Fluoxetine and norfluoxetine plasma concentrations in major depression: a multicenter study.

OBJECTIVE: Prior studies examining the relationship between fluoxetine plasma concentrations and response in major depression have either found no relationship between plasma concentration and response or suggested a curvilinear relationship with a therapeutic window. To elucidate this relationship, plasma concentrations of fluoxetine, norfluoxetine, fluoxetine plus norfluoxetine, and fluoxetine/norfluoxetine ratio were compared to therapeutic response. METHOD: A total of 839 patients (577 women, 262 men; mean age = 40 [SD = 11] with a DSM-III-R diagnosis of major affective disorder who were in the course of either depression or bipolar disorder not otherwise specified and had a minimum baseline score of 16 on the 17-item Hamilton Depression Rating Scale were initially treated. Response was defined as follows: 1) nonresponders had less that a 50% or more reduction from baseline Hamilton depression score, 2) nonremitting responders had a 50% or more reduction from baseline Hamilton depression score but a final score higher than 7, and 3) remitters had a final Hamilton Depression score of 7 or lower. Plasma fluoxetine and norfluoxetine concentrations were measured after 8 weeks of fixed-dose treatment of 20 mg/day. RESULTS: Plasma concentration data were available from 615 patients. Plasma concentration were similar in responders, both remitting and nonremitting (N = 411), and nonresponders (N = 204) for fluoxetine concentrations, for norfluoxetine concentrations, as well as for the sum of fluoxetine and norfluoxetine and for the ratio of fluoxetine to norfluoxetine. No apparent relationship was observed between plasma drug concentration and clinical response. CONCLUSION: Plasma concentrations of fluoxetine and norfluoxetine do not appear to be related to clinical outcome and should not be used to make treatment decisions.

Rapid conversion from one monoamine oxidase inhibitor to another.

BACKGROUND: Numerous sources state that switching from one monoamine oxidase (MAO) inhibitor to another can be done only after a 14-day washout period. In hospitalized patients and severely depressed outpatients, such a wait may be impracticable. METHOD: We reviewed the case histories of eight consecutive and random patients whom we converted from one MAO inhibitor to another within less than the recommended waiting period. RESULTS: Only one patient experienced troubling adverse effects, and these effects were brief and time-limited. The patient's symptoms were indicative of either withdrawal from tranylcypromine or a mild serotonin syndrome. All other patients tolerated the conversion well with minimal or no adverse effects. Four of the eight patients eventually responded to the new MAO inhibitor. CONCLUSION: These results suggest that some patients can be cautiously but rapidly switched from one MAO inhibitor to another without prolonged drug-free periods. Unquestionably, this strategy should be used only when the clinical picture mandates a rapid conversion. Further, it should be reserved for those patients with established high compliance and should include close monitoring and the use of a low-tyramine diet. Extreme caution must still be undertaken in utilizing this approach until larger studies more accurately determine the frequency of serious adverse effects.

Breast enlargement during chronic antidepressant therapy.

Recent reports of mammoplasia during selective serotonin re-uptake inhibitor (SSRI) therapy suggested that this side effect may be more common than previously reported. We examined 59 women receiving > or = 2 months treatment with an SSRI or venlafaxine for changes in breast size in relation to menopausal status, weight gain and duration of drug therapy. Serum prolactin, estradiol and beta-hCG were also measured before and during treatment in a subgroup of patients. Twenty-three out of 59 patients (39%) reported some degree of mammoplasia. Significantly more SSRI vs. venlafaxine patients reported mammoplasia (p < 0.01). Eighty-four percent with mammoplasia had weight gain vs. 30% without mammoplasia (p < 0.001). The rate of mammoplasia was unrelated to age, menopausal status or duration of treatment. Serum prolactin increased during treatment in the paroxetine subgroup (p < 0.03). In conclusion, antidepressant-induced mammoplasia may be more common than previously expected.

Efficacy of buspirone in generalized anxiety disorder with coexisting mild depressive symptoms.

BACKGROUND: This study was designed to evaluate the anxiolytic efficacy of buspirone in patients with a diagnosis of generalized anxiety disorder (GAD) with coexisting mild depressive symptoms. METHOD: Patients who participated in this multicenter study scored >/= 18 on the Hamilton Rating Scale for Anxiety (HAM-A) and between 12 and 17 on the Hamilton Rating Scale for Depression (HAM-D). Following a 7- to 10-day placebo lead-in phase, patients who continued to qualify were randomly assigned to receive either buspirone titrated from 15 to 45 mg/day (N = 80) or placebo (N = 82) for the next 6 weeks. 121 patients completed 6 weeks of treatment. The primary efficacy measure was the HAM-A, taken weekly during the study. RESULTS: Buspirone-treated patients averaged a 12.4-point reduction from their baseline total HAM-A score of 24.9, while their counterparts on placebo averaged a 9.5-point reduction from their mean baseline total HAM-A score of 25.6. This 2.9-point difference in HAM-A reductions between treatment groups was significantly different (p < .03). Buspirone patients decreased their HAM-D scores by an average 5.7 points from their mean baseline total HAM-D score of 15.8, while placebo patients decreased their HAM-D scores by an average 3.5 points from their mean baseline score of 16.3 (p < .05). Overall, the incidence of adverse events was similar for both treatment groups, but buspirone-treated patients reported significantly more nausea, dizziness, somnolence, and sweating than placebo patients. CONCLUSION: Buspirone is superior to placebo in improving anxiety and depressive symptoms in GAD patients who have coexisting depressive symptoms.

TRH stimulation test as a predictor of acute and long-term antidepressant response in major depression.

We assessed the prognostic utility of the TRH stimulation test by examining (a) the relationship between pre-treatment delta TSH and acute response to fluoxetine treatment, and (b) the relationship between the change in delta TSH (delta delta TSH value) after repeated TRH testing at 6 weeks of fluoxetine treatment and long-term outcome during maintenance fluoxetine or placebo therapy. 43 MDD patients were studied with sequential TRH tests at 6-week intervals. Fluoxetine 'responders' were defined as patients with a Hamilton Depression Rating Scale score < or = 7 by week 9 of treatment and who remained in remission at least 3 additional weeks. These subjects were then randomized to one of four fluoxetine/placebo treatment groups and long-term outcome assessed. Overall, there was no difference in the mean pre-treatment delta TSH values between acute fluoxetine responders and nonresponders. Moreover, we observed similar delta delta TSH values in patients who maintained long-term remission compared to those who relapsed during maintenance with either fluoxetine or placebo. In contrast to prior reports of an higher delta delta TSH value in long-term remitters, the present observation of similar mean delta delta TSH values patients with long-term remission compared to those who relapsed suggest a limited prognostic utility for the TRH stimulation test in MDD.

Treatment algorithms in treatment-resistant depression.

When faced with a patient having treatment-resistant depression, it is essential to maintain a systematic approach to diagnosis and treatment: 1. Consider the presence of comorbid medical or psychiatric illness that may contribute to or cause the refractory state 2. Determine the affective subtype of depression (e.g., unipolar vs. phenotypic variant of bipolar depression) 3. Ensure the presence of adequate antidepressant dosage, plasma concentrations (where applicable), and duration of treatment 4. Apply systematic treatment algorithms, which means (1) initiate the most efficacious "first-line" therapy for a specific depressive subtype (even if that is an MAOI) and (2) initiate augmentation strategies in a systematic fashion. Augmentation strategies should be initiated only after first reviewing prior therapy, considering available treatment alternatives, and examining the relative risk:benefit ratio for each treatment option in the current clinical context. Following these guidelines should prevent the development of "therapeutic nihilism" in both the patient and physician, as well as enhance the ultimate treatment outcome for patients with treatment-resistant depression.

Novel strategies for treatment-resistant depression.

This article describes a highly selective constellation of the more unique strategies for managing the treatment-resistant patient. In light of the often-devastating toll that treatment-resistant depression takes on an individual's life, it behooves us to continue the search for more effective strategies for those patients that fail more traditional interventions. As each successive move down the treatment algorithm flowchart becomes necessary, the risk/benefit ratio may shift toward less well-substantiated, but still biologically informed, strategies. Although some of the more unusual treatments described in this article represent minimally charted territories, the more promising techniques are deserving of further careful exploration.

Cerebral HMPAO SPECT in patients with major depression and healthy volunteers.

1. The authors examined the regional cerebral distribution of [Tc-99m] HMPAO using single photon emission computed tomography (SPECT) in patients with major depression and in healthy controls. 2. 19 patients and 16 healthy controls had SPECT images of the brain acquired with 740 MBq (20 mCl) of [Tc-99m] HMPAO on a triple-headed camera equipped with fan beam collimators. 3. Mean counts per pixel were measured in 13 regions of each hemisphere and compared to the mean activity in the whole brain, the ipsilateral hemisphere, and cerebellum. A "laterality score" was calculated for each structure by subtracting the mean counts per pixel in a region of the right hemisphere from the mean counts in the homotopic region of the left hemisphere and normalizing the difference by the average in both regions. The degree of hemispheric asymmetry was calculated from the absolute values of the laterality scores. 4. The distribution of HMPAO was more variable in patients than in controls; while the mean activity ratios were not significantly different in any region. Asymmetries between homotopic regions of the limbic system were more pronounced in patients than in controls. However, there were no consistent left-to-right asymmetries in either group. 5. The present data indicate that regional cerebral distribution of HMPAO may not be discretely abnormal in depression, but demonstrates heightened variability in depressives (vs. control subjects).

Efficacy of alprazolam in reducing fluoxetine-induced jitteriness in patients with major depression.

BACKGROUND: Serotonin selective reuptake inhibitors (SSRIs) have become the most widely prescribed antidepressants in the United States. The selective influence of SSRIs on serotonin neurotransmission has resulted in a specific constellation of adverse effects termed "jitteriness" syndrome, which occurs in at least 30% of patients taking SSRIs. Because there have been no systematic studies examining treatment of SSRI-induced jitteriness, we conducted a prospective study of the efficacy of adjunctive alprazolam therapy for fluoxetine-induced jitteriness symptoms. METHOD: Fifty-four subjects with major depression were treated with fluoxetine 20 mg/day. Subjects experiencing an increase in jitteriness symptoms within 2 weeks of starting fluoxetine were given adjunctive alprazolam 0.5 mg to 4.0 mg daily for 2 weeks followed by a 2-week taper period. RESULTS: Eighteen (33.3%) of 54 patients experienced jitteriness symptoms during fluoxetine treatment. We observed a statistically significant reduction in the severity and number of jitteriness symptoms with adjunctive alprazolam. Moreover, in most cases jitteriness symptoms did not reappear during the alprazolam taper period or after alprazolam was discontinued. CONCLUSION: These observations suggest that a brief course of adjunctive alprazolam treatment may be efficacious in reducing the duration and severity of jitteriness symptoms resulting from antidepressants that are selective for serotonin.