A Preliminary, Open-Label Study of Naltrexone and Bupropion Combination Therapy for Treating Binge Drinking in Human Subjects.

AIMS: The combination of bupropion and naltrexone has shown efficacy in reducing binge drinking in animal models. This study assessed the tolerability and potential utility of combined naltrexone and bupropion in reducing binge drinking in human subjects. METHODS: This preliminary study employed an open-label, single-arm, 12-week, prospective design. Twelve men and women who exhibited a minimum of five (men) or three (women) binge drinking episodes per month over the past 3 months were recruited. All subjects received both bupropion-extended release 300 mg/day and naltrexone 50 mg/day and were monitored throughout the 3-month treatment period. Binge drinking was assessed using the timeline follow-back method. RESULTS: Treatment with combined naltrexone and bupropion reduced the average number of drinks per binge drinking day from 7.8 drinks to 6.4 drinks and reduced the average percentage of binge drinking days per month from 19% (5.7 days/month) to 5% (1.5 days/month). Naltrexone and bupropion were generally well tolerated, with insomnia, headache and nausea/diarrhea being the most common side effects. Six subjects elected to stay on medication after the trial. CONCLUSIONS: This study suggests that combined naltrexone and bupropion therapy should be further investigated for tolerability and efficacy in reducing binge drinking in humans.

Effects of paroxetine on cardiovascular response to mental stress in subjects with a history of coronary artery disease and no psychiatric diagnoses.

RATIONALE: Paroxetine may decrease mental stress-induced cardiovascular responses and so benefit individuals with heart disease, even those with no psychiatric illness. OBJECTIVES: The effects of paroxetine on cardiovascular measures during a speech task were evaluated in psychiatrically healthy subjects with a history of coronary artery disease (CAD). METHODS: Eight subjects completed this double-blind, placebo-controlled, cross-over study in which each subject took 1 month of paroxetine and 4 weeks of placebo in random order. While on each study, medication, blood pressure, heart rate, and plasma norepinephrine concentrations were measured during a period of relaxation and during a mental stressor. The mental stressor consisted of thinking about a stressful topic, speaking about the topic, and listening to a tape-recorded replay of the speech. RESULTS: While on paroxetine, systolic blood pressure and diastolic blood pressure were 10-15% lower (p < 0.005) during the stressor, relative to measures obtained while on placebo. Pulse and plasma norepinephrine concentrations during stress trended lower during paroxetine treatment but did not reach statistical significance. CONCLUSION: Paroxetine has antihypertensive properties during periods of psychological stress in psychiatrically healthy subjects with a history of CAD, and so should be evaluated for potential cardio-protective qualities.

Dose-response studies with protirelin.

BACKGROUND: A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (protirelin [TRH]) has been found consistently in a portion of patients with major depression. One hypothesis to explain this observation is that pituitary TRH receptors are down-regulated in major depression. One prediction stemming from this hypothesis is that prolactin (PRL) as well as TSH responses to TRH should be attenuated. To adequately test the pattern of protirelin-induced TSH and PRL responses with a protirelin dose-response design is necessary. METHODS: Four doses of protirelin (25, 100, 500, and 800 micrograms) were infused in an ascending schedule at intervals of 3 to 7 days in patients with major depression and in control subjects. Seven women and six men with major depression were compared with age- and gender-matched controls (five women and seven men). The TSH and PRL responses were measured at regular intervals following each dose of protirelin. RESULTS: No significant group differences in baseline levels of thyroid hormones or cortisol were present. Depressed men exhibited significant reductions in both TSH and PRL responses to protirelin across all doses compared with control men. Depressed women exhibited significant reductions in TSH responses but not in PRL responses compared with control women. CONCLUSIONS: The findings that men with major depression exhibit reductions in both protirelin-induced TSH and PRL responses support the hypothesis that TRH receptors are downregulated in depression. The findings in women are less clear and may represent the greater variance in the protirelin-induced PRL responses found in women.

Panic, suicide, and agitation: independent correlates of the TSH response to TRH in depression.

We investigated the relationship between suicidality, agitation, panic attacks, and the thyrotropin-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH), and tested the hypothesis that panic would account for the association between a reduced TSH response and the other conditions. Twenty-seven euthyroid primary unipolar depressed inpatient women received a TRH test and systematic psychiatric assessment. Panic attacks were insufficient to explain the link between the TSH response and suicidal intent, lethality, and agitation; each condition was independently associated with a lower TSH response. In an additive fashion, copresence of conditions further reduced TSH response. The symptom constellation of panic, agitation, and suicidality in depression may correlate with the greatest reduction in TSH response.

Is there paradoxical growth hormone response to thyrotropin-releasing hormone in depression?

Several investigators have reported a paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) in depressed patients, but other studies have failed to confirm this. In the present study, the GH response to TRH was studied in depressed patients and normal subjects. The rate of paradoxical GH response to TRH in depression was no different than that observed in control subjects. This was the case whether the data was examined using mean values or using frequency of abnormal responses. Patients with blunted thyrotropin (TSH) responses did not differ in GH release from patients with normal TSH response. A variety of factors may have contributed to the earlier reports of a positive GH response to TRH, including the definition of paradoxical GH release and the fact that depressed patients exhibit more frequent spontaneous diurnal GH release than do normal subjects.

Is carbamazepine helpful in paroxysmal behavior disorders?

Carbamazepine was used to treat two patients with paroxysmal behavioral episodes and preexisting psychiatric disease. Carbamazepine abolished the paroxysmal episodes. Its effects on the preexisting disease were less clear. These data suggest carbamazepine treatment for paroxysmal behavior.

Evidence of preference for a high-concentration sucrose solution in alcoholic men.

OBJECTIVE: The purpose of this study was to test in humans the finding from animal studies indicating an association between preference for more concentrated sweet solutions and excessive alcohol drinking. METHOD: The hedonic response to five different concentrations of sucrose solution was evaluated in 20 detoxified alcoholic and 37 nonalcoholic Caucasian men. All subjects repetitively tasted solutions with 0.05, 0.10, 0.21, 0.42, and 0.83 M sucrose concentrations and rated themselves on two scales measuring the intensity of sweetness and the likability of the solutions. RESULTS: A bimodal distribution of responses to the sweet solutions occurred in the nonalcoholic comparison group, with peaks at 0.05 M and 0.42 M. In the alcoholic group, 65% of the subjects preferred the highest sucrose concentration (0.83 M), compared with only 16% of the nonalcoholic group. CONCLUSIONS: The results of this exploratory study support the hypothesis suggesting a positive association between the preference for stronger sweet solutions and alcohol dependence.

TSH response to TRH in depression with and without panic attacks.

Low thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) has been repeatedly described in approximately 25% of patients with major depression. Panic disorder appears related to depression along several dimensions, including prevalence of low TSH response to TRH. The authors divided 46 patients with primary unipolar depression by gender and by presence or absence of concurrent panic attacks and compared their TRH test results with those of 106 normal control subjects, controlling for confounding variables. Depressed patients with panic had higher prevalence of low TSH response and significantly lower mean TSH response than depressed patients without panic. The latter were indistinguishable from normal control subjects.

Lithium potentiation of tricyclic antidepressants following lack of T3 potentiation.

Four patients whose depressions were failing to respond to administration of tricyclic antidepressants were given separate trials of T3 and lithium. In all four cases, T3 failed to potentiate the antidepressant, whereas the lithium did.

Neuroendocrine effects of intravenous clomipramine in depressed patients and healthy subjects.

OBJECTIVE: Neuroendocrine challenge paradigms have been used to asses serotonergic systems in depression, but limitations in the specificity of many of these tests have been noted. In this study, the neuroendocrine responses to acute intravenous administration of the serotonin (5-HT) reuptake inhibitor clomipramine were assessed in depressed patients and matched control subjects. METHODS: Thirty hospitalized patients who met DSM-III-R criteria for major depression, and 30 healthy control subjects who were matched for age, sex, and season of year for the time of study, received 12.5 mg of intravenously administered clomipramine. RESULTS: The depressed patients demonstrated significant blunting of prolactin responses to clomipramine, as well as trends toward blunted ACTH and cortisol responses. There was no difference between the patient and control groups in growth hormone responses, plasma clomipramine levels, or self-reports of side effects. CONCLUSIONS: These data support the hypothesis that depressed patients have abnormal neuroendocrine responses to the intravenous administration of the 5-HT reuptake inhibitor clomipramine. Further study is required to delineate the mechanisms responsible for the abnormal response to intravenously administered clomipramine in depression.

A dramatic behavioral response to thyrotropin-releasing hormone following low-dose neuroleptics.

A dramatic improvement in mood and behavior after TRH occurred during treatment with low-dose neuroleptics in a patient with major depression and borderline personality disorder. This response was observed during both open and double-blind trials. The administration of TRH alone or with higher dosages of neuroleptics, was ineffective. Twenty other patients with major depression, including several with borderline personality disorder, were studied in an identical design but did not show similar improvement.

The TRH test during dopamine receptor blockade in depressed patients.

In an evaluation of the possible role of dopamine on TRH test results, 21 depressed patients were given TRH before and after one week of treatment with a low dose of haloperidol. Haloperidol significantly increased serum prolactin (both basal and after TRH) and cortisol levels, decreased body temperature, and had no effect on serum TSH, growth hormone, or thyroid hormone levels. Five of six patients with initial TSH blunting were retested with TRH; in four patients the TSH response remained blunted. These data render it unlikely that dopamine exerts a major inhibitory input on TSH secretion in depression.

The prolactin response to thyrotropin-releasing hormone in depressed patients and normal subjects.

The prolactin (PRL) response to thyrotropin-releasing hormone (TRH) was studied in depressed patients (while ill or during remission) and in normal volunteers. Depressed women were shown to have lower basal PRL and lower PRL after TRH, but similar proportional PRL responses, compared to normal women. Depressed women also had basal thyroxine levels that were higher than those of the control women. No significant changes in PRL were noted in depressed men; in fact, there was almost complete overlap of all PRL variables between depressed and normal male subjects. Examination of the responses of PRL and of thyrotropin (TSH) to TRH revealed a significant positive relationship between the two in depressed women, but no association in men.

Apparent complex partial seizures in a bipolar patient after withdrawal of carbamazepine.

A 64-year-old woman with long-standing bipolar illness was treated with carbamazepine and clonazepam with minimal success. Discontinuation of carbamazepine and clonazepam was followed by episodic amnesia, purposeless behavior, déjà vu, and confusion. Although her EEG was normal, the episodes were compatible with complex partial seizures and ceased after carbamazepine and clonazepam were reinstituted. This case raises the question of whether discontinuing carbamazepine and clonazepam can induce complex partial seizures in bipolar patients.

Serotonin, suicide, and aggression: clinical studies.

Both suicidal and aggressive, impulsive behaviors have been linked to putative dysregulation in central serotonergic systems. We review data examining the role of serotonin (5-HT) in suicide from postmortem studies and clinical investigations of suicide attempters, including our own preliminary work derived from neuroendocrine challenges with the 5-HT uptake inhibitor clomipramine. Various approaches to the study of 5-HT and aggressive, impulsive behavior, including cerebrospinal fluid studies, investigations of peripheral measures of 5-HT, and neuroendocrine studies utilizing 5-HT probes, are highlighted. Several important caveats, including the challenge of quantifying "suicidality" and "aggression" in reliable and valid ways, should be considered in interpreting the results of clinical studies of 5-HT and suicide and aggression.

Appearance of mania in drug-resistant bipolar depressed patients after treatment with L-triiodothyronine.

L-Triiodothyronine (T3) has been reported to potentiate the antidepressant effects of tricyclic antidepressants (TCAs) in patients who do not respond to these drugs, while thyroxine (T4) has been used to treat rapid-cycling bipolar disorder patients. The development of mania in antidepressant-resistant bipolar depressed patients after T3 was added to their antidepressant treatment is reported. It is speculated that thyroid hormone-catecholamine receptor interaction might underlie these T3-associated clinical manifestations. It is concluded that T3 did not prevent the switch to mania in the bipolar depressed patients reported here. Further study is necessary to determine if T3 plays a role in promoting the switch to mania in depressed patients treated with T3 in conjunction with TCAs, and if bipolar depressed patients are particularly vulnerable to mania from the combined effects of TCAs and T3.

Administration of chlordiazepoxide affects [3H][3-MeHis2]thyrotropin-releasing hormone binding in rat brain.

The effects of acute and subchronic administration of chlordiazepoxide (CDZ) on [3H][3-methyl-histidyl2]thyrotropin-releasing hormone binding to thyrotropin-releasing hormone (TRH) receptors in membrane preparations from various regions of rat brain were examined. Acute administration of CDZ (50 mg/kg x 3 within 24 h) did not alter either the equilibrium dissociation constant (Kd) or the maximum number of binding sites (Bmax) in cerebellum (CB), olfactory bulbs (OB), frontal cortex (Cx), hypothalamus (HT) or corpus striatum (ST). However, the Kds of the pyriform cortex/amygdala (PC/A) (Kd = 3.6 +/- 0.1 nM compared to 1.9 +/- 0.1 nM in the control group; p less than 0.01) and the hippocampus (HP) (Kd = 7.8 +/- 0.7 nM compared to 2.1 +/- 0.1 nM in the control group; p less than 0.01) were increased. There were no changes in Bmax. Subchronic administration of CDZ (50 mg/kg/day for 7 days) increased the Kd of the PC/A complex (p less than 0.05), the OB (p less than 0.05) and the HP (p less than 0.01) without altering in Bmax. These results, showing regional differences in the response of TRH receptors to acute and subchronic CDZ administration, suggest that reduced affinity of TRH receptors in the PC/A complex, OB and HP may be related to some of the neurobiological actions of CDZ and/or its metabolites.

The interaction between GABA and dopamine: implications for schizophrenia.

A role for gamma-aminobutyric acid (GABA) in the pathophysiology of schizophrenia was first suggested by Eugene Roberts in 1972. Since then considerable work has been accomplished in both the clinical and basic sciences regarding GABA and schizophrenia. Although it was originally thought that GABA might be useful in treating schizophrenia because of its inhibition of dopaminergic activity, recent data have shown that in certain models GABA has the opposite effect on dopaminergic functions. Regardless of the relationships of GABA to dopamine, neither biochemical nor pharmacological studies have been able to demonstrate a clear and reproducible GABA disturbance in schizophrenia. A number of problems contribute to the difficulty in studying GABA in schizophrenia, including the lack of specific and nontoxic GABA agonists as well as the complexity of the GABA system in brain. Interest in GABA research in schizophrenia appears to have waned, but several areas nevertheless appear promising for clinical investigation.

Is there a tardive dysmentia?

A change in the phenomenology of schizophrenia has been observed over the past several decades; affective disturbances and phasic courses have become more evident. Although there is no obvious single explanation for these changes, several ideas have been considered. The advent and use of antipsychotic drugs over the past 30 years stands out as the most significant change. Because it is well known that chronic treatment with antipsychotic drugs can induce tardive dyskinesia and has been hypothesized to induce a supersensitivity psychosis, it is reasonable to believe that other behavioral changes may occur over time. We here describe a behavioral disorder that we have termed tardive dysmentia, involving changes in affect, activation level, and interpersonal interaction. A relationship between tardive dysmentia and tardive dyskinesia is suggested. It is our hypothesis that tardive dysmentia contributes to the changing course of schizophrenia and occurs after long-term treatment with antipsychotic drugs.

Effects of thyroid state on preference for and sensitivity to ethanol in Fischer-344 rats.

1. It has been reported by several groups that thyroid status can alter ethanol preference in rats. However, results using different methods and different strains of rats have not been consistent. 2. In this study, thyroidectomy or T4 augmentation was used to produce hypothyroidism or hyperthyroidism, respectively, in adult male Fischer-344 rats. 3. Preference for weak solutions (4 or 5%) of ethanol or tap water and ethanol-induced sedation and hypothermia were compared in hypothyroid, hyperthyroid and euthyroid rats. 4. No significant differences in preference indices (the ratios of ethanol to total liquid consumed) among the three groups were observed; however, for ethanol to contribute a greater portion of total calories ingested by hypothyroid rats than by euthyroid or hyperthyroid rats. 5. The duration of sleep resulting from a single i.p. injection of 2.5 mg/kg ethanol was increased (by 34%) in hyperthyroid rats and decreased (by 16%) in hypothyroid rats compared to euthyroid controls. Only the effect of hyperthyroidism was significant at the 0.05 level. 6. Colonic temperatures differed with thyroid state (hyperthyroid > euthyroid > hypothyroid) but the decrease produced by ethanol did not differ by thyroid state. 7. Observed differences in ethanol-induced sedation are consistent with differences in brain TRH levels and effects on neurotransmitter systems associated with different thyroid states.