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A variety of evidence from laboratory and animal studies suggests that lithium has neurotrophic and cytoprotective properties, and may ameliorate or prevent some disease states. We investigated whether such a protective effect can be observed in human psychiatric patients receiving lithium therapy. We carried out a retrospective chart review of 1028 adult psychiatric male and female outpatients attending four lithium clinics in metropolitan New York City. Patients were divided into two groups based on lithium usage, and the prevalence of neurological and cardiovascular disorders was compared. The main outcome measures were the occurrence in the two patient groups of a variety of neurological disorders and myocardial infarction. Odds ratios were calculated to assess the risk of having a disorder for patients receiving lithium compared to patients not receiving lithium: for seizures, the odds ratio was 0.097; for amyotrophic lateral sclerosis, the odds ratio was 0.112; for dementia not otherwise specified, the odds ratio was 0.112; and for myocardial infarction, the odds ratio was 0.30. Logistical regression analysis showed that lithium treatment is a significant negative predictive factor in the prevalence of each of these disease states, when age, duration of clinic attendance, and use of anti-psychotic medications are taken into account. Our results show that patients receiving regular lithium treatment have a reduced prevalence of some neurological disorders and myocardial infarctions. One possible explanation of these results is that a protective effect of lithium observed in laboratory and animal studies may also be present in human patients receiving regular lithium therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pregabalin is a new anxiolytic that acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the alpha2-delta subunit of voltage-gated calcium channels. The current study evaluated the anxiolytic efficacy of BID versus TID dosing of pregabalin in patients with generalized anxiety disorder. Outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition generalized anxiety disorder and having baseline Hamilton Anxiety (HAM-A) total scores > or =20 were randomized to 6 weeks of double-blind treatment with pregabalin 200 mg/d (BID; N = 78), 400 mg/d (BID; N = 89), or 450 mg/d (TID; N = 88) or placebo (N = 86). Mean improvement in HAM-A total score at last observation carried forward end point was significantly greater on pregabalin 200 (P = 0.006), 400 (P = 0.001), and 450 mg/d (P = 0.005) compared with placebo. Pairwise comparisons of BID versus TID dosing found no difference in HAM-A change score at end point. All 3 pregabalin dosage groups showed significantly greater efficacy versus placebo at end point on the HAM-A psychic and somatic anxiety factor scores. Improvement on both factors was rapid: significance versus placebo was achieved as early as the first assessment at week 1, with > or =30% reduction in HAM-A severity and equal or greater improvement for every subsequent visit in > or =38% of patients in all 3 pregabalin dosage groups (P < or = 0.001). Pregabalin was well tolerated, and despite the fixed-dose study design, discontinuations caused by adverse events ranged from 9% to 13%--comparable with that observed with placebo (8%). This study demonstrates that pregabalin is an effective treatment of generalized anxiety disorder, with BID dosing showing similar efficacy and comparable tolerability with TID dosing.

Objective: To determine the impact of acute depression on quality of life (QOL) in patients with bipolar I disorder and to compare these results with published data on QOL in patients with unipolar depression., Methods: Quality of life was assessed using the SF-36 in bipolar patients (n = 958) who had recently experienced an episode of acute bipolar depression and participated in a large randomized, double-blind, safety and efficacy trial. Seven studies that included SF-36 data from patients with unipolar depression were identified in the published literature and descriptive comparisons of SF-36 scores were made between the unipolar depression trials and this bipolar depression trial., Results: There were 920 patients who completed the SF-36. Mean transformed scores, which could range from 0 to 100, were very low in bipolar depressed patients for the role-physical (36.7), vitality (22.4), social functioning (29.9), role-emotion (11.4), and mental health (31.0) subscales. Mean SF-36 scores for all subscales were significantly and inversely correlated (p < 0.0001) with the HAM-D indicating that patients with milder depressive symptoms had better QOL. Further, the mean SF-36 scores for the bipolar sample were consistently lower compared with published data on QOL in unipolar depression on four of the eight subscales: general health; social functioning; role-physical, and role-emotional., Conclusions: While both unipolar and bipolar depression have serious detrimental effects on patient QOL, our results suggest that some aspects of QOL may be worse in bipolar depression.

Background: Fatigue and sleepiness are primary symptoms of depression that may not resolve with antidepressant therapy. Modafinil is a novel agent that has been shown to improve wakefulness and lessen fatigue in a variety of conditions. In this study, we examined the utility of modafinil as an adjunct therapy to treat fatigue and sleepiness in patients with major depression who are partial responders to antidepressants., Method: Patients with partial response to anti-depressant therapy given for at least a 6-week period for a current major depressive episode (DSM-IV criteria) were enrolled in this 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients received once-daily doses (100-400 mg) of modafinil or matching placebo as adjunct treatment to ongoing antidepressant therapy. The effects of modafinil were evaluated using the Hamilton Rating Scale for Depression (HAM-D), the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Change (CGI-C), and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Adverse events were monitored throughout the study., Results: One hundred thirty-six patients were randomized to treatment, with 118 patients (87%) completing the study. Most patients (82%) were fatigued, and one half of patients (51%) were sleepy. Modafinil rapidly improved fatigue and daytime wakefulness, with significantly greater mean improvements from baseline than placebo in fatigue (FSS) scores at week 2 (p < .05) and sleepiness (ESS) scores at week 1 (p < .01); the differences between modafinil and placebo at week 6 were not statistically significant. Assessment of the augmentation effects of modafinil (HAM-D, CGI-C, and SF-36) did not significantly distinguish modafinil from placebo. Modafinil was well tolerated in combination with a variety of antidepressants., Conclusion: Modafinil may be a useful adjunct therapy for the short-term management of residual fatigue and sleepiness in patients who are partial responders to antidepressant therapy.

We evaluated 355 subjects who entered one of six double-blind placebo-controlled antidepressant drug trials with respect to the occurrence of antecedent adverse life events and their meaning to the patient. Patients were also assessed with regard to the degree of social support they received for the negative life event. The groups differed as to whether they did or did not meet the criteria for melancholic depression; 43 one-week placebo responders were statistically significantly more likely to believe that adverse life events predisposed them to depressive illness and that such life events precipitated their current depression, compared to 312 one-week placebo non-responders. Of the 312 patients who went on to the double-blind phase in which they were treated with either drug (n = 204) or placebo (n = 108), it was noted that, for both melancholic and non-melancholic patients, responders to drug treatment (but not placebo) had a more favourable ratio of social support received/social support desired than non-responders. Non-melancholic responders to both drug and placebo were statistically significantly more likely to report fewer adverse life events and have a less strong belief that adverse life events predispose one to depressive illness than non-responders. Melancholic patients did not show this trend.

Objective: To examine the effect of hypomanic states on maladaptive personality traits and personality disorders, the authors evaluated personality traits and disorders of patients during an episode of hypomania and after successful somatic treatment., Method: The authors used the Structured Interview for DSM-III Personality Disorders to study 66 outpatients who had a lifetime diagnosis of bipolar disorder and who met the minimum Research Diagnostic Criteria for hypomania. All patients had a knowledgeable informant separately undergo the Structured Interview for DSM-III Personality Disorders during the patient's hypomanic state. Outpatients who successfully recovered from the hypomanic episode (N = 47) and their informants were read-ministered the interview 4-8 weeks after the initial assessment., Results: During the hypomanic state, informants generally reported higher levels of maladaptive personality traits among patients than patients themselves. For the patients who recovered successfully from the hypomanic episode, a reduction in all maladaptive personality traits except schizoid and dependent traits was reported by both patients and their informants; however, the decrease reported by patients generally was much greater than that reported by informants. In addition, schizoid traits actually increased after successful treatment according to patient reports but were unchanged according to informant reports., Conclusions: Hypomania may be associated with an exacerbation of maladaptive personality traits, which may be attenuated after successful treatment. Even with the attainment of euthymic mood, however, about 50% of the cohort had at least one personality disorder, which suggests that a high degree of comorbidity may exist between bipolar disorders and maladaptive personality traits or personality disorders.

The influence of major depression on patients' and informants' reports of personality traits was examined using the Structured Interview for DSM-III Personality Disorder, both before and after successful antidepressant or placebo treatment (N = 58). According to patients' reports, Cluster A and C traits decreased significantly from pre- to posttreatment, but Cluster B traits were unchanged, excluding an increase in histrionic traits. According to informants' reports, Cluster A and B traits did not change from pre- to posttreatment, but Cluster C traits decreased significantly after treatment, not including passive-aggressive traits. Moreover, informants generally reported much higher levels of maladaptive personality traits than patients themselves. These results suggest that informants should be used in future research on personality disorders until better assessment techniques are developed.

In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.

We investigated whether and how acute depressive symptoms affect the self-report of maladaptive personality traits. Sixty-eight acutely depressed patients underwent the Structured Interview for DSM-III Personality Disorder (SIDP) before and after pharmacological treatment, allowing us to determine whether self-reported maladaptive personality traits are different during depression and after successful clinical recovery. After the initial SIDP administration (during an episode of major depression), patients received desipramine treatment (dose range 150-300 mg/day) over a course of 4-5 weeks before readministration of the SIDP. For those who recovered from their depression (n = 39), cluster III trait scores were significantly lower than those assessed at baseline, and there was a lower frequency of cluster III categorical diagnoses for a personality disorder after treatment than before treatment. Recovered patients also had significantly lower cluster I personality trait scores after treatment as compared with baseline ratings. For those who did not recover from their depression after treatment (n = 29), cluster I trait scores were in fact higher than those measured at baseline, but there were no differences in categorical diagnoses before and after treatment. Cluster II personality traits and categorical diagnoses were not different between those who did and did not recover from their depression. Thus, depression may have a significant effect on the assessment of cluster I and cluster III personality traits. It is possible that cluster I and III 'personality traits' may be interwoven with depressive features and therefore subject to state influences, whereas cluster II personality traits may entail enduring, long-term characteristic modes of thinking, feeling, and behaving.

Using a longitudinal life-table analysis, we assessed the efficacy of lithium alone, administered within the context of a naturalistic clinical setting, by calculating the probability of patients remaining free of an affective episode (manic or depressive) over a five-year course. In addition, for those who suffered a manic or depressive relapse, we attempted to analyse the subsequent course of patients who suffered a manic/hypomanic or depressive relapse and were then restabilised on lithium plus either a neuroleptic, carbamazepine, or a benzodiazepine, or lithium plus an antidepressant. Lithium alone offered an average 83% probability against an affective relapse after one year, 52% after three years, and 37% after five years. For patients who failed on lithium alone, it appeared that combination treatment offered greater protection against subsequent affective relapse than the initial course on lithium alone.

These data provide evidence for the antidepressant efficacy of paroxetine. Paroxetine- and imipramine-treated patients were significantly different from placebo-treated patients, but little different to each other, on all depressive outcome measures. However, paroxetine appeared to have a possibly greater and earlier beneficial effect on anxiety symptoms associated with depression, when compared with imipramine. Both active therapies were effective in treating patients with severe depression. Side effects for paroxetine were typical of other serotonin (5-HT) uptake inhibitors but different from those of imipramine. In particular, anticholinergic and cardiovascular symptoms were reduced, and premature withdrawal less likely.

Objective: The authors' goals were to examine the effects of somatic treatment and placebo in patients with and without endogenous/melancholic depression., Method: Before entry into one of four trials of antidepressant drugs versus placebo, 231 patients were assessed as to whether they met Research Diagnostic Criteria for definite endogenous depression and/or DSM-III criteria for major depressive episode with melancholia. These patients were prospectively assessed for subsequent response to antidepressant treatment or placebo. Previous studies of the effect of endogenous/melancholic depression on treatment response were also reviewed., Results: Of the 76 patients with DSM-III melancholia given active medication, 41 (54%) had a complete or partial response, but only 10 (23%) of the 44 patients with melancholia given placebo had a complete or partial response. Of the 76 depressed patients without melancholia given active medication, 46 (61%) had a complete or partial response, and 15 (43%) of the 35 depressed patients without melancholia given placebo had a complete or partial response. Moderately depressed patients with DSM-III melancholia had a significantly better response to active medication than did severely depressed patients with melancholia and showed the greatest difference between response to active medication and response to placebo. The results of the review of previous studies of the effect of endogenous/melancholic depression on treatment response were mixed., Conclusions: Depressed patients with melancholia were not particularly different from depressed patients without melancholia in their responses to antidepressant medication but did differ from patients without melancholia in their responses to active medication versus placebo, particularly if their depression was moderate and not severe. This suggests that patients with DSM-III melancholia may be unresponsive to nonsomatic treatments.

This study evaluated the relationship of sociotropic and autonomous personality traits with response to pharmacotherapy for 217 depressed outpatients using the Sociotropy-Autonomy Scale. Sociotropy was related to nonendogenous depression, whereas autonomy was related to endogenous depression. Subjects who had high autonomous-low sociotropic traits showed greater response to antidepressants (and greater drug-placebo differences) than those who had high sociotropic-low autonomous traits (who showed no drug-placebo differences). Hierarchical multiple regression analysis showed that the sociotropy-autonomy, but not the endogenous-nonendogenous, distinction was a predictor of drug treatment response. The combination of endogeneity and autonomy predicted response to placebo. If replicated, these findings may enable better matching of patient traits to various treatment modalities for depression.

We attempted to prospectively examine the effects of personality traits in 68 acutely depressed patients treated with desipramine over 4-5 weeks to assess whether the presence or absence of these traits played a role in response to antidepressant treatment. Overall the 39 responders had statistically significantly lower cluster III personality trait scores than non-responders, and a trend toward lower cluster I and cluster II scores. We then followed the 39 desipramine responders for up to 6 months on the dose to which they responded in accordance with standard clinical practice. Overall 23 of the 39 sustained their initial improvement, with eight relapsing and eight dropping out between 5 weeks and 6 months. When comparing these three groups with the 29 initial non-responders, those who sustained the 6-month response had statistically significantly lower cluster II, cluster III, and total personality scores than initial responders who relapsed, initial responders who dropped out and did not complete 6 months of treatment, and initial non-responders.

Depressive illness among the elderly is an important public health concern. However, treatment of the elderly may be complicated by age-related changes in physiology, general medical status, and susceptibility to side effects. There is therefore a need for improved treatment modalities for depressed elderly patients. Paroxetine is an antidepressant that acts through selective inhibition of serotonin reuptake. It lacks the anticholinergic and cardiovascular side effects of most first- and second-generation antidepressants. The authors present the combined data from two similarly designed comparisons of paroxetine and doxepin in outpatients over 60 years of age with major depression. The results show that paroxetine was an effective as doxepin in alleviating depression as measured on the Hamilton Rating Scale for Depression (HAM-D) total score, the Montgomery and Asberg Depression Rating Scale (MADRS), and the Hopkins Symptom Checklist (SCL) depression factor score. Paroxetine was significantly superior to doxepin on the Clinical Global Impressions (CGI) scale for severity of illness, the HAM-D retardation factor, and the HAM-D depressed mood item. Doxepin produced significantly more anticholinergic effects, sedation, and confusion. Paroxetine was associated with more reports of nausea and headache. These results suggest that paroxetine may be a valuable tool for the treatment of major depression in the elderly.

The dexamethasone suppression test (DST) and the depressive attributional style questionnaire (ASQ) were administered to 105 depressed patients prior to participation in a double-blind outpatient study and to 29 normal controls. The depressed patients were classified into three groups (1) met criteria for both research diagnostic criteria for definite endogenous depression and DSM III melancholia; (2) met criteria for neither, and (3) met criteria for one but not both. The group that met criteria for both RDC endogenous depression and DSM-III melancholia had a statistically greater frequency of abnormal DST versus the group that met neither criteria and the normal controls. With regard to ASQ, patients who met both criteria had statistically higher bad event internality scores but statistically lower bad event stability and globality scores as opposed to the group that met neither criteria. In general, normal controls had significantly lower bad event ASQ scores than the three depressive groups. There was no correlation between ASQ and DST, as both DST suppressors and nonsuppressors had similar ASQ scores and there was no correlation between ASQ bad event attributions and initial severity of depression.

We studied 75 patients on prophylactic antidepressants (imipramine or amitriptyline) to examine the effect of antidepressant dose on long-term prophylaxis of depression and to see whether lowering the dose during the prophylactic period affected subsequent relapse. There was no statistically significant difference in maintenance and prophylactic doses between the group that completed the 2 years free of a depressive episode, the group that had a depressive relapse and the group that dropped out of treatment before the end of the prophylactic period. However, the group that completed the 2 years free of a depressive episode had significantly less of a difference between the maintenance and prophylactic doses than the other 2 groups. Overall, 11/31 who remained on the same dose during the prophylactic period vs the maintenance period relapsed vs 17/25 who had their dose lowered during the prophylactic period vs the maintenance period. The difference was statistically significant.

To compare the safety and antidepressant efficacy of paroxetine, imipramine, and placebo, data from six centres using the same protocol were pooled. A double-blind parallel-group design was used, with therapy lasting six weeks. From week 2 onwards, both the 240 paroxetine-treated and the 237 imipramine-treated patients were significantly different from the 240 placebo-treated patients, but no different from each other. Side-effects with paroxetine were less likely to lead to drop-out than with imipramine. Paroxetine had a possible earlier antidepressant effect than imipramine, and a possible earlier beneficial effect on anxiety symptoms associated with depression.

We evaluated learning and memory in 50 depressed patients prior to and following 4 week treatment with imipramine compared to 21 normal controls tested at corresponding times. At baseline, the depressives did worse than normals on most memory tasks with the difficult memory tasks, regardless of store, modality or type of task best distinguishing between depressive and normal memory. Following imipramine treatment, responders performed better than nonresponders on the difficult memory tasks, and not significantly differently from controls on most tasks. This, as well as the fact that the responders improved to a greater degree than controls on most measures (in a few cases the difference was statistically significant) and the fact that at 4 weeks complete responders to imipramine did significantly better than partial responders to imipramine, indicates that relief from depression is highly related to improved memory functioning. The finding that complete responders to imipramine were not significantly worse than normal controls suggests that imipramine did not have significant adverse effects on memory.

1. In order to evaluate the efficacy of antidepressants in the prevention of recurrent depression, a longitudinal life-table analysis was carried out involving 217 unipolar patients whose depressive symptoms had remitted following treatment with one of five standard tricyclics (imipramine, amitriptyline, desipramine, nortriptyline, and doxepin). 2. Following six months continued euthymic mood these patients were maintained on the medication to which they initially responded to in a clinical setting over a 5 year period. These patients were compared against a group of 28 individuals who were treated acutely for their depression and responded to one of the above the 5 standard antidepressants, but following 5-6 months continuation treatment were taken off the antidepressant at their own request. 3. Though there was a lower rate of relapse in patients receiving active medication vs the no treatment group, the frequency of relapse was high for the group on active drug. 4. Using the longitudinal life-table method of Fleiss there was a pessimistic-optimistic average relapse rate of 30%, 50%, and 60%, at 1, 2, and 3 years respectively while on active drug vs a 51%, 74%, and 83% relapse rate on no treatment. Overall 87 of 217 patients on active drug (40.1%) were observed to have suffered a depressive relapse over the 5 year course.

To evaluate the role of maladaptive thinking patterns in depression, the authors administered the Dysfunctional Attitude Scale to 112 depressed patients before and after 3-6 weeks of treatment with antidepressants or placebo. Twenty-two normal subjects were also assessed twice. Depressed patients had a significantly higher initial mean score than control subjects, but during treatment their score significantly decreased, and the posttreatment score of those with complete recoveries was nearly as low as the control subjects' final score. The higher the initial dysfunctional attitude score the poorer the response to treatment. Patients with endogenous depression had significantly lower scores than nonendogenously depressed patients.

A number of promising antidepressant compounds are presently either being developed in the laboratory or are being tested clinically by pharmaceutical firms and universities around the world. New compounds are sought which will provide: 1. fewer side effects, particularly anticholinergic and cardiovascular effects; 2. more rapid onset of action than 7-10 days required of most antidepressants now used; 3. efficacy in a higher percentage of patients than the 65-70 per cent estimated to respond to currently available antidepressant therapies. Compounds now being investigated include: new tricyclics which are unlike those commonly in use; the tetracyclics; the salts of naturally occurring cations such as lithium and rubidium; and various chemically unrelated new compounds. In addition, several drugs currently being tested as anorectics seem promising for future antidepressant drugs research.

Previous studies have suggested that the activity of erythrocyte catechol-O-methyltransferase (COMT) may be reduced in women with bipolar and particularly unipolar affective illness. More recently, increased COMT activity in both men and women with affective disorder was reported. The activity of COMT in erythrocytes was determined in 184 outpatients with primary affective disorder at the Lithium Clinic of the New York State Psychiatric Institute. COMT activity was determined by a modification of the Axelrod and Cohn method with dopamine as substrate. This change resulted in an apparent threefold increase in the values for COMT activity; however, when both methods were compared, the results correlated (r = 0.97, p less than 0.001, N = 37). We found that the values for women were not significantly lower than those for men. In addition, there was no difference between patients with affective disorder and controls. Further, no difference was demonstrated between patients diagnosed as bipolar or uni-polar. Parameters such as mood, medication, and inpatient or outpatient status had no effect on COMT activity. The results of previous studies are discussed in an attempt to reconcile the different results.

The body composition of three unipolar and 17 bipolar patients, studied during the depressive state, was compared with that of 48 controls. The ratio of extracellular to intracellular water content was significantly less in male patients than in male controls: the difference between female patients and female controls was not statistically significant. In patients of both sexes, residual sodium concentration was greater in patients than in controls. The intracellular content of potassium was the same in patients as in controls. In six patients, body composition was studied prior to lithium carbonate therapy, after 17 days of treatment, and 17 days after discontinuing administration of the drug. The significant changes were a decrease in body weight during therapy, and a decrease in body water content and an increase in residual sodium concentration after drug treatment was discontinued.

The elimination half-life (t1/2E) of lithium carbonate in red blood cells, plasma, and urine was measured in 30 patients hospitalized for primary affective disorder. Duration of Li treatment at time of sampling was found to have a direct effect on lengthening time course. Patients on their initial course of Li had the lowest t1/2s: 1.12 (urine), 1.28 (plasma), and 1.22 days (red blood cells); those less than 1 yr on Li had intermediate values: 1.85, and 1.65, and 1.75 days; and those more than 1 continuous year on Li had the longest mean t1/2s: 2.40, 2.43, and 2.24 days. These results for urine (p less than 0.01) and plasma (p less than 0.05) are further evidence that Li may stimulate the production of an endogenous regulator of Li efflux. This regulator may prove to be an important factor in planning of long-term Li prophylaxis.

Thirty-one children (age range, 7-14 years) of 18 probands with a bipolar disorder according to Research Diagnostic Criteria were assessed on clinical and psychological measures and compared with 18 matched normal control children. The authors found higher rates of childhood psychopathology in the children of the probands than in the control children. In addition, the experimental group was characterized by 1) a pattern on the WISC-R of higher verbal than performance IQs, 2) higher ratios of color to movement determinants on the Rorschach test, and 3) an overrepresentation of left-handedness. The implications of these findings are briefly discussed.