A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression.

OBJECTIVE: To directly compare the efficacy of lithium carbonate and liothyronine sodium (triiodothyronine) in the augmentation of therapeutic response in antidepressant nonresponders. DESIGN: A randomized, double-blind, placebo-controlled study of 2 weeks' duration. SETTING: The Mood Disorders Program, Clarke Institute of Psychiatry and the University of Toronto, Ontario. PATIENTS: Fifty outpatients, males and females, with unipolar, nonpsychotic major depression who had failed to respond to treatment with desipramine hydrochloride or imipramine hydrochloride. RESULTS: Both liothyronine and lithium were more effective than placebo in reducing scores on the Hamilton Rating Scale for Depression. However, the antidepressant augmenting effect of these two compounds did not differ from each other. When response was defined as a 50% or more reduction in the Hamilton Rating Scale for Depression scores and a final score less than 10, we found that 10 of 17 subjects responded to liothyronine, nine of 17 responded to lithium and three of 16 responded to placebo. CONCLUSIONS: Our study suggests that both lithium and liothyronine may be considered as alternatives in augmenting antidepressant response in patients who do not respond to treatment with a tricyclic antidepressant.

Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis.

BACKGROUND: Several trials have addressed the efficacy of liothyronine sodium therapy in euthyroid, nonpsychotic depressed patients refractory to tricyclic antidepressant therapy. We undertook a meta-analysis of these trials. METHODS: The MEDLINE database (1966 to May 1995) and published reference lists were examined for controlled clinical trials of triiodothyronine augmentation in euthyroid patients with refractory depression. Quality assessment and data abstraction were performed independently by two reviewers. Results were aggregated three ways: the relative response rate compared with controls, accepting each trial's definition of clinical response; absolute improvement in response rates; and improvements in depression scores, analyzed as continuous variables without a prespecified threshold for clinical response. RESULTS: Aggregating eight studies with a total of 292 patients, patients treated with triiodothyronine augmentation were twice as likely to respond as controls (relative response, 2.09; 95% confidence interval [CI], 1.31 to 3.32; P = .002). This corresponded to a 23.2% absolute improvement in response rates (95% CI, 4.5% to 41.9%; P = .02). Improvements in depression scores were moderately large (standardized effect size, 0.62; P < .001). However, study quality was uneven, and results were statistically heterogeneous. Among the four randomized double-blind studies, pooled effects were not significant (relative response, 1.53; 95% CI, 0.70 to 3.35; P = .29), but one study with negative results accounted for most of the intertrial heterogeneity in results. CONCLUSIONS: Triiodothyronine augmentation may be an effective empirical method of increasing response rates and decreasing depression severity scores in a subgroup of patients with depression refractory to tricyclic antidepressant therapy, but the total number of patients randomized was small, and additional placebo-controlled data are required for a definitive verdict. Since therapeutic trends now favor other drugs, future trials might usefully examine triiodothyronine augmentation with selective serotonin reuptake inhibitors or compare potentiation strategies, eg, lithium vs triiodothyronine, for managing refractory depression. Such trials would benefit from much larger sample sizes than those reviewed here.

Hormonal and subjective responses to intravenous meta-chlorophenylpiperazine in bulimia nervosa.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with bulimia nervosa (BN). Our goal was to further examine central serotonergic function in bulimic patients using neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist meta-chlorophenylpiperazine (mCPP). METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to intravenous mCPP (0.1 mg/kg) and placebo in 16 patients with BN, free of medication, and 14 normal control subjects. Plasma prolactin and cortisol levels were used as neuroendocrine measures, whereas subjective responses were measured using a visual analog scale of 10 different mood states. RESULTS: Compared with controls, the BN group exhibited blunted prolactin and net cortisol responses following mCPP challenge. Subjective responses, while preliminary, also differed between groups on items related to anxiety, calmness, and altered self-awareness. CONCLUSION: Evidence of dysfunction at or downstream of central serotonergic receptors in BN confirms and extends findings of prior research.

Carbamazepine and thyroid function in affectively ill patients. Clinical and theoretical implications.

Thyroid function was examined in 50 affectively ill patients before and four weeks after carbamazepine treatment. Carbamazepine significantly and substantially decreased peripheral thyroid hormone levels while increases in thyrotropin levels, although significant, were of much smaller magnitude. Furthermore, the decreases in levels of thyroxine (T4) and free T4 were significantly greater in carbamazepine responders than in nonresponders. These findings are discussed in light of current theories of the role of the thyroid axis in affective illness.

Hormonal and subjective responses to intravenous m-chlorophenylpiperazine in women with seasonal affective disorder.

BACKGROUND: There is emerging evidence of serotonergic dysfunction in patients with seasonal affective disorder (SAD). We examined central serotonergic function in female patients with SAD (fall-winter pattern) by means of neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist m-chlorophenylpiperazine. METHODS: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to m-chlorophenylpiperazine (0.1 mg/kg intravenously) and placebo in 14 unmedicated female patients with SAD in the depressed state and 15 female normal controls. All testing was done in the fall-winter months and during the follicular phase of the menstrual cycle. Plasma prolactin and cortisol levels were used as neuroendocrine measures, while subjective responses were assessed by means of visual analog scales of 10 mood states. RESULTS: On the basis of net responses to m-chlorophenylpiperazine (placebo effects subtracted from drug effects), patients with SAD exhibited blunted prolactin responses and less sadness than normal controls in response to the drug. When order of presentation of drug and placebo was taken into consideration, altered "calm" and "high" responses were also found in the patient group. CONCLUSION: Evidence of dysfunction at or downstream to central serotonergic receptors in female patients with SAD confirms and extends findings from previous research.

Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial.

Some hypothyroid patients receiving levothyroxine replacement therapy complain of depressive symptoms despite normal TSH measurements. It is not known whether adding T(3) can reverse such symptoms. We randomized 40 individuals with depressive symptoms who were taking a stable dose of levothyroxine for treatment of hypothyroidism (excluding those who underwent thyroidectomy or radioactive iodine ablation of the thyroid) to receive T(4) plus placebo or the combination of T(4) plus T(3) in a double-blind manner for 15 wk. Participants receiving combination therapy had their prestudy dose of T(4) dropped by 50%, and T(3) was started at a dose of 12.5 micro g, twice daily. T(4) and T(3) doses were adjusted to keep goal TSH concentrations within the normal range. Compared with the group taking T(4) alone, the group taking both T(4) plus T(3) did not report any improvement in self-rated mood and well-being scores that included all subscales of the Symptom Check-List-90, the Comprehensive Epidemiological Screen for Depression, and the Multiple Outcome Study (P > 0.05 for all indexes). In conclusion, the current data do not support the routine use of combined T(3) and T(4) therapy in hypothyroid patients with depressive symptoms.

Peripheral thyroid hormone levels in treatment resistant depression.

BACKGROUND: Various abnormalities of thyroid function have been inconsistently reported in major depression. The inconsistency between studies may be due to several factors including the stage of treatment resistance. METHODS: One hundred and one patients with major depressive disorder receiving their first antidepressant for their current major depressant episode had baseline thyroid function test performed. On completion of treatment, their stage of antidepressant resistance was determined. RESULTS: Severity of depression but not any peripheral thyroid hormone level was associated with stage of anti-depressant treatment resistance. CONCLUSIONS: Stage of treatment resistance does not appear to be a factor in the variability in peripheral thyroid hormone levels in unipolar major depression.

Folate, B12, and life course of depressive illness.

Forty-four consecutive, unmedicated outpatients with a major depressive disorder were evaluated to determine the relationships in life course, severity of depressive illness, and serum folate and B12 levels. Duration of current episode was significantly inversely correlated with folate levels. Age at onset of illness was significantly correlated with B12. In a subgroup of recurrent depressives, current age and age at onset of depressive illness were positively correlated with folate. The findings are discussed in light of the current hypotheses regarding the association of folate and mood.

Motor activity in depressed patients treated with carbamazepine.

Motor activity in 19 depressed patients treated with carbamazepine was assessed using self-contained monitors worn on the wrist. Those whose depression improved demonstrated significant increases in motor activity. Nonresponders as a group did not show decreased motor activity, suggesting that carbamazepine was not producing sedation or hypoactivity at clinically relevant doses. Activity counts were negatively correlated with ratings of global severity of depression on the Bunney-Hamburg Scale and with degree of motor retardation rated on the BPRS during treatment. The selective increases in motor activity in those who improved are consistent with psychomotor changes related to amelioration of depression.

Normal urinary free cortisol and plasma MHPG in panic disorder: clinical and theoretical implications.

Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic function have been reported in patients with panic disorder. Mean urinary free cortisol and plasma MHPG were measured in 12 medication-free panic disorder patients and 12 normal controls. No significant difference in urinary free cortisol and plasma MHPG was observed between the patients and controls. There was no relationship between plasma MHPG and urinary free cortisol in the panic patients or normal controls. These findings are described within the context of current concepts of stress and noradrenergic dysfunction in panic disorder.

Acute stress increases thyroid hormone levels in rat brain.

BACKGROUND: In experimental animals, exposure to uncontrollable stress induces a number of behavioral and biochemical changes that resemble symptoms seen in human depression and other psychiatric conditions. The present study used a yoked design to examine the effects of uncontrollable footshock stress on brain thyroid hormones in male and female rats. METHODS: Animals in one group received 15 trials where footshock could be terminated by pressing a lever (escapable shock). Rats in a second group received the same amount of shock, but had no control over shock termination (inescapable shock). Control rats received no shock. RESULTS: No significant differences were found among the three groups, for either males or females, in whole brain levels of thyroxine (T4) 3 hours after the footshock session. In contrast, significant group differences in brain levels of triiodothyronine (T3) were found for both males and females. In males, brain T3 was elevated by 21% in the inescapable shock group when compared to controls (p < .012). In females, brain T3 increased by 19% in the escapable shock group when compared to controls (p < .026). Plasma levels of both T3 and T4 were at control levels for all groups. CONCLUSIONS: These results provide the first demonstration that brain T3 levels change rapidly in response to acute stress. The data further suggest that the effects of stress controllability on brain T3 levels may be different for males and females.

Thyroid function and affective illness: a reappraisal.

It has been generally accepted that increased thyroid function facilitates treatment response in depression. Recent data show that response to several antidepressant treatments, particularly lithium and carbamazepine, are associated with decreased thyroid hormone levels. An alternative hypothesis that decreased thyroid indices are related to antidepressant response is proposed and clinical and research implications are discussed.

Inhibition by fluoxetine of cytochrome P450 2D6 activity.

Potent inhibition of cytochrome P450 2D6 (CYP2D6) in human liver microsomes by fluoxetine and its major metabolite norfluoxetine was confirmed (apparent inhibition constant values, 0.2 mumol/L). Several other serotonergic agents were also found to be competitive inhibitors of this genetically polymorphic enzyme. The O-demethylation ratio of dextromethorphan that expressed CYP2D6 activity in 19 patients receiving fluoxetine fell in the region of the antimode separating the O-demethylation ratio values observed in 208 extensive metabolizers from 15 poor metabolizers of a control group of healthy subjects. Inhibition of CYP2D6 activity in patients undergoing treatment with fluoxetine or other serotonin uptake inhibitors could contribute to toxicity or attenuated response from concurrent medications that are substrates of this enzyme. Other in vitro studies indicated that CYP2D6 catalyzes the O-demethylation of oxycodone to form oxymorphone. This reaction was inhibited by fluoxetine and its normetabolite in liver microsomes from both extensive and poor metabolizer individuals, indicating that these compounds are not selective inhibitors of CYP2D6 activity.

Thyroid hormone levels and recurrence of major depression.

OBJECTIVE: The relationship between basal thyroid hormone levels and acute antidepressant response has been studied, but any relationship between basal thyroid hormone levels and long-term course of depressive illness has not been evaluated. METHOD: The authors used a Cox regression survival analysis to evaluate the relationship between life course of depressive illness and basal levels of thyroid hormones (triiodothyronine [T(3)], thyroxine [T(4)], and thyrotropin) in 75 outpatients with unipolar major depressive disorder. RESULTS: Time to recurrence of major depression was inversely related to T(3) levels but not to T(4) levels. CONCLUSIONS: These data may be of clinical interest in view of the fact that T(3) is used to augment antidepressant response.

Anxious and nonanxious depression.

The authors used the anxiety summary score described by Clayton and associates to assess anxious and nonanxious subtypes of depression in a group of 134 outpatients with major depression. Patients with anxious depression were only slightly less likely to respond to their first tricyclic antidepressant than patients with nonanxious depression. When functional severity or symptom severity was controlled for, this differential treatment response did not hold.

Ontario Child Health Study: suicidal behavior in youth age 12-16 years.

The authors report on the prevalence and correlates of suicidal behavior in youth age 12-16 years. The data, from a community prevalence survey, show that 5%-10% of the male and 10%-20% of the female youth reported suicidal behavior within a 6-month period. Suicidal behavior in youth appeared to be related to psychiatric disorder in general as well as to family dysfunction and parental arrest.

Personality features of obsessive-compulsive disorder.

The authors evaluated personality dysfunction in 23 patients with primary obsessive-compulsive disorder and an age- and sex-matched group of patients with major depressive disorder. There were no significant differences between the two patient groups with respect to mean personality trait scores or the frequency or type of personality disorder diagnosis. A mixed personality disorder with avoidant, dependent, and passive-aggressive features was most commonly observed in the obsessive-compulsive group. There was a very low frequency of schizoid or compulsive personality disorder.

The Tridimensional Personality Questionnaire in major depression.

The authors examined Tridimensional Personality Questionnaire scores in 40 patients with unipolar nonpsychotic major depression before and after antidepressant treatment. They found that scores on the novelty seeking and reward dependence dimensions were not affected by depressed state or by treatment response status. However, scores on the harm avoidance dimension were significantly lower in antidepressant responders and were altered by depressed state.

Antidepressant effects of carbamazepine.

Thirty-five depressed patients diagnosed by DSM-III criteria participated in a double-blind study of the acute antidepressant effects of the anticonvulsant carbamazepine, at average doses of 971 mg/day, achieving mean +/- SD blood levels of 9.3 +/- 1.9 micrograms/ml (range, 3-12.5 micrograms/ml). Twenty patients (57%) showed at least mild improvement, and 12 showed more substantial improvement. Possible clinical predictors of antidepressant response to carbamazepine are discussed. These preliminary data suggest that carbamazepine has some acute antidepressant efficacy in addition to the growing evidence that it has acute antimanic and longer-term prophylactic efficacy in both phases of manic-depressive illness.

Neuropsychiatric manifestations of altered thyroid state.

The authors assessed the mood and cognitive effects of sequential T4, T3, and withdrawal of thyroid hormone replacement on 25 patients who had had thyroidectomies for thyroid cancer. The patients experienced increased sadness and anxiety when they were without medication, but not significant difference in mood was noted between T4 and T3. The patients who experienced increased affective symptoms when not taking medication were more likely to have histories of affective illness or mood lability.