The relationship between mood instability and depression: implications for studying and treating depression.

BACKGROUND: Most individuals with depressed mood report mood fluctuations (Mood Instability) within hours or days. This is not recognized in diagnostic criteria or standard rating scales for depression. HYPOTHESIS: That mood instability is a distinct component of the development of depression that has been omitted from criteria for depression because of reliance on retrospective recall and structured interviews. The inclusion of Mood Instability would enhance research into causes and treatment of depression. STUDIES: We examined three datasets that used retrospective and prospective measures of depressed symptom ratings and mood instability to determine the relationship between the two. Study 1 used data from the 1991 UK Health and Lifestyle Surveys (HALS). Studies 2 and 3 used clinical samples. The scales used to assess mood instability were the mood instability factor from the Eysenck Personality Inventory Neuroticism Scale, the Affective Lability Scale (ALS), and the Visual Analogue Depression Scale (VAS). The depression scales (depressive symptoms) were the General Health Questionnaire (GHQ) depression factor, the Beck Depression Inventory IA (BDI) and the mean from the Visual Analogue Depression Scale (VAS). We used partial correlation analysis to assess the association between mood instability and depression and exploratory factor analysis to determine the factor structure of items pooled from the mood instability and depression scales from studies 1 and 2. RESULTS: Mood Instability was found to be moderately associated with depressive symptoms. The Pearson's r-values ranged from 0.49 to 0.57. The correlation was lower when recalling mood in the past. The factor analytic solution supported the hypothesis that MI and depressive symptoms are related but distinct constructs. CONCLUSIONS: Reliance exclusively on the retrospective assessment of depressive symptoms has occluded the widespread occurrence of mood instability. Including Mood Instability in diagnostic and assessment criteria would enhance causal and treatment research in depression.

Prevention of cannabinoid withdrawal syndrome by lithium: involvement of oxytocinergic neuronal activation.

Cannabis (i.e., marijuana and cannabinoids) is the most commonly used illicit drug in developed countries, and the lifetime prevalence of marijuana dependence is the highest of all illicit drugs in the United States. To provide clues for finding effective pharmacological treatment for cannabis-dependent patients, we examined the effects and possible mechanism of lithium administration on the cannabinoid withdrawal syndrome in rats. A systemic injection of the mood stabilizer lithium, at serum levels that were clinically relevant, prevented the cannabinoid withdrawal syndrome. The effects of lithium were accompanied by expression of the cellular activation marker Fos proteins within most oxytocin-immunoreactive neurons and a significant increase in oxytocin mRNA expression in the hypothalamic paraventricular and supraoptic nuclei. Lithium also produced a significant elevation of oxytocin levels in the peripheral blood. We suggest that the effects of lithium against the cannabinoid withdrawal syndrome are mediated by oxytocinergic neuronal activation and subsequent release and action of oxytocin within the CNS. In support of our hypothesis, we found that the effects of lithium against the cannabinoid withdrawal syndrome were antagonized by systemic preapplication of an oxytocin antagonist and mimicked by systemic or intracerebroventricular injection of oxytocin. These results demonstrate that oxytocinergic neuronal activation plays a critical role in the action of lithium against the cannabinoid withdrawal syndrome in rats, thus providing a potentially novel strategy for the treatment of cannabis dependence in humans.

Sertraline treatment of generalized social phobia: a 20-week, double-blind, placebo-controlled study.

OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of sertraline, a selective serotonin reuptake inhibitor, in the treatment of generalized social phobia. METHOD: Adult outpatients with generalized social phobia (N=204) from 10 Canadian centers were randomly assigned to receive sertraline or placebo in a 2:1 ratio for a 20-week double-blind study following a 1-week, single-blind, placebo run-in. The initial dose of sertraline was 50 mg/day with increases of 50 mg/day every 3 weeks permitted after the fourth week of treatment (dosing was flexible up to a maximum of 200 mg/day). Primary efficacy assessments were the percentage of patients rated much or very much improved on the Clinical Global Impression (CGI) improvement item and the mean changes from baseline to study endpoint in total score on the social phobia subscale of the Marks Fear Questionnaire and total score on the Brief Social Phobia Scale. RESULTS: In intent-to-treat endpoint analyses of 203 of the patients, significantly more of the 134 patients given sertraline (N=71 [53%]) than of the 69 patients receiving placebo (N=20 [29%]) were considered responders according to their CGI improvement scores at the end of treatment. The mean reductions in the social phobia subscale of the Marks Fear Questionnaire and in the total score on the Brief Social Phobia Scale were 32.6% and 34.3% in the sertraline group and 10.8% and 18.6% in the placebo group, respectively. Analysis of covariance showed superiority of sertraline over placebo on all primary and secondary efficacy measures. Sertraline was well tolerated: 103 (76%) of the 135 sertraline-treated patients and 54 (78%) of the 69 placebo-treated patients completed the study. CONCLUSIONS: Sertraline is an effective treatment for patients with generalized social phobia.

Prevention of relapse in generalized social phobia: results of a 24-week study in responders to 20 weeks of sertraline treatment.

The aim of this study was to evaluate the efficacy, tolerability, and effects on quality of life of sertraline, a selective serotonin reuptake inhibitor, in the prevention of relapse of generalized social phobia. Fifty adult outpatients with generalized social phobia who were rated much or very much improved on the Clinical Global Impression Scale of Improvement (CGI-I) after 20 weeks of sertraline treatment (50-200 mg/day) were randomly assigned in a one-to-one ratio to either continue double-blind treatment with sertraline or immediately switch to placebo for another 24 weeks. The initial 20-week study was placebo-controlled, and 15 responders to placebo also continued to receive double-blind placebo treatment in the continuation study. Eighty-eight percent of patients in the sertraline-continuation group and only 40% of patients in the placebo-switch and placebo-responder groups completed the study. In intent-to-treat endpoint analyses, 1 (4%) of 25 patients in the sertraline-continuation group and 9 (36%) of 25 patients in the placebo-switch group had relapsed at study endpoint (chi2 = 8.0, Fisher exact test, p = 0.01). The relative risk (hazards ratio) for relapse associated with placebo-switch relative to sertraline-continuation treatment was 10.2 (95% confidence interval, 1.3-80.7). Mean CGI-Severity, Marks Fear Questionnaire (MFQ) Social Phobia subscale, and Duke Brief Social Phobia Scale (BSPS) total scores were reduced by 0.07, 0.34, and 1.86 in the Sertraline-Continuation group and increased by 0.88, 4.09, and 5.99 in the Placebo-Switch group (all F > 5.3, p < 0.03), respectively. CGI-Severity, MFQ Social Phobia subscale, and BSPS scores also increased in the Placebo-Responder group. Discontinuations because of lack of efficacy were 4% in the sertraline-continuation group, 28% in the placebo-switch group (chi2 = 5.36, Fisher exact test, p = 0.049), relative to sertraline, and 27% in the placebo-responder group. Sertraline was effective in preventing relapse of generalized social phobia. Future research should assess whether improvements may be maintained or further increased by longer periods of treatment or through the addition of cognitive-behavioral techniques.

A controlled trial of cognitive behavioral treatment of panic in alcoholic inpatients with comorbid panic disorder.

Patients entering a 4-week inpatient alcoholism treatment program were screened for anxiety symptoms. Those with panic disorder with or without agoraphobia were randomly assigned to two groups. The treatment group received 12 hours of cognitive-behavioral treatment (CBT) for panic disorder in addition to the regular alcoholism treatment program: the control group received the regular program. Dropouts from the treatment group were also followed. Problem drinking and anxiety symptoms were measured at the start of the study, and at 3, 6, and 12 months posttreatment. Abstinence from drinking, and anxiety and mood symptoms improved after treatment in all of the groups; there were few differences in outcome between the groups. We concluded that this particular intervention had not been more effective than the regular alcohol treatment program in reducing problem drinking in those with panic disorder.

Physical illness as an outcome of chronic anxiety disorders.

BACKGROUND: The literature indicates increased rates of some medical conditions in patients with anxiety disorders. We used the Saskatchewan Health databases to examine the development of nonpsychiatric medical diseases in patients with anxiety disorders. This study has a large population base, and the Saskatchewan health plan does not limit the provision of services to this population. METHOD: We observed the annual incidence of specified medical conditions in patients with anxiety disorders and in control subjects over a 10-year period. Subjects in both groups had not been treated for the specified medical conditions before the start of the observation period. RESULTS: The anxiety cohort had a significantly higher relative risk of developing medical diseases compared with the control group. The highest relative risk, indicated by the hazard ratio, was for cerebrovascular disease (hazard ratio 2, 95% CI 1.09-3.65). Hazard ratios were significant for cerebrovascular disease and atherosclerosis as well as for ischemic heart, gastrointestinal, hypertensive, and respiratory diseases. CONCLUSIONS: This study provides additional evidence for an association between anxiety disorder and the later development of medical morbidity.

Antidepressants upregulate messenger RNA levels of the neuroprotective enzyme superoxide dismutase (SOD1).

OBJECTIVE: To investigate the effect of amitriptyline, bupropion, doxepin or venlafaxine on the gene expression of the neuroprotective enzyme superoxide dismutase (SOD1) in a catecholamine cell in vitro model. DESIGN: Molecular study of a cultured cell line. INTERVENTIONS: Rat pheochromocytoma (PC12) cells were incubated in 1 and 10 mumol/L of various antidepressant medications for 24 or 48 hours. OUTCOME MEASURES: Northern blot analysis. RESULTS: Amitriptyline up-regulated SOD1 messenger RNA in a time- and dose-dependent manner. The greatest up-regulation was following incubation with 10 mumol/L amitriptyline for 48 hours. The addition of bupropion, doxepin or venlafaxine to PC12 cell cultures also up-regulated SOD1 mRNA. CONCLUSIONS: These findings suggest that some antidepressants have the ability to positively regulate neuroprotective genes.

Efficacy of divalproex sodium in patients with panic disorder and mood instability who have not responded to conventional therapy.

OBJECTIVE: To determine the efficacy of divalproex sodium in the treatment of psychiatric outpatients with treatment refractory panic disorder and comorbid mood instability. METHOD: This was an 8-week, open-trial, flexible-dose outcome study conducted at a tertiary care referral centre. Individuals with panic disorder who failed to respond to a cognitive behavioural treatment program and standard antipanic medication, who also suffered from mood instability, were chosen to participate in the study. Divalproex sodium was administered at a flexible dose to reach serum levels of 300 to 600 mumol/L (45 to 90 ug/ml) unless limited by tolerance. Patients were rated by self- and rater-administered questionnaires that measured the number of panic attacks, the degree of agoraphobic avoidance, the levels of depression, anxiety, and mood swings, and the perceived sense of well being. RESULTS: Thirteen subjects were enrolled in the study, and 10 subjects completed it. Two dropped out early because of the medication's side effects, and 1 was lost within the first month of follow-up. All 10 subjects showed significant improvement in depressive and anxiety symptoms and mood instability. There was also a statistically and clinically significant improvement in panic attacks and measures of quality of life. CONCLUSIONS: These findings suggest that divalproex sodium is useful in the treatment of patients with panic disorder and concomitant mood instability, who are refractory to conventional treatment. Double-blind trials will be required to verify these findings.

Reduction of length of stay in an acute care psychiatric unit.

OBJECTIVE: To study the association between reduced length of stay in an acute care psychiatric unit and readmission rates. METHOD: Data on average length of stay, total discharges and readmission rates from April 1988 to March 1994 for 2 hospitals with high average lengths of stay was obtained from the Canadian Institute for Health Information database. RESULTS: The average length of stay decreased from 25 days to 16 days, reaching the national level at one hospital. An initial increase in the readmission rate subsequently declined to pre-study levels. There was no change in length of stay at the other hospital. CONCLUSION: Reducing the length of stay in an acute care facility by 9 days to an average of 16 days did not lead to a sustained increase in the readmission rate.

Phenelzine reduces plasma vitamin B6.

Plasma levels of the active form of vitamin B6 (pyridoxal phosphate) in 19 patients taking phenelzine were found to be reduced on the average to approximately 54% of the value in a control group. There was no correlation of pyridoxal phosphate level with phenelzine daily dosage over the range of 30 mg to 90 mg. No symptoms of vitamin B6 deficiency peripheral neuropathy were found.

Verbal learning by major depressive disorder patients during treatment with fluoxetine or amitriptyline.

After 1 week of a single-blind placebo period, and prior to being randomly assigned to receive treatment with either fluoxetine or amitriptyline, patients meeting strict criteria for a diagnosis of major depressive disorder were given an auditory verbal learning test of working memory, and a blood sample was drawn. After 3 weeks of drug treatment with either amitriptyline or fluoxetine, the patients' symptoms were evaluated, the verbal learning test was repeated, and a second blood sample was taken. The clinical evaluation, the verbal learning test and the blood drawing were repeated a third time 3 weeks after the second assessment. The amount of anticholinergic activity in the blood samples was measured by a competitive radioligand binding assay and expressed in atropine equivalents. Analyses of variance indicated that there were no significant differences at the predrug Assessment 1 between patients subsequently assigned to the fluoxetine group compared with those assigned to the amitriptyline group. At Assessments 2 and 3, the fluoxetine and the amitriptyline groups showed equal clinical improvement but patients receiving amitriptyline did not perform as well on the verbal learning task. Serum anticholinergic activity at Assessments 2 and 3 was considerably higher in the amitriptyline group. This supports the hypothesis that blockade of muscarinic receptors impairs working memory formation. Equally effective antidepressant drugs with little or no anticholinergic action, such as fluoxetine, may be preferable in patients with pre-existing mild cognitive impairment or in patients where a slight reduction in cognitive performance is not acceptable.

Longitudinal effect of amitriptyline and fluoxetine treatment on plasma phenylacetic acid concentrations in depression.

Unconjugated (U-PAA), conjugated (C-PAA), and total phenylacetic acid (T-PAA) concentrations in blood plasma and monoamine oxidase (MAO) activity in platelets towards phenylethylamine (PE) were determined in 40 drug-free, depressed patients (23 melancholic, 17 nonmelancholic) from five psychiatric treatment centers, and in 34 normal healthy volunteers. No significant differences were found between controls and all depressed patients or between melancholic and nonmelancholic depressed patients. Treatment of the depressed patients with amitriptyline or fluoxetine over a 6-week period resulted in clinical improvement and in a significant increase in plasma PAA concentrations. A decline in the Beck and Hamilton rating scores during treatment correlated significantly with increases in the concentrations of unconjugated, conjugated, and total phenylacetic acid but not with MAO activity, which did not change during treatment. At each of the three assessment times, however, plasma PAA concentrations and psychiatric rating scores were not significantly correlated. Except for higher end-of-study T-PAA concentrations in the amitriptyline-treated subjects, no significant differences were found between the effects of the two drugs with regard to plasma phenylacetic acid levels, MAO activity, or rating scores.

Less frequent lithium administration and lower urine volume.

OBJECTIVE: This study was designed to determine whether patients maintained on a regimen of lithium on a once-per-day schedule have lower urine volumes than do patients receiving multiple doses per day. METHOD: This was a cross-sectional study of 85 patients from a lithium clinic who received different dose schedules. Patients were admitted to the hospital for measurement of lithium level, creatinine clearance, urine volume, and maximum osmolality. RESULTS: Multiple daily doses of lithium were associated with higher urine volumes. The dosing schedule, duration of lithium treatment, and daily dose of lithium did not affect maximum osmolality or creatinine clearance. CONCLUSIONS: Urine volume can be reduced by giving lithium once daily and/or by lowering the total daily dose. Lithium-induced polyuria seems to be related to extrarenal as well as to renal effects.

A comparison of fluoxetine and amitriptyline in the treatment of major depression.

Fluoxetine, a new serotonin uptake blocking antidepressant, was compared with amitriptyline in a double-blind study. Patients were diagnosed as having major depression, according to DSM-III criteria, when interviewed with the Diagnostic Interview Schedule. There was significant improvement in patient and observer ratings of depression in both groups, with no difference between groups. Recent memory improved significantly in the fluoxetine group but not in the amitriptyline group. Numbers of patients reporting side-effects were similar but the profiles of side-effects were different, with more patients on amitriptyline reporting anticholinergic and intolerable side-effects.

Deuterium-labelled p-tyramine challenge test and phenolsulfotransferase activity in depressed patients--failure to replicate decreased p-tyramine conjugation in depression.

1. Depressed and normal subjects were challenged with deuterium-labelled p-tyramine and urine was collected for 3 h. 2. Urinary excretion of conjugated p-tyramine was not significantly different between normal, melancholic and non-melancholic depressed subjects. 3. Platelet phenolsulfotransferase activity to p-tyramine (p less than 0.05) and to phenol (p less than 0.005) were significantly lower in the depressed patients.

The prevalence of anxiety disorders among patients with mitral valve prolapse syndrome and chest pain.

Nineteen patients from a cardiology practice with complaints of chest pain and with mitral valve prolapse syndrome were compared with 26 patients with chest pain but no discernible cardiac disorder. Instruments included a truncated form of the Diagnostic Interview Schedule, the symptom checklist 90 revised (SCL-90-R), the McGill Pain Questionnaire, and life events, physical activity, and family history questionnaires. Neither panic disorder nor self-rated anxiety were more common in the mitral valve prolapse group. This study failed to confirm the reported high association between mitral valve prolapse syndrome and panic disorder.

The prevalence of overanxious disorder and separation anxiety disorder: results from the Ontario Child Health Study.

Data from a community epidemiological study of 1,869 families (Ontario Child Health Study) was used to evaluate the effect of different ways of operationalizing DSM-III-R criteria for overanxious disorder (OAD) and separation anxiety disorder (SAD) among adolescents aged 12 to 16. The authors determined that a high threshold for symptoms to qualify as present, the presence of one or both of the essential symptoms, and the presence of four or more auxiliary symptoms for OAD and three or more for SAD gave prevalence of OAD of 3.6% and SAD of 2.4%. There was high overlap between the presence of OAD and SAD and externalizing disorder and depression, but one-half of youth with OAD and SAD had pure anxiety disorder. Youth with OAD and SAD were just as impaired as youth with externalizing disorder and depression, except that they admitted to less social isolation and their schoolwork was less affected.

A case of atypical psychosis associated with alexithymia and a left fronto-temporal lesion: possible correlations.

The case history is presented of a man with an atypical psychosis and classical clinical features of alexithymia. On his last admission, the patient presented with starvation and hypernatremic coma. A CT scan, which was done because of the coma, revealed a large left fronto-temporal arachnoid cyst. The significance of this finding is reviewed in the light of previously suggested organic bases for alexithymia and related syndromes. Although the symptom of alexithymia is present, the patient's other symptoms do not fit readily into existing diagnostic categories and the resulting diagnostic dilemma is discussed.