months on lithium were included in the study. Subjects were given either AMPT or placebo, in a randomized double-blind manner, in two test sessions of 4 days each. RESULTS Subjects did not have any significant changes in mood during AMPT or placebo administration; however, 24-48 hours after the last active AMPT dose subjects had a transient relapse of hypomanic symptoms. Relapse of hypomanic symptoms did not correlate with increases in serum levels of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol. CONCLUSIONS These findings suggest that the mechanism of prevention of manic relapse by long-term lithium therapy may be dependent on stability of the catecholamine system.

Effects of antiglucocorticoid treatment on 5-HT1A function in depressed patients and healthy subjects

Clinical studies suggest that 5-HT1A receptor function may be blunted in depression, while 5-HT1A agonists may possess antidepressant activity. Preclinical findings implicate changes in 5-HT1A receptor sensitivity in the mechanism of antidepressant action. The hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in depression could be related to these observations, since 5-HT1A receptors are inhibited by glucocorticoids. To evaluate the interaction of the HPA and 5-HT1A systems, we pretreated 15 unipolar depressed patients and 12 healthy control subjects with the antiglucocorticoid ketoconazole (KTCZ) prior to administration of a test dose of the 5-HT1A agonist ipsapirone (IPS). Neuroendocrine (ACTH, cortisol, growth hormone), physiological (hypothermia), and behavioral responses to IPS were assessed. As expected, KTCZ inhibited cortisol biosynthesis, but non-HPA responses to IPS were not enhanced. This study failed to show that glucocorticoid modulation of 5-HT1A receptor function is altered in depression.

Seasonal Variation in Neuroendocrine and Mood Responses to IV L-Tryptophan in Depressed Patients and Healthy Subjects

Seasonality of mood disorders might involve alterations in the rhythmicity of serotonin [5-HT] function. We examined seasonal effects on the neuroendocrine and mood responses to L-tryptophan (L-TRP) in depressed patients and healthy subjects. In this study, 126 drug-free patients with DSM-III-R major depression and 58 healthy subjects received in IV infusion of L-TRP. Serum prolactin (PRL) and plasma tryptophan levels were measured. Mood was assessed with visual analogue scales. Cosinor analysis revealed seasonal variation in peak change (Δ) PRL and baseline tryptophan levels in the combined depressed and in unipolar, nonmelancholic, and nonpsychotic patients. Peak Δ PRL and tryptophan levels were inversely correlated in combined depressed and unipolar patients. Seasonality was more evident in female than in male patients. These data support previous evidence that 5-HT function is abnormal in depression and further suggest a seasonal variability of such abnormalities that is absent in healthy subjects.

The resistance to depressive relapse in menopausal women undergoing tryptophan depletion: preliminary findings

Changes in neuroendocrine function may predispose menopausal women to psychological disturbances characterized by depressed mood, anxiety, irritability, fatigue, insomnia, forgetfulness and decline in Libido. The acute tryptophan depletion paradigm was employed to examine the serotonergic contribution to mood and cognitive function in menopausal women who were within 4 weeks of recovery from an episode of major depression. MenopausaL women whose depression was responsive to treatment with oestradiol, the selective serotonin reuptake inhibitor fluoxetine, or a combination of both treatments underwent assessment of mood and verbal memory on active tryptophan depLetion and sham depLetion test days. Although performance on the deLayed paragraph recall subtest of the Wechsler Memory Scale was impaired by tryptophan depletion, no subjects experienced a relapse of depression or a significant worsening of mood. Results from this pilot study indicate that menopausal women who have recently recovered from a major depressive episode do not experience a worsening of mood with acute tryptophan depletion, despite the existence in this sample of some known risk factors for depressive relapse as a result of these procedures. While preliminary, the results suggest that serotonin may be Less critical to the pathogenesis of depression during the menopause.

Lithium and desipramine versus desipramine alone in the treatment of severe major depression : a preliminary study

Improvement following lithium augmentation is well-documented in depressed patients resistant to tricyclic antidepressants. However, response latency to lithium augmentation is extremely variable, suggesting other mechanisms may be involved. To evaluate whether long-term tricyclic treatment is necessary for lithium augmentations effect, the rapidity and magnitude of response to lithium combined with desipramine from the start of treatment was compared to desipramine alone in severely depressed patients. Patients with DSM-III-R major depression were randomized to double-blind, placebo-controlled treatment with either lithium + desipramine or placebo + desipramine for 4 weeks. Response criteria were based on Hamilton Depression Rating Scale scores and global improvement. Analysis of covariance of Hamilton scores demonstrated that lithium + desipramine was superior to placebo + desipramine at week 1 (P < 0.009), week 2 (P < 0.028), and week 3 (P < 0.07), although not at week 4. There were more responders to the combination than to monotherapy (P < 0.042). These preliminary data suggest that lithium + desipramine may have some efficacy in severely depressed patients. Further studies with larger samples are needed to confirm these findings.