No change in neuropsychological dysfunction or emotional processing during treatment of major depression with cognitive-behaviour therapy or schema therapy.

BACKGROUND: Impaired neuropsychological functioning is a feature of major depression. Previous studies have suggested that at least some aspects of neuropsychological functioning improve with successful treatment of major depression. The extent to which medications may affect the degree of normalization of these functions is unclear. The aim of the current study was to examine the course of neuropsychological functioning during treatment of major depression with cognitive-behaviour therapy (CBT) or schema therapy (ST). METHOD: A total of 69 out-patients with a primary diagnosis of major depression and 58 healthy controls completed mood ratings, neuropsychological measures, and measures of emotional processing at baseline and after 16 weeks. Participants were randomized after baseline assessment to a year-long course of CBT or ST. Patients reassessed at 16 weeks were medication-free throughout the study. RESULTS: Significant neuropsychological impairment was evident at baseline in depressed participants compared with healthy controls. After 16 weeks of psychotherapy, mean depression rating scores fell more than 50%. However, no neuropsychological measures showed convincing evidence of significant improvement and emotional processing did not change. CONCLUSIONS: Persisting impairment in neuropsychological functioning after the first 16 weeks of CBT or ST suggests a need to modify psychological treatments to include components targeting cognitive functioning.

A polymorphism of the GTP-cyclohydrolase I feedback regulator gene alters transcriptional activity and may affect response to SSRI antidepressants.

Tetrahydrobiopterin (BH(4)) is an essential cofactor for synthesis of many neurotransmitters including serotonin. In serotonergic neurons, BH(4) is tightly regulated by GTP-cyclohydrolase I feedback regulator (GFRP). Given the pivotal role of the serotonergic system in mood disorders and selective serotonin reuptake inhibitors (SSRIs) antidepressant function, we tested the hypothesis that GFRP gene (GCHFR) variants would modify response to antidepressants in subjects with major depression. Two single nucleotide polymorphisms (rs7164342 and rs7163862) in the GCHFR promoter were identified and occurred as two haplotypes (GA or TT). A multiple regression analysis revealed that homozygous individuals for the TT haplotype were less likely to respond to the SSRI fluoxetine than to the tricyclic antidepressant nortriptyline (P = 0.037). Moreover, the TT haplotype showed a reduced transcription rate in luciferase reporter gene assays, which may impact on BH(4)-mediated neurotransmitter production, thus suggesting a biological process through which GCHFR promoter variants might influence antidepressant response.

Five-year outcome of cognitive behavioral therapy and exposure with response prevention for bulimia nervosa.

BACKGROUND: Few data exist examining the longer-term outcome of bulimia nervosa (BN) following treatment with cognitive behavioral therapy (CBT) and exposure with response prevention (ERP). METHOD: One hundred and thirty-five women with purging BN received eight sessions of individual CBT and were then randomly assigned to either relaxation training (RELAX) or one of two ERP treatments, pre-binge (B-ERP) or pre-purge cues (P-ERP). Participants were assessed yearly following treatment and follow-up data were recorded. RESULTS: Eighty-one per cent of the total sample attended long-term follow-up. At 5 years, abstinence rates from binging were significantly higher for the two exposure treatments (43% and 54%) than for relaxation (27%), with no difference between the two forms of exposure. Over 5 years, the frequency of purging was lower for the exposure treatments than for relaxation training. Rates of recovery varied according to definition of recovery. Recovery continued to increase to 5 years. At 5 years, 83% no longer met DSM-III-R criteria for BN, 65% received no eating disorder diagnosis, but only 36% had been abstinent from bulimic behaviors for the past year. CONCLUSIONS: This study provides possible evidence of a conditioned inoculation from exposure treatment compared with relaxation training in long-term abstinence from binge eating at 5 years, and the frequency of purging over 5 years, but not for other features of BN. Differences among the groups were not found prior to 5 years. CBT is effective for BN, yet a substantial group remains unwell in the long term. Definition of recovery impacts markedly on recovery rates.

Association of a functional polymorphism in the adrenomedullin gene (ADM) with response to paroxetine.

To identify genes that may be relevant to the molecular action of antidepressants, we investigated transcriptional changes induced by the selective serotonin reuptake inhibitor paroxetine in a serotonergic cell line. We examined gene expression changes after acute treatment with paroxetine and sought to validate microarray results by quantitative PCR (qPCR). Concordant transcriptional changes were confirmed for 14 genes by qPCR and five of these, including the adrenomedullin gene (Adm), either approached or reached statistical significance. Reporter gene assays showed that a SNP (rs11042725) in the upstream flanking region of ADM significantly altered expression. Association analysis demonstrated rs11042725 to be significantly associated with response to paroxetine (odds ratio=0.075, P<0.001) but not with response to either fluoxetine or citalopram. Our results suggest that ADM is involved with the therapeutic efficacy of paroxetine, which may have pharmacogenetic utility.

Personality disorders improve in patients treated for major depression.

OBJECTIVE: To examine the stability of personality disorders and their change in response to the treatment of major depression. METHOD: 149 depressed out-patients taking part in a treatment study were systematically assessed for personality disorders at baseline and after 18 months of treatment using the SCID-II. RESULTS: Personality disorder diagnoses and symptoms demonstrated low-to-moderate stability (overall kappa = 0.41). In general, personality disorder diagnoses and symptoms significantly reduced over the 18 months of treatment. There was a trend for the patients who had a better response to treatment to lose more personality disorder symptoms, but even those who never recovered from their depression over the 18 months of treatment lost, on average, nearly three personality disorder symptoms. CONCLUSION: Personality disorders are neither particularly stable nor treatment resistant. In depressed out-patients, personality disorder symptoms in general improve significantly even in patients whose response to their treatment for depressive symptoms is modest or poor.

Antidepressant treatment is associated with a reduction in suicidal ideation and suicide attempts.

OBJECTIVE: To measure changes in suicidal behaviours during 6 months of treatment with antidepressants. METHOD: A group of depressed patients (n = 195) were assessed for suicidal behaviours in the 6 months prior to treatment. They were prospectively assessed for suicidal behaviours during 6 months of treatment with antidepressants. RESULTS: Patients who made suicide attempts fell from 39 in the 6 months prior to treatment to 20 during treatment. Significant suicidal ideation reduced from 47% at baseline to 14% at 3 weeks remaining below this during the rest of the treatment. Twenty patients had emergent suicidal ideation; five of them had not experienced some level of suicidal behaviour in the 6 months prior to treatment. CONCLUSION: Suicide behaviours are common in depressed out-patients. Antidepressant treatment is associated with a rapid and significant reduction in suicidal behaviours. The rate of emergent suicidal behaviour was low and the risk benefit ratio for antidepressants appears to favour their use.

Predictors of drug response in depression.

Although the major classes of antidepressant drugs have been available for over 30 years, clinicians are still unable to predict accurately the response of their depressed patients to medication. This article reviews both clinical and biologic predictors of treatment response and makes recommendations for future studies. The tricyclic antidepressants remain the drugs of choice in major depressive disorders. Lithium has a place in bipolar depressions. Monoamine oxidase inhibitors have a role in depressions accompanied by marked anxiety and/or panic symptoms, in patients who have previously responded to them, and as a second-choice treatment in those depressed patients who have not responded to tricyclic antidepressants. Electroconvulsive therapy or additional antipsychotic drugs are frequently necessary in very severe and delusional depressions. Biologic predictors of response, despite some interesting leads that may in the long term be of considerable importance, are not yet sufficiently established to be of routine clinical usefulness, although either dexamethasone nonsuppression or a shortened rapid eye movement latency may identify depressed patients who require biologic treatment.

The cross-national epidemiology of panic disorder.

BACKGROUND: Epidemiological data on panic disorder from community studies from 10 countries around the world are presented to determine the consistency of findings across diverse cultures. METHOD: Data from independently conducted community surveys from 10 countries (the United States, Canada, Puerto Rico, France, West Germany, Italy, Lebanon, Taiwan, Korea, and New Zealand), using the Diagnostic Interview Schedule and DSM-III criteria and including over 40,000 subjects, were analyzed with appropriate standardization for age and sex differences among subjects from different countries. RESULTS: The lifetime prevalence rates for panic disorder ranged from 1.4 per 100 in Edmonton, Alberta, to 2.9 per 100 in Florence, Italy, with the exception of that in Taiwan, 0.4 per 100, where rates for most psychiatric disorders are low. Mean age at first onset was usually in early to middle adulthood. The rates were higher in female than male subjects in all countries. Panic disorder was associated with an increased risk of agoraphobia and major depression in all countries. CONCLUSIONS: Panic disorder is relatively consistent, with a few exceptions, in rates and patterns across different countries. It is unclear why the rates of panic and other psychiatric disorders are lower in Taiwan.

Schizophrenia and bipolar affective disorder: perspectives for the development of therapeutics.

Schizophrenia and bipolar disorder remain two of the most severe and difficult to treat psychotic disorders hampered by our poor understanding of their pathologies. The development of typical antipsychotic drugs opened an avenue of investigation through the dopamine D2 receptor in schizophrenia. With the reintroduction of the atypical antipsychotic clozapine came the development of a new generation of atypical agents and hypotheses challenging the centrality of this receptor in explaining antipsychotic effects. Evaluation of these competing theories does not provide sufficient evidence to displace the importance of the dopamine D2 receptor in antipsychotic efficacy, but does raise limitations of it as an explanatory hypothesis. Further, the treatment of other symptom domains in schizophrenia remains relatively neglected and open for the development of novel therapies. Similar to schizophrenia, bipolar disorder presents a diversity of clinical states but unlike schizophrenia, its mainstay of treatment, lithium, has not had a clear receptor target impeding understanding of the disorder's pathology and treatment. This has pushed investigation into other domains emphasising a number of intracellular signalling pathways and glial-neuronal interactions. The heavy genetic loading of bipolar disorder has allowed linkage analyses to identify a number of putative regions, however, the diversity of phenotypes complicates such studies. Polymorphisms of candidate genes have yielded potential leads such as dopamine beta hydroxylase in mood disorder and the serotonin transporter for treatment response. It is anticipated that combiningthe above approaches may hold promise for the development of more effective treatments.

Mood response to methylphenidate and the Dexamethasone Suppression Test as predictors of treatment response to zimelidine and lithium in major depression.

Sixteen patients with a major depressive disorder underwent a Dexamethasone Suppression Test, and 15 of these patients were given intravenous methylphenidate and their mood response recorded. There was no association between the Dexamethasone Suppression Test and mood response to methylphenidate. Neither of these markers predicted clinical antidepressant response with zimelidine, although among zimelidine nonresponders, a clinical improvement upon the addition of lithium was predicted by a positive mood response to methylphenidate.

Total cholesterol and suicidality in depression.

There exists considerable controversy regarding an association between low total cholesterol and increased mortality from suicide. As suicide mortality is a crude marker for suicidal ideation and behavior, we investigated the association between total cholesterol and suicidality in a depressed sample. Ninety men and women meeting structured criteria for a major depressive episode of at least moderate severity participated in a study of predictors of treatment response. A three level variable codified the degree of suicidality in the previous month: no suicidal thoughts (39/90), suicidal ideation or plan (38/90), and a suicide attempt (13/90). There was a significant univariate association between lower cholesterol levels and increasing degrees of suicidality. In a multivariate analysis, this association was the only one that neared statistical significance (p = 0.068). Although it is premature to conclude that these variables are causally associated, data from a number of sources suggest that this association is worthy of further study.

Endocrine and behavioral responses to methylphenidate in normal subjects.

Methylphenidate (0.3 mg/kg) was administered intravenously to 20 normal subjects. Behavioral responses varied considerably among individuals. Both cortisol and growth hormone showed significant increases (p less than 0.001). The adrenocorticotrophic hormone (ACTH) response seemed insufficient to explain the increase in cortisol. For men only, the increase in cortisol correlated positively with the increase in epinephrine (r = 0.77, p less than 0.05) and correlated negatively with baseline cortisol (r = -0.70, p less than 0.05), with increase in growth hormone (r = -0.70, p less than 0.05), and with the increase in "energy" (r = -0.83, p less than 0.01). The growth hormone response varied between the sexes, and for men, the growth hormone correlated with both an increase in "energy" (r = 0.70, p less than 0.05) and "friendliness" (r = 0.68, p less than 0.05). For all subjects, baseline heart rate correlated with the increase in "energy" (r = -0.69, p less than 0.002). In a separate study, six male subjects received, on different occasions, saline and a lower dose of methylphenidate. Together, these studies show that the increases in cortisol, growth hormone, and epinephrine, and the decrease in prolactin are dose-dependent.

Elevated levels of acute phase plasma proteins in major depression.

Levels of acute phase and other plasma proteins were measured in 21 men with major depression, 28 men with alcohol dependence, and 12 men who acted as controls. The depressed men had significantly elevated levels of the acute phase proteins, haptoglobin and alpha-1-antichymotrypsin, and of immunoglobulin G. The elevations in haptoglobin and alpha-1-antichymotrypsin were highly correlated with each other, and were correlated with the severity of depression and negatively correlated with the thyroid stimulating hormone response to thyrotropin. The alcoholic men had elevated haptoglobin levels, but significantly decreased levels of immunoglobulin G. These findings provide further evidence for an inflammatory response during depression.

Temperament and hypercortisolemia in depression.

OBJECTIVE: The authors examined the relationships among depression severity, melancholia, and cortisol level and the relationship between temperament, as measured with the Tridimensional Personality Questionnaire, and cortisol level. METHOD: Morning and afternoon cortisol levels of 40 healthy comparison subjects and 96 patients with major depression were measured. The depressed patients were rated for depression severity and melancholia, and they completed the Tridimensional Personality Questionnaire. RESULTS: Temperament, especially dependence and extravagance, but not depressive symptoms, was the major determinant of the hypercortisolemia observed in the depressed patients. CONCLUSIONS: For research in biological psychiatry to advance, more attention needs to be paid to the individual differences in biology that underlie any state-dependent biologic dysfunction.

Relationship between dissociation, childhood sexual abuse, childhood physical abuse, and mental illness in a general population sample.

OBJECTIVE: The aim of this study was to examine the relationship between childhood sexual abuse, childhood physical abuse, current psychiatric illness, and measures of dissociation in an adult population. METHOD: The authors used a randomly selected sample of 1,028 individuals. Each subject completed a semistructured face-to-face interview that included measures of childhood sexual abuse, childhood physical abuse, DSM-III-R psychiatric diagnoses, and selected items from the Dissociative Experiences Scale. RESULTS: Many individuals experienced occasional dissociative symptoms, and 6.3% of the population suffered from three or more frequently occurring dissociative symptoms. Among these individuals, the rate of childhood sexual abuse was two and one-half times as high, the rate of physical abuse was five times as high, and the rate of current psychiatric disorder was four times as high as the respective rates for the other subjects. Logistic regression modeling showed that physical abuse and current psychiatric illness were directly related to a high rate of dissociative symptoms but sexual abuse was not. The influence of sexual abuse was due to its associations with current psychiatric illness and with childhood physical abuse. Childhood physical abuse was not directly related to current psychiatric illness. Its association appeared to be mediated by its link to childhood sexual abuse. CONCLUSIONS: This study confirms that a small proportion (approximately 6%) of the general population suffer from high levels of dissociative symptoms. It calls into question the hypothesized direct relationship between childhood sexual abuse and adult dissociative symptoms.

No association between novelty seeking and the type 4 dopamine receptor gene (DRD4) in two New Zealand samples.

OBJECTIVE: In 1986 and 1987, Cloninger postulated the existence of the heritable behavioral trait of novelty seeking and its putative underpinnings in the dopaminergic systems of the ventral midbrain. Two widely reported studies found significant associations between novelty seeking and the type 4 dopamine receptor gene (DRD4), although a more recent study did not. The authors' objective was to investigate this association in two New Zealand samples. METHOD: The authors studied two nonoverlapping samples: subjects in a depression treatment trial (N = 86) and subjects from 14 pedigrees dense with alcoholism (N = 181). DRD4 genotyping was based on a standard protocol. RESULTS: Novelty seeking and DRD4 were not statistically associated. CONCLUSIONS: In these samples, there was no suggestion that the DRD4 polymorphism contributed to individual differences in the behavioral trait of novelty seeking.

Prevalence and comorbidity of mental disorders in persons making serious suicide attempts: a case-control study.

OBJECTIVE: The aim of this study was to compare the prevalence and comorbidity patterns of psychiatric disorders in subjects making medically serious suicide attempts and in comparison subjects. METHOD: The association between mental disorders and the risk of a suicide attempt was examined in 302 consecutive individuals who made serious suicide attempts and 1,028 randomly selected comparison subjects. Each subject completed a semistructured interview, and a significant other underwent a parallel interview; best-estimate DSM-III-R diagnoses were then generated. RESULTS: Of those who made serious suicide attempts, 90.1% had a mental disorder at the time of the attempt. Multiple logistic regression showed that those who made suicide attempts had high rates of mood disorders (odds ratio = 33.4, 95% confidence interval = 21.9-1.2); substance use disorders (odds ratio = 2.6, 95% confidence interval = 1.6-4.3); conduct disorder or antisocial personality disorder (odds ratio = 3.7, 95% confidence interval = 2.1-6.5); and nonaffective psychosis (odds ratio = 16.8, 95% confidence interval = 2.7-105.8). The relationship between psychiatric morbidity and suicide risk varied with age and gender. The incidence of comorbidity was high: 56.6% of those who made serious suicide attempts had two or more disorders. The risk of a suicide attempt increased with increasing psychiatric morbidity: subjects with two or more disorders had odds of serious suicide attempts that were 89.7 times the odds of those with no psychiatric disorder. CONCLUSIONS: Individuals who made serious suicide attempts had high rates of mental disorders and of comorbid disorders. Subjects with high levels of psychiatric comorbidity had markedly high risks of serious suicide attempts.

Doxepin plasma concentrations in clinical practice. Could there be a pharmacokinetic explanation for low concentrations?

During therapeutic use of doxepin, we have often observed unexpectedly low doxepin plasma concentrations in patients on moderate dosages, e.g. 100 to 200mg daily. While non-compliance seemed the most likely explanation, we present the data for 6 patients in whom we considered non-compliance unlikely. The data can be explained by hypothesizing that in some patients, there is not a linear dosage-plasma concentration relationship and that on a steady dosage, plasma concentrations are not always maintained. If these phenomena can be more carefully documented they may assume clinical importance; indeed for 2 of the patients studied the falling plasma concentrations on a steady dosage were associated with a recurrence of depression.

Reduction in basal afternoon plasma ACTH during early treatment of depression with fluoxetine.

RATIONALE: Subjects with depression may exhibit activation of the hypothalamic-pituitary-adrenal (HPA) axis, but little is known about the response of basal hormone levels to antidepressant therapy. OBJECTIVES: To determine whether treatment of depression with standard antidepressant medications resulted in reductions in basal activity of afternoon cortisol, ACTH and AVP. A secondary aim was to examine whether there was any difference in hormonal response between an SSRI (fluoxetine) and a tricyclic antidepressant (nortriptyline). METHODS: Forty-three subjects with a DSM-IV diagnosis of depression (Hamilton score 18.9+/-0.6 at baseline) had five basal venous blood samples drawn at 15-min intervals between 1400 and 1500 hours for cortisol, ACTH and AVP, before and 6 weeks after randomisation to treatment with fluoxetine (n=27) or nortriptyline (n=16). RESULTS: Both medications resulted in a similar improvement in depression as determined by Hamilton score. In the group as a whole, ACTH levels showed a significant decrease over the 6 weeks (4.1+/-0.4 pmol/l at baseline versus 3.3+/-0.3 at 6 weeks, P<0.05), while cortisol and AVP levels were unchanged. Further analysis revealed that the fall in plasma ACTH occurred predominantly in the subgroup treated with fluoxetine (drug x time interaction by ANOVA, P=0.035). There was a significant relationship between cortisol and ACTH at baseline (r=0.48, P=0.002), that weakened considerably after treatment (r=0.22, P=0.16). The subgroup with baseline hypercortisolemia [mean cortisol >276 nmol/l (10 microg/dl), n=18] demonstrated a reduction in both cortisol and ACTH following treatment, but also showed a loss of the relationship between the two. CONCLUSIONS: It is postulated that the initial recovery of the HPA axis during the treatment of depression with fluoxetine is mediated via restoration of glucocorticoid negative feedback on ACTH levels.

The prognostic significance of thyroid function in mania.

Free thyroxine index (FT4I) and thyroxine (T4) levels were measured in 31 manic patients shortly after admission to a psychiatric hospital. Over one-third had elevated thyroid hormone levels, and this was largely due to increases in FT4I. Increased FT4I levels were associated with greater sleep disturbance and with being male, and were negatively associated with having had hospital admissions in the past six months. More interestingly, however, low FT4I levels prospectively predicted more hospital admissions in the 12 months from index admission, and this was not due to past admissions predicting future admissions. This adds to the growing literature on important relationships between thyroid hormones and treatment outcome in patients with affective disorders.