Pretreatment frontal EEG and changes in suicidal ideation during SSRI treatment in major depressive disorder.

OBJECTIVE: We investigated frontal quantitative EEG (QEEG) as predictor of changes in suicidal ideation (SI) during SSRI treatment in major depressive disorder (MDD). METHOD: Eighty-two subjects meeting DSM-IV criteria for MDD entered an 8-week, prospective, open-label treatment with flexible dose SSRIs and completed at least 4 weeks of treatment. We assessed MDD severity with the 17-item Hamilton Depression Rating Scale (HAM-D-17); change in SI was measured with HAM-D item no. 3. We recorded four-channel EEGs (F7-Fpz, F8-Fpz, A1-Fpz, A2-Fpz) before treatment. RESULTS: During the first 4 weeks of treatment 9 (11%) subjects experienced worsening SI. Left-right asymmetry of combined theta + alpha power correlated significantly with change in SI from baseline, even when adjusting for changes in depression severity (HAM-D-17) and for the SSRI utilized. CONCLUSION: Frontal QEEG parameters before treatment may predict worsening SI during SSRI treatment in MDD.

Patterns of axis I comorbidity in early-onset versus late-onset major depressive disorder.

BACKGROUND: This study of a large clinical sample of depressed patients examined whether childhood onset as compared with adult onset Major Depressive Disorder (MDD) would confer a greater risk for Axis I comorbidity and whether childhood onset MDD would also differ from adult onset MDD in the pattern of comorbid disorders. METHODS: We examined lifetime co-occurrence of Axis I disorders among 381 adult outpatients with MDD by Structured Clinical Interview for DSM-III-R-Patient Edition (SCID-P). Subjects were divided into childhood onset (n = 47), adolescent onset (n = 101) and adult onset (n = 233) MDD groups. RESULTS: We found that the two early-onset groups exhibited significantly increased rates of Axis I comorbidity. The childhood onset group accounted for a disproportionately high percentage of depressed adults with two or more comorbid Axis I disorders. Social and simple phobias and alcohol abuse/dependence were significantly more prevalent among individuals with childhood onset MDD than among individuals with adult onset MDD. Alcohol abuse/dependence, but not anxiety disorders, was significantly more prevalent among adolescent onset than adult onset MDD groups. Panic, generalized anxiety, obsessive-compulsive and somatoform disorders were equally distributed across MDD onset groups. Comorbid disorders were much more likely to have followed onset of MDD among individuals with childhood compared with adult onset, except for social phobia which more frequently preceded the depression. The relative ordering among the comorbid conditions with respect to whether they followed or preceded MDD did not vary notably across the three age of onset groups. CONCLUSIONS: We conclude that early-onset MDD is associated with an increased density of Axis I comorbidity that seems to be limited to specific disorders.

Major depressive subtypes and treatment response.

The purpose of this study was to investigate the relationships between depressive subtypes and response to fluoxetine treatment in a large cohort of outpatients. We studied 294 outpatients with major depressive disorder who were then treated with fluoxetine 20 mg/day for 8 weeks. Treatment outcome was evaluated with the Hamilton Depression Rating Scale (HDRS)-17, the Clinical Global Impressions-Severity, and with the HDRS-8; the latter is proposed to be a relatively more specific measure of depression severity than the HDRS-17. We assessed the relationships between degree of treatment response and several depressive subtypes (melancholic, atypical, hostile, and anxious depression, double depression, and depression with comorbid personality disorders), after adjusting for baseline depression severity. We found that nonanxious depressives (patients without any comorbid anxiety disorder) improved slightly but significantly more during treatment than anxious depressives on all outcome measures. Melancholic depression was associated with slightly less improvement on the HDRS-17 only, whereas the other subtypes of depression were not associated with differences in treatment outcome.

Folate, vitamin B12, and homocysteine in major depressive disorder.

OBJECTIVE: The authors examined the relationships between levels of three metabolites (folate, vitamin B12, and homocysteine) and both depressive subtype and response to fluoxetine treatment in depressed patients. METHOD: Fluoxetine, 20 mg/day for 8 weeks, was given to 213 outpatients with major depressive disorder. At baseline, depressive subtypes were assessed, and a blood sample was collected from each patient. Serum metabolite levels were assayed. Response to treatment was determined by percentage change in score on the 17-item Hamilton Depression Rating Scale. RESULTS: Subjects with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine. Homocysteine and B12 levels were not associated with depressive subtype or treatment response. CONCLUSIONS: Overall, the results are consistent with findings linking low folate levels to poorer response to antidepressant treatment. Folate levels might be considered in the evaluation of depressed patients who do not respond to antidepressant treatment.

Compounds containing cytosolic choline in the basal ganglia: a potential biological marker of true drug response to fluoxetine.

OBJECTIVE: Studies have identified two types of antidepressant response: true drug response and placebo pattern response. This study examined the relationship between true drug response and choline-creatine ratios in the basal ganglia of depressed patients treated with fluoxetine. METHOD: The authors evaluated drug-free outpatients with major depression before (N = 41) and after (N = 15) 8 weeks of fluoxetine treatment, 20 mg/day, by using proton magnetic resonance spectroscopy. RESULTS: There was a significant difference in the degree of change from baseline to week 8 in choline-creatine ratios between the true drug response group (N = 8) and the placebo pattern response/nonresponse group (N = 7); the true drug response patients had a 20% increase in choline-creatine ratios, and the placebo pattern response/nonresponse patients had a 12% decrease in choline-creatine ratios. CONCLUSIONS: These data suggest that true drug response to fluoxetine treatment in depression may be associated with an increase in choline-creatine ratios in the basal ganglia.

Early nonresponse to fluoxetine as a predictor of poor 8-week outcome.

OBJECTIVE: The purpose of this study was to quantify the proportion of patients who show no response to a fixed dose of fluoxetine after 2, 4, and 6 weeks of treatment and then respond by week 8. METHOD: In an open trial, 143 outpatients who met DSM-III-R criteria for major depressive disorder were treated with a regimen of fluoxetine, 20 mg/day. The authors analyzed the proportion of patients who had less than a 20% decrease from baseline in their scores on the Hamilton Rating Scale for Depression after 2, 4, and 6 weeks and who went on to have a 50% or greater reduction by week 8. A last-observation-carried-forward strategy was used to calculate conditional probabilities of 8-week response. Kaplan-Meier survival analysis was used to estimate probabilities of response at week 8 given degrees of response at week 2. RESULTS: Eighty-two subjects (57.3%) who started the trial responded by week 8. Of those subjects who showed no improvement at weeks 2, 4, and 6, the proportions of responders at week 8 were 36.4%, 18.9%, and 6.5%, respectively. The Kaplan-Meier estimate of 8-week response given nonresponse at week 2 was 0.45. CONCLUSIONS: The proportion of patients with no response to antidepressant treatment by 4 or 6 weeks who responded by week 8 was substantially less than that for subjects who had at least a partial response. Nonresponse as early as week 2 predicted 8-week outcome.

Patterns of personality disorder comorbidity in early-onset versus late-onset major depression.

OBJECTIVE: This study tested the hypothesis that in a population of adult outpatients with major depression, those with an early onset of depression would have a greater prevalence of personality disorders than those with a late onset of depression. METHOD: The 404 subjects were patients participating in depression treatment studies at the Massachusetts General Hospital. They were administered the Structured Clinical Interview for DSM-III-R-Patient Version to assess the current presence of major depression and the age at onset of the initial depressive episode. The subjects were then divided into two groups: those with early onset (before 18 years of age) and those with late onset (at age 18 or later). The prevalence of personality disorders was determined through use of the physician-rated Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) and the patient-rated Personality Diagnostic Questionnaire-Revised (PDQ-R). RESULTS: The patients with early onset of major depression had a significantly higher prevalence of avoidant, histrionic, narcissistic, and borderline personality disorders according to the SCID-II. The PDQ-R scores indicated that avoidant, dependent, passive-aggressive, histrionic, narcissistic, borderline, and antisocial personality disorders were significantly more prevalent among the patients with early onset of major depression. CONCLUSIONS: Overall, the results are consistent with the view that early-onset depressive illness is distinguished from late-onset major depression by more frequent association with persistent disturbances in behaviors and attitudes.

Timing of onset of antidepressant response with fluoxetine treatment.

OBJECTIVE: The purpose of this study was to assess the time until onset of antidepressant response with fluoxetine treatment. METHOD: The authors evaluated 182 outpatients with major depression who had a sustained acute response to fluoxetine treatment. The outpatients received 8 weeks of treatment with 20 mg/day of fluoxetine and were assessed biweekly with the 17-item Hamilton Depression Rating Scale. The onset of response was defined as a 30% decrease in score on the Hamilton depression scale that persisted and led to a 50% decrease by week 8. The Kaplan-Meier product limit and Cox regression analysis were used to model the relationship between relevant variables and time until onset of response. RESULTS: The authors found that at weeks 2, 4, and 6, the probabilities of having an onset of response (for responders) were 55.5%, 24.7%, and 9.3%, respectively. The cumulative probabilities of onset of response at each time point were 55.5%, 80.2%, and 89.5%. Neither demographics nor clinical characteristics of depression predicted time until initial response. CONCLUSIONS: These data suggest that more than half of eventual responders to fluoxetine treatment at 8 weeks start to respond by week 2; over 75% start to respond by week 4. Conversely, the lack of onset of response at 4-6 weeks was associated with about a 73%-88% chance that patients would not have an onset of response by 8 weeks.

Course and treatment of atypical depression.

Atypical depression is the most common form of depression in outpatients, but compared with melancholia, little is known about its comorbidity, course, and treatment. Beyond the well-characterized constellation of symptoms that define atypical depression (mood reactivity, hypersomnia, leaden paralysis, hyperphagia, and rejection sensitivity), specific Axis I and II comorbid conditions may differentiate atypical from other depressed patients. Similarly, age at onset, duration of episodes, frequency of relapses and recurrences, and frequency of complete remission in atypical depression may be different. It has not even been established if atypical depression is a stable subtype or if it is just one of several forms of depression that an individual may express during a lifetime of recurrent depressions. Monoamine oxidase inhibitors (MAOIs) are superior to tricyclic antidepressants (TCAs) for the treatment of atypical depression, but few studies have compared MAOIs to the newer generation of antidepressants (SSRIs, bupropion, venlafaxine, nefazodone, and mirtazapine). Because of the favorable benefit/risk ratio, clinicians tend to use these newer antidepressants for all outpatients, including those with atypical depression, even though the literature is limited. A review and critique of the relevant literature on atypical depression will be presented.

Four cases of obstructive sleep apnea associated with treatment-resistant mania.

The authors describe four cases in which obstructive sleep apnea complicated the course and treatment of mania. An association between weight gain, obstructive sleep apnea, and lithium treatment is also illustrated.

Efficacy of fluvoxamine in the treatment of major depression with comorbid anxiety disorders.

BACKGROUND: Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared with major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in depressive symptoms and anxiety levels in outpatients with major depression with comorbid anxiety disorder following 12 weeks of open treatment with fluvoxamine. METHOD: We enrolled 30 outpatients (mean +/- SD age = 39.4 +/- 11.3 years; 16 women and 14 men) with DSM-IV major depressive disorder accompanied by one or more current comorbid DSM-IV anxiety disorders in our study. Patients were treated openly with fluvoxamine initiated at 50 mg/day, with an upward titration to a maximum of 200 mg/day (mean +/- SD dose = 143 +/- 45 mg/day). Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and Clinical Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) scales for both depression and anxiety. Intent-to-treat analysis was used to assess outcome. RESULTS: The mean +/- SD number of comorbid anxiety disorders per patient was 2.1 +/- 1.1. Following fluvoxamine treatment, the mean +/- SD HAM-D-17 score dropped from 20.2 +/- 3.3 to 1 1.0 +/- 7.0 (p < .0001). The mean +/- SD depression CGI-S score dropped from 4.0 +/- 0.6 to 2.4 +/- 1.1 (p < .0001), and the mean +/- SD anxiety CGI-S score decreased from 4.1 +/- 0.8 to 2.5 +/- 1.2 (p < .0001). Eighteen (60%) of the 30 patients had CGI-I scores < or = 2 for both anxiety and depression at endpoint, with 53% showing a > or = 50% reduction in HAM-D-17 scores at endpoint. CONCLUSION: Although preliminary, our findings suggest that fluvoxamine is effective in treating outpatients with major depression with comorbid anxiety disorder, having a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are needed, in a larger sample, to confirm our findings.

Residual symptoms in depressed patients who respond acutely to fluoxetine.

BACKGROUND: Antidepressants have unequivocal efficacy as compared with placebo, but many patients have residual symptoms despite a robust response to antidepressant therapy. The purpose of this study is to assess residual symptoms in outpatients who respond acutely to fluoxetine. METHOD: Two hundred and fifteen outpatients with major depressive disorder as assessed with the Structured Clinical Interview for DSM-III-R (SCID-P) were treated openly with fluoxetine 20 mg/day for 8 weeks. One hundred and eight (50.2%) were considered full responders (final 17-item Hamilton Rating Scale for Depression [HAM-D] score < or =7). Percentages of full responders who continued to have subthreshold or full major depressive disorder symptoms were calculated. The relationship between residual symptoms and Axis I and Axis II (assessed with SCID-II for personality disorders) comorbidity was assessed. RESULTS: Of the 108 responders, 19 (17.6%) had no subthreshold or threshold SCID-P major depressive disorder symptoms, while 28 (25.9%) had 1 symptom, and 61 (56.5%) had 2 or more symptoms. No statistically significant relationships were found between number of residual symptoms and selected Axis I comorbid conditions or total number of Axis II disorders. CONCLUSION: Less than 20% of full responders to fluoxetine by HAM-D criteria were free of all SCID-P subthreshold and threshold major depressive disorder symptoms after 8 weeks of treatment. While depressed patients benefit from antidepressants, most continue to have some symptoms of depression. The high prevalence of residual symptoms among antidepressant responders suggests the need for further study including whether residual symptoms abate with longer treatment or increased dose of fluoxetine. Other strategies, such as cognitive behavioral therapy, may be needed to address residual symptoms.

Relapse in patients on long-term fluoxetine treatment: response to increased fluoxetine dose.

BACKGROUND: Although several studies have examined the long-term efficacy of antidepressants, relatively little attention has been paid to the management of relapses or recurrences during continued antidepressant treatment. This study examined whether depressed patients who had recovered and then relapsed on fluoxetine 20 mg/day would benefit from an increase in fluoxetine dose. METHOD: Eighteen patients who relapsed on fluoxetine 20 mg/day during long-term treatment with fluoxetine as part of a placebo-controlled study had their fluoxetine dose raised to 40 mg/day and were followed for at least 1 month (mean time = 4.7 months). RESULTS: Twelve (67%) were full responders, 3 (17%) partial responders, and 3 (17%) dropped out because of side effects (e.g., insomnia and agitation). Of those patients who had either full or partial response (N = 15; 83%), 3 complete responders had a recurrence on 40 mg/day after a mean of 5.8 months and 1 partial responder had a recurrence 11 months later. Overall, 11 (61%) of 18 patients maintained their response during their follow-up while taking the higher dose of fluoxetine. CONCLUSION: An increase in dose of fluoxetine to 40 mg/day appears to be an effective strategy in the treatment of relapse among depressed patients who had initially responded to fluoxetine 20 mg/day.

Amphetamine and maternal behavior: dose response relationships.

Primiparous rats received 0.05, 0.25, 0.50, or 1.50 mg d-amphetamine/kg body weight, injected IP, when offspring reached 3-4 and 10-11 days of age. A multidimensional analysis of their maternal behavior revealed that at doses as low as 0.25 mg/kg, amphetamine had a disruptive effect on mother-pup intercontact interval, retrieval latency, inter-retrieval interval, number of pup retrieved and number of corners to which they were retrieved, time nest building, number of paper strips used, nursing time, time in motion, and number of squares entered. Disruption was dose-dependent for all the preceding except number of corners and time nest building. Amphetamine had no effect on the rate of maternal locomotion. The impact of amphetamine on nursing was significantly greater at pup ages of 3-4 days than at 10-11 days. Drug-induced augmentation of arousal exceeding optimal levels for adequate care-giving and locomotor stimulation incompatible with elements of maternal behavior may account for dose-dependent impairment in the range of 0.25 to 1.50 mg/kg d-amphetamine.

Tryptophan depletion in SSRI-recovered depressed outpatients.

RATIONALE: Recently, a number of studies have challenged the finding that acute tryptophan depletion (TD) increases depressive symptoms in medicated, formerly depressed patients. The present study examined the effects of acute nutritional TD on remitted depressed patients currently treated with selective serotonin reuptake inhibitors. In an attempt to clarify conflicting earlier findings, the effects of a number of clinical variables on outcome were also investigated. METHODS: Ten patients underwent TD in a double-blind, controlled, balanced crossover fashion. The control session followed the procedure of Krahn et al. (1996 Neuropsychopharmacology 15:325-328). Sessions were 5-8 days apart. RESULTS: TD was significantly related to increased scores on clinician-rated depression and anxiety scales, and on self-rated depression, anxiety, and somatic symptoms. The control challenge had no effect, despite the fact that the reductions in plasma tryptophan during the control session were unexpectedly high. Some evidence was found for a threshold in the relationship between reduction of plasma tryptophan and mood response. CONCLUSIONS: The mood effect of TD in medicated, formerly depressed patients was confirmed. A threshold may exist for mood effects following TD, implying that recent negative findings may have been caused by insufficient depletion. No other predicting or mediating factors were identified, although the variable "history of response pattern to medication" deserves further study.

Nutrition and depression: the role of folate.

A relationship between folate and neuropsychiatric disorders has been inferred from clinical observation and from the enhanced understanding of the role of folate in critical brain metabolic pathways. Depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency. Conversely, borderline low or deficient serum or red blood cell folate levels have been detected in 15-38% of adults diagnosed with depressive disorders. Recently, low folate levels have been linked to poorer antidepressant response to selective serotonin reuptake inhibitors. Factors contributing to low serum folate levels among depressed patients as well as the circumstances under which folate and its derivatives may have a role in antidepressant pharmacotherapy must be further clarified.

CCK-8 modulation of mesolimbic dopamine: antagonism of amphetamine-stimulated behaviors.

Rats (N = 15) were implanted with cannulae above the dopaminergic A10 ventral tegmental area (VTA). Two weeks later, four measures of open field behavior were quantified for 10 minutes commencing 30 minutes after parenteral d-amphetamine (1.5 mg/kg) and directly after bilateral infusion of 1.5 microliter of: (a) artificial CSF only (VEH), (b) 1.25 microgram desulfated CCK (DS-CCK), or (c) 1.25 microgram sulfated CCK (CCK). Additional rats with bilateral cannulae directed toward the A10 terminal zones of nucleus accumbens were similarly tested with either VEH (N = 2) or sulfated CCK (N = 2). With VTA infusions, both the number of occurrences and duration of rearing were significantly reduced in CCK rats, while neither the number of square crossings nor duration of forward locomotion were significantly modified from controls. With nuclei accumbens septi (NAS) infusions, CCK-8 reduced rearing behavior more than ambulatory behavior in this preliminary testing. With either VTA or NAS infusions, no significant differences from controls were found upon two derived measures of motoric performance, namely, "velocity" (number of squares crossed per second in locomotion) and "vertical stability" (seconds per rear). These results suggest a modulation of dopaminergically-mediated behavior by (sulfated) CCK-8 at the cell body region and terminal fields of the mesolimbic (A10) dopamine system.

Hostility changes following antidepressant treatment: relationship to stress and negative thinking.

It is unclear whether changes in hostility following treatment are primarily related to improvement in depressive symptoms or are also closely associated with reductions in negative thinking or perceived stress. We evaluated 94 outpatients with major depression before and after eight weeks of fluoxetine treatment by administering the Symptom Questionnaire (SQ) Hostility Scale, the Hamilton Rating Scale for Depression (HAM-D), the Cognitions Questionnaire (CQ) and the Perceived Stress Scale (PSS). We observed significant elevations in scores on these questionnaires in depressed patients as compared to normal controls. Following treatment with fluoxetine, there was a statistically significant reduction in scores on all four questionnaires. We observed that changes in SQ Hostility were significantly positively related to changes in both depression severity and perceived stress, with these relationships remaining significant after adjusting for gender and baseline SQ Hostility. The relationship between SQ Hostility changes and reductions in negative thinking became significant only after adjusting for gender and baseline SQ hostility. Our results suggest that the marked decrease in hostility following antidepressant treatment is related to a reduction in depressive symptoms, stress levels and negative thinking.

Dopamine denervation of frontal cortex or nucleus accumbens does not affect ACTH-induced grooming behaviour.

Studies with dopamine (DA) receptor antagonists have implicated brain DA systems in the increased grooming behaviour elicited by intracerebroventricular (i.c.v.) administration of ACTH or exposure to a novel environment. To evaluate the potential contributions of DA terminals innervating frontal cortex and nucleus accumbens, stereotaxically guided injections of 6-hydroxydopamine (6-OHDA) were made into these regions of rat brain following peripheral administration of desmethylimipramine and pargyline. Despite an 88% mean reduction of DA, and 68% mean reduction of noradrenaline in frontal cortex, the amount of grooming behaviour observed either in a novel cage, or after i.c.v. injection of ACTH1-24 was not detectably altered. The lesions also did not affect locomotor activity measured during the scoring of grooming, in an open field, in photocell cages, or in a running wheel, even in the animals most severely depleted of DA. Following nucleus accumbens 6-OHDA infusions, depletions of DA as great as 99% were obtained. Animals with accumbens depletions greater than 90% showed the expected attenuation of amphetamine-stimulated locomotor activity. Nevertheless, they exhibited normal grooming scores in a novel cage, and in response to i.c.v. ACTH1-24. It is concluded that dopaminergic terminals in nucleus accumbens and probably those in frontal cortex are not necessary for the expression of novelty- or ACTH-induced grooming.

Impairment in T-maze reinforced alternation performance following nucleus basalis magnocellularis lesions in rats.

Rats were trained on a reinforced alternation paradigm using an elevated T-maze. After pre-surgical training subjects received either ibotenic acid (4 micrograms/0.4 microliter) or vehicle (pH 7.4, 0.4 microliter) bilaterally into the region of the nucleus basalis magnocellularis--an important source of neocortical acetylcholine projections. Acetylcholinesterase staining of sectioned brains revealed a loss of neocortical, but not hippocampal staining in lesioned animals. On the T-maze task, lesioned rats showed significantly impaired choice performance relative to controls. They also demonstrated significant side biases, the degree of which was correlated with choice performance deficit.