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Udgivelsesdato: 2010-Sep CONTEXT: Clues from the epidemiology of schizophrenia suggest that low levels of developmental vitamin D may be associated with increased risk of schizophrenia. OBJECTIVE: To directly examine the association between neonatal vitamin D status and risk of schizophrenia. DESIGN: Individually matched case-control study drawn from a population-based cohort. SETTING: Danish national health registers and neonatal biobank. PARTICIPANTS: A total of 424 individuals with schizophrenia and 424 controls matched for sex and date of birth. MAIN OUTCOME MEASURES: The concentration of 25 hydroxyvitamin D(3) (25[OH]D3) was assessed from neonatal dried blood samples using a highly sensitive liquid chromatography tandem mass spectroscopy method. Relative risks were calculated for the matched pairs when examined for quintiles of 25(OH)D3. RESULTS: Compared with neonates in the fourth quintile (with 25[OH]D3 concentrations between 40.5 and 50.9 nmol/L), those in each of the lower 3 quintiles had a significantly increased risk of schizophrenia (2-fold elevated risk). Unexpectedly, those in the highest quintile also had a significantly increased risk of schizophrenia. Based on this analysis, the population-attributable fraction associated with neonatal vitamin D status was 44%. The relationship was not explained by a wide range of potential confounding or interacting variables. CONCLUSIONS: Both low and high concentrations of neonatal vitamin D are associated with increased risk of schizophrenia, and it is feasible that this exposure could contribute to a sizeable proportion of cases in Denmark. In light of the substantial public health implications of this finding, there is an urgent need to further explore the effect of vitamin D status on brain development and later mental health.

Background: The aim of this study was to examine minor physical anomalies and quantitative measures of the head and face in patients with psychosis vs healthy controls. Methods: Based on a comprehensive prevalence study of psychosis, we recruited 310 individuals with psychosis and 303 controls. From this sample, we matched 180 case-control pairs for age and sex. Individual minor physical anomalies and quantitative measures related to head size and facial height and depth were compared within the matched pairs. Based on all subjects, we examined the specificity of the findings by comparing craniofacial summary scores in patients with nonaffective or affective psychosis and controls. Results: The odds of having a psychotic disorder were increased in those with wider skull bases (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.02-1.17), smaller lower-facial heights (glabella to subnasal) (OR, 0.57; 95% CI, 0.44-0.75), protruding ears (OR, 1.72; 95% CI, 1.05-2.82), and shorter (OR, 2.29; 95% CI, 1.37-3.82) and wider (OR, 2.28; 95% CI, 1.43-3.65) palates. Compared with controls, those with psychotic disorder had skulls that were more brachycephalic. These differences were found to distinguish patients with nonaffective and affective psychoses from controls. Conclusions: Several of the features that differentiate patients from controls relate to the development of the neuro-basicranial complex and the adjacent temporal and frontal lobes. Future research should examine both the temporal lobe and the middle cranial fossa to reconcile our anthropomorphic findings and the literature showing smaller temporal lobes in patients with schizophrenia. Closer attention to the skull base may provide clues to the nature and timing of altered brain development in patients with psychosis.

Delayed and persistent ("true drug") improvement characterizes the response to antidepressant medication. Early or nonpersistent ("placebo") benefit is typical of a placebo response. The prediction was that patients with a true drug response would sustain their benefit best if they continued to receive the drug and that patients with a placebo response would have an equivalent prognosis whether they continued to receive the drug or were switched to placebo.Patients with major depression who met the study's response criteria (a modified Hamilton Depression Rating Scale scoreor =7 and failure to meet major depression criteria after each of the last 3 weeks following 12 to 14 weeks of treatment with fluoxetine hydrochloride, 20 mg/d) were enrolled in a 50-week randomized placebo substitution trial during which the return of depressive symptoms defined relapse. The timing and persistency of response during initial treatment defined true drug or placebo response patterns.Patients with a true drug response pattern relapsed significantly more frequently if they were switched to placebo than if they continued to receive fluoxetine (P.001 for weeks 12-26, P.005 for weeks 26-50, and P.41 for weeks 50-62). Patients with a placebo response pattern had an equivalent outcome whether maintained on fluoxetine therapy or placebo (P.20 for weeks 12-26, test invalid for weeks 26-50, and P.67 for weeks 50-62). Patients with a placebo response pattern relapsed more often when they continued to receive fluoxetine than patients with a true drug response pattern (P.01 for weeks 12-26, P.10 for weeks 26-50, and P.36 for weeks 50-62).These findings confirm that pattern analysis validly differentiates true drug from nonspecific initial responses and extend its use to the continuation and maintenance phases of treatment for depression. Investigations into the mechanisms of antidepressant activity might best be limited to those that can account for delayed efficacy. Fluoxetine's efficacy during the continuation and maintenance phases of treatment may be limited to patients with a true drug pattern of initial response.

Background: Depressive disorders are commonly comorbid with alcoholism, particularly in treatmentseeking samples. If antidepressant treatment were safe and improved the treatment outcome in the subset of actively drinking alcoholics with depression, this would be of clinical importance. Methods: We conducted a randomized, 12-week placebo-controlled trial of imipramine hydrochloride combined with weekly relapse prevention psychotherapy. The subjects were 69 actively drinking alcoholic outpatients with current depressive disorders. The first onset of depression was either antecedent to the abuse of alcohol or occurred during prolonged periods of sobriety. Depression and drinking outcomes at 12 weeks, as well as their relationship, were measured. Results: Imipramine treatment was safe and associated with improvement in depression in both adequately treated and intention-to-treat samples. While there was no overall effect on drinking outcome, patients whose mood improved showed decreased alcohol consumption that was more marked in those treated with imipramine. Conclusions: Imipramine treatment is effective for primary depression among actively drinking alcoholic outpatients, and may improve alcoholic outcome for those whose depression responds to treatment.

The literature is inconclusive on the role of antidepressant medications in treating drug dependence. Studies have either not focused on depressed patients or have selected patients with depressive disorders based on cross-sectional symptoms rather than a syndromal diagnosis. A clinical trial of an antidepressant was, therefore, conducted on drug-dependent patients with syndromal depression.Patients receiving methadone hydrochloride maintenance treatment were selected if they met the criteria for a DSM-III-R depressive disorder that was chronologically primary, had persisted during a past abstinent period or was long-standing, and persisted during at least 1 month of stable methadone treatment. Subjects were randomized to a 12-week, double-blind, placebo-controlled trial of imipramine hydrochloride. A favorable response was defined as a Clinical Global Impression scale score for depression of 2 ("much improved") or 1 ("very much improved") and at least a 75% reduction in self-reported drug or alcohol use or abstinence.One hundred thirty-seven patients were randomized, and 84 completed a minimum adequate trial of at least 6 weeks. Among the 84 adequately treated patients, 57% (24/42) receiving imipramine were rated as responders compared with 7% (3/42) receiving placebo (P.001). On measures of mood, there was a robust effect of imipramine. Imipramine was superior to placebo on some self-reported measures of substance use and craving, and mood improvement was associated with improvement in self-reported substance use. However, few patients achieved urine-confirmed abstinence.Imipramine was an effective antidepressant in patients receiving methadone who were selected via syndromal criteria for depressive illness. Imipramine may reduce substance abuse among patients whose mood improves; however, this effect was less robust.

Since Aubrey Lewis' classic study there has been debate about whether the distinction between depressive subtypes is categorical or dimensional. 1-6 A recent article by Kendler et al 7 supports a categorical classification of depressive subtypes. Using a different means of validating nosological distinctions, our group reached similar conclusions and we think it relevant to review the similarities and differences between our findings and those of Kendler et al. In a prospective epidemiological study of adult female twins, Kendler et al used latent class analysis and identified 3 depressive subtypes—mild typical, atypical, and severe typical depression. Subjects with atypical depression were characterized by reversed vegetative depressive symptoms (overeating and oversleeping). These groups differed on many validating criteria, supporting a categorical distinction. We reached a similar conclusion using psychopharmacologic dissection, a distinctly different method. 8 In a series of 6 studies, patients with nonautonomous mood were randomized to receive imipramine, phenelzine

Background: We attempt to identify the time when patients whose conditions are unimproved while receiving antidepressants are unlikely to respond and should have their treatment changed. Methods: A total of 593 patients were studied. The course of treatment for patients was examined to determine the weeks at which patients who received drug therapy had a better chance of being rated as responders at the study end (week 6) vs patients who received placebo. Results: At the end of week 3, 19 (32%) of the 59 patients who received drug therapy and 6 (10%) of the 57 patients who received placebo and who never minimally improved were rated as responders at week 6. For those who showed no improvement by week 4, the effects of drug therapy and the placebo were equal. Patients who received drug therapy and whose conditions were unimproved but who had been minimally improved at some point had a superior prognosis with drug therapy vs placebo until week 4. Of those unimproved at week 4 but minimally improved at some point previously, 20 (39%) of the 51 patients who received drug therapy vs 3 (8%) of the 36 patients who received pIacebo were rated as responders at week 6. Of the 75 patients who minimally improved while receiving drug therapy at the end of week 5, 33 (44%) had a chance of being rated a responder at the end of week 6 vs 9 (26%) of the 35 patients receiving placebo. Conclusions: Patients tolerant of an adequate dose, whose conditions have never been at least minimally improved by the end of week 4, should have their treatment regimen altered. These patients represented a minority of drug-treated patients in the sample studied (ie, 39/392 [10%]). Patients whose conditions minimally improve at some prior week but not after week 5 should have their treatment changed. Patients whose conditions minimally improve in week 5 should continue treatment until week 6.

We employed a study design that permitted a double-blind 12-week contrast of imipramine hydrochloride and phenelzine sulfate therapies in patients who met Columbia University criteria for atypical depression and were unresponsive to 7 weeks of treatment with placebo. These patients were found to benefit selectively from therapy with monoamine oxidase inhibitors compared with tricyclic drug therapy. This supports our observation about treatment response in depressed patients with reversed vegetative features. The design we utilized in this study has not previously been reported, to our knowledge. It was hypothesized that it would offer the advantage of the removal of a portion of placebo responders and serve to replicate our original findings. Treatment response to therapy with both imipramine and pheneizine in placebo nonresponders was uniformly lower (roughly 20% less than corresponding rates for patients who did not participate in the initial 6-week placebo trial). This is consistent with the view that the lower response rates were a result of the removal of some "placebo" responders in the drug groups. We think this is a useful design that should be considered in all studies of placebo and two active treatment regimens.

In an initial study with 120 patients with reactive mood and associated atypical symptoms, phenelzine sulfate was superior to imipramine hydrochloride and placebo. Since their response to phenelzine appears to be unique, this suggests that atypical depression may be a distinct subgroup of unipolar depressive illness. Unexpectedly, the benefit of antidepressants was limited to patients who also had spontaneous panic attacks. To help establish the validity of this syndrome, a new sample of 90 atypical depressives was studied. The clinical and demographic characteristics of the original and replication sample were virtually identical at baseline. In addition, the treatment response with either placebo, imipramine, or phenelzine was also indistinguishable in the two patient groups. The outcome in the replication study supports the hypothesis that this may be a distinct unipolar depressive subgroup. In the replication sample, a history of panic attacks did not appear to be a relevant predictor. We discuss the explanations for this discrepancy in the two patient samples.

• In any antidepressant study, placebo response in patients assigned active drug is a troubling source of variance. There have been few attempts to identify the patients whose conditions improve as a result of true drug effect, in contrast with improvement that is a result of nonspecific effects. In a previous report we demonstrated that true drug effect seemed to be characterized by a two-week delay in onset and persistence. We described a method of pattern analysis to identify such patients. In this report, we describe the use of pattern analysis to replicate our initial findings. Data from a new sample of 150 nonmelancholic patients support the hypothesis that true drug effect is characterized by a two-week delay in onset and persistence of improvement, once achieved. There was little evidence of the onset of antidepressant effect before two weeks. The theoretical and clinical implications of this work are discussed.

We investigated the antidepressant efficacy of l-deprenyl (selegiline), a selective monoamine oxidase B inhibitor (MAOI), in a six-week open trial of 17 patients with atypical depression. Such patients have previously been shown to benefit from nonselective MAOIs such as phenelzine sulfate. Ten patients (59%) responded to l-deprenyl, but nine required dosages above the 10 to 20 mg/day used in previous investigations. l-Deprenyl was superior to six weeks of placebo administered to diagnostically similar patients in a separate double-blind study. In contrast with previous findings with pheneizine, responders to l-deprenyl differed from nonresponders by having lower baseline anxiety ratings. Even at high dosages, there appeared to be fewer side effects with l-deprenyl than with nonselective MAOIs.

• Data from three six-week placebo-controlled randomized antidepressant trials were pooled to test the hypothesis that a four-week trial is insufficient to reach a determination of drug failure in depressed patients. We compared global clinical ratings at weekly intervals for patients receiving drug and patients receiving placebo and calculated the proportion of patients whose clinical status changed over time. We predicted, and found, that a significant proportion of patients who showed no clear-cut response at four weeks would show much improvement at six weeks in drug but not placebo conditions. Baseline Research Diagnostic Criteria diagnosis, baseline illness severity, and drug dose adjustments after four weeks did not predict either late clinical improvement or relapse between four and six weeks. Additional placebo-controlled studies are needed to replicate our findings concerning the advantage of extending trials to five or six weeks in samples of patients of various depressive subtypes.

• One hundred nineteen patients who met specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 71% with phenelzine, 50% with imipramine, and 28% with placebo. Phenelzine was widely superior to placebo and also showed superiority to imipramine. Phenelzine superiority appeared even greater after an additional six-week continuation phase. Imipramine was only moderately effective in this atypical depressive sample. Unexpectedly, the superiority of either phenelzine or imipramine to placebo was largely confined to patients in subsets of the study sample who were prospectively judged to also have a history of spontaneous panic attacks and/or show hysteroid dysphoric features. This is consonant with some but not other recent findings and requires replication. Overall, the concept of atypical depression as a subtype that is preferentially responsive to monoamine oxidase inhibitors is supported.

• An algorithm for transcribing Research Diagnostic Criteria diagnoses for depressive disorders to similar categories in the DSM-III was applied to 103 depressed outpatients previously diagnosed by Research Diagnostic Criteria. All had Hamilton Depression Rating Scale scores of 18 or less. Among 64 patients completing a six-week, double-blind study comparing desipramine hydrochloride with placebo, desipramine was significantly more effective than placebo in patients with DSM-III major depression but not in those with dysthymic disorder. Among patients with major depression, a significant drug-placebo response difference was demonstrated even in those without melancholia. These findings support the clinical usefulness of the DSM-III in the treatment of depressed outpatients. Independent of DSM-III diagnosis, however, evidence of panic attacks seemed to identify patients who benefited from desipramine therapy. This suggests that the DSM-III hierarchy, which excludes consideration of panic in patients with major depression, may require revision.

Many clinical and theoretic attempts have been made to link anxiety disorders and the beta-adrenergic nervous system. Six patients with panic disorder, who had panic attacks produced by sodium lactate infusions, were given repeated lactate infusions that were immediately preceded by intravenous administration of propranolol hydrochloride. In all cases, propranolol pretreatment infusion failed to prevent panic attacks, anxiety, tachycardia, and increased systolic BP during the lactate infusion.

• One hundred ninety-four nonmelancholic depressed outpatients with features of atypical depression took part in a 6-week randomized trial of imipramine hydrochloride, phenelzine sulfate, and placebo. Their courses of illness were also rated for chronicity. Significantly more patients responded to phenelzine (71%) than to imipramine (48%), which benefited significantly more patients than placebo (26%). Both chronicity and DMS-III diagnosis predicted response on several outcome measures. For example, patients with dysthymic disorder responded better to treatment than did those with major depression, suggesting that dysthymic disorder can be treated with medication. Placebo response correlated inversely with chronicity, regardless of DMS-III diagnosis. Atypical depression and longitudinal course of illness may add to the usefulness of DMS-III depressive diagnosis as a predictor of antidepressant response.

• The efficacy of desipramine for mild depression was tested in a double-blind, placebo-controlled study of outpatients with scores below 19 on the Hamilton Rating Scale for Depression (HAM-D). Of 103 such patients, 23 dropped out and 16 improved during a ten-day placebo period. Among 64 patients completing the randomized portion of the study, significantly more improved with desipramine than with placebo. The Research Diagnostic Criteria (RDC) category of major depressive disorder largely accounted for the drugplacebo response difference found for the entire sample. Patients with intermittent depressive disorder improved significantly less frequently with desipramine than patients with major depressive disorder. Independent of RDC diagnosis, severity of illness correlated with outcome. Thus, patients with pretreatment HAM-D scores at or above the median demonstrated significant drug effect, while patients with lower pretreatment HAM-D scores did not.

• Sixty patients meeting specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 67% with phenelzine, 43% with imipramine, and 29% with placebo. At week 6, phenelzine was superior to placebo on many measures, while the superiority of imipramine to placebo was confined to several variables. Phenelzine was superior to imipramine on the interpersonal sensitivity and paranola factors of the 90-Item Hopkins Symptom Checklist, with trends toward superiority on several other measures, while imipramine was not differentially superior on any measure. Atypical depressive patients with a history of spontaneous panic attacks and hysteroid dysphoric patients both showed extremely low rates of response to placebo and high rates of response to phenelzine. Conversely, those without panic or hysteroid dysphoric features responded equally to all three treatments. Responders to phenelzine also had greater platelet monoamine oxidase inhibition while receiving drug therapy than did nonresponders. Completion of the 120-patient sample will allow more detailed analyses.

• A previous study reported that unipolar depressives excrete significantly lower amounts of urinary tyramine-O-sulfate following oral administration of a tyramine hydrochloride load than do normal control subjects. This study replicates and extends those findings by showing that within the heterogeneous group of unipolar depressives, patients with melancholia and bipolar patients with a history of melancholia manifest a tyramine excretion deficit. A small subgroup of medication-free patients in remission from episodes of melancholia had abnormally low tyramine sulfate excretion levels while they were euthymic, supporting the suggestion that reduced tyramine sulfate excretion following oral tyramine loading is a trait marker for depression. Further study of the role of trace amines in affective illness is warranted. Clinical application is not warranted until further evaluation of the sensitivity, specificity, and reproducibility of this oral tyramine challenge test.