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.

Canterbury Health, Ageing and Life Course (CHALICE) study: rationale, design and methodology.

AIMS: New Zealand's ageing population threatens the financial sustainability of our current model of health service delivery. The Canterbury Health, Ageing and Life Course (CHALICE) study aims to develop a comprehensive and flexible database of important determinants of health to inform new models. This paper describes the design, methodology, and first 300 participants of CHALICE. METHODS: Commencing August 2010, CHALICE is a multidisciplinary prospective random cohort study and biobank of 1,000 Canterbury adults aged 49-51 years at inception, stratified by self-identified Maori (n=200) and non-Maori (n=800) ethnicity. Assessment covers sociodemographic, physical, cognition, mental health, clinical history, family and social, cardiovascular, and lifestyle domains. Detailed follow-up assessment occurs every 5 years, with a brief postal follow-up assessment undertaken annually. RESULTS: For the first 300 participants (44 Maori, 256 non-Maori), the participation rate is 63.7%. Overall, 53.3% of participants are female, 75.3% are living in married or de facto relationships, and 19.0% have university degrees. These sociodemographic profiles are comparable with the 2006 Census, Canterbury region, 50-54 years age group percentages (50.7%, 77.2%, and 14.3%, respectively). CONCLUSIONS: CHALICE has been designed to provide quality data that will inform policy development and programme implementation across a broad spectrum of health indicators.

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.

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.

Measures of temperament and character are differentially impacted on by depression severity.

BACKGROUND: Cloninger's Temperament and Character Inventory (TCI) is a widely used measure of personality. Two scales of the TCI, harm avoidance (HA) and self directedness (SD), have been shown to be influenced by depressed mood. We examined how the seven TCI scales and their subscales are correlated with depression severity before and after treatment. We also examined whether changes in personality measures could be attributed to changes in depression severity. METHODS: Two clinical samples of depressed out-patients were recruited for trials to examine predictors of treatment response to antidepressants (N=195) and psychotherapies (N=177). Assessment included the Montgomery-Asberg depression rating scales (MADRS), Hopkins Symptom Checklist (SCL-90) and TCI at baseline and after treatment. RESULTS: After treatment, in both samples, depression severity correlated significantly with HA and negatively with SD. Multiple regression analysis revealed that changes in SD and HA over treatment were related to improvement in depression. In the psychotherapy trial baseline MADRS scores correlated with low SD and high HA. LIMITATIONS: The trial results are applicable to mild-moderately depressed out-patients. CONCLUSIONS: Depression severity influences the total scales and most of the subscale measures of HA and SD. Some personality traits, as measured by the TCI, were not impacted upon by mood. Clinically mood should be taken into account when assessing personality measures of negative affect using the TCI.

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.

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.

Proteomic analysis of rat hippocampus exposed to the antidepressant paroxetine.

Antidepressant drugs can exert significant effects on the mood of a patient suffering major depression and other disorders. These drugs generally have pharmacological actions on the uptake or metabolism of the neurotransmitters serotonin, noradrenaline and, to a lesser extent, dopamine. However, there are many aspects of antidepressant action we do not understand. We have applied proteomic analysis in a rat hippocampal model in an attempt to identify relevant molecules that operate in pathways functionally relevant to antidepressant action. Rats were administered either 5 mg/kg daily of the antidepressant paroxetine or vehicle for 12 days, then hippocampal protein was recovered and resolved by 2-D gel electrophoresis. After antidepressant exposure, we observed increased expression or modification of cytochrome c oxidase, subunit Va, cyclin-dependent kinase inhibitor 2A interacting protein, dynein, axonemal, heavy polypeptide 3 and RHO GDP-dissociation inhibitor alpha. Decreased expression or modification was observed for complexin 1 (CPLX1), alpha-synuclein, parvalbumin, ribosomal protein large P2, prohibitin, nerve growth factor, beta subunit (NGFB), peroxiredoxin 6 (PRDX6), 1-acylglycerol-3-phosphate O-acyltransferase 2_predicted, cystatin B (CYTB) and lysosomal membrane glycoprotein 1. CPLX1, the most strongly regulated protein observed, mediates the fusion of cellular transport vesicles with their target membranes and has been implicated in the pathophysiology of mood disorders, as well as antidepressant action. CPLX1 and the other proteins identified may represent links into molecular processes of importance to mood dysregulation and control, and their respective genes may represent novel candidates for studies of antidepressant pharmacogenetics.

Upstream genetic variant near INSIG2, influences response to carnitine supplementation in bipolar patients with valproate-induced weight gain.

BACKGROUND: The protein product of INSIG2 is involved in cholesterol and triglyceride metabolism and homeostasis. Variation at rs7566605 near the gene INSIG2 has been associated with increased BMI. OBJECTIVE: To evaluate the effect of rs7566605/INSIG2 genotype on the ability of valproate-treated bipolar patients (BMI ≥ 25 kg/m2) to lose weight using carnitine supplementation during a 26-week lifestyle intervention study. DESIGN: Forty-eight bipolar patients with clinically significant treatment emergent weight gain were genotyped at the rs7566605 SNP. Participants were randomised to l-carnitine (15 mg/kg/day) or placebo for 26 weeks in conjunction with a moderately energy restricted, low-fat diet. Weight and body fat percent were measured fortnightly. Waist circumference measurements and dual-energy X-ray absorptiometry were used to assess changes in body composition. Obesity-related biomarkers were measured at baseline and 26 weeks. RESULTS: There was a significant interaction between rs7566605/INSIG2 genetic status and treatment with carnitine or placebo. Carnitine had no significant effect on body composition measures in G allele homozygous patients who lost between 0.97 and 2.23 kg of fat. However C allele carriers on average gained 2.28 kg when given a placebo. Carnitine supplementation in this group enabled average weight loss of 2.22 kg of fat (p = 0.01). Approximately half of this mass was in the vital truncal compartment (p = 0.002). Bioinformatic analysis detected that the SNP lies in a highly conserved 336 bp sequence which potentially affects INSIG2 gene expression. CONCLUSIONS: C-carriers at rs7566605, possibly regulating the homeostasis gene INSIG2, lost significantly less weight in this lifestyle intervention study. This effect was reversed by carnitine supplementation.

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.

Thyroid indices and treatment outcome in bulimia nervosa.

OBJECTIVE: This study examined the thyroxine (T4) and free T4 (FT4) status of women with bulimia nervosa and its value as a predictor of outcome. METHOD: A total of 135 women with bulimia nervosa underwent 12-weeks cognitive behavioral therapy treatment. Prior to and at 3-year follow-up patients completed psychiatric assessments and serumT4 and FT4 were measured. RESULTS: At 3-year follow-up, 71% had no eating disorder and 29% met criteria for any eating disorder diagnosis. Mean T4 and FT4 concentrations were within normal ranges. Pre-treatment T4 and FT4 concentrations were inversely associated with food restriction and purging frequency, respectively. Compared with women with no eating disorder, those with any eating disorder at follow-up had lower pretreatment T4 concentrations. When pre-treatment food restriction, oral contraceptive use and binge frequency where controlled for, low T4 concentration was the only predictor of eating disorder diagnosis at follow-up. CONCLUSION: Low T4 concentrations at pretreatment may be a predictor of poor outcome in bulimia nervosa.

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.

Brain function and personality in normal males: a SPECT study using statistical parametric mapping.

Understanding the differences between individuals' personality types at a functional brain level is now possible due to recent developments in both functional brain imaging and personality models. The psychobiological model for temperament and character offers one approach to exploring personality. This study uses SPECT imaging to investigate brain function in relationship to the personality traits in the Temperament and Character Index. A general linear model approach was implemented at a voxel-by-voxel level, using quartile groupings for the personality predictors. t contrasts were used to investigate significant clusters of activation or deactivation. The results show a number of significant relationships between personality traits and regional cerebral blood flow, which show distinct nonlinear trends. All seven of the Cloninger personality traits were significantly related to regional cerebral blood flow. The results suggest that differences in brain function in some regions may reflect differences in personality traits.

A differential response to nortriptyline and fluoxetine in melancholic depression: the importance of age and gender.

OBJECTIVE: To consider the impact of age and gender on the antidepressant response to nortriptyline and fluoxetine in melancholic depression. METHOD: Of 191 depressed patients, 113 met study criteria for melancholia. All patients were randomized to receive either fluoxetine or nortriptyline. Response rates, defined as an improvement of 60% or more on the Montgomery Asberg Depression Rating Scale over 6 weeks of antidepressant treatment on an intention to treat basis, were examined by age, and by age and gender. RESULTS: Melancholic depressed patients 40 years or older, especially men, had a markedly superior response to nortriptyline compared with fluoxetine. Conversely, melancholic depressed patients, age 18-24 years, especially women, had a markedly superior response to fluoxetine. CONCLUSION: Age and gender appear to be critical variables in understanding differential antidepressant responses to tricyclic antidepressants and selective serotonin reuptake inhibitors in melancholic depression.

A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression.

The multi-drug resistance gene ABCB1 (or MDR1) encodes a P-glycoprotein (P-gp) that regulates passage of many substances across the blood-brain barrier. The antidepressant amitriptyline and its metabolites (including nortriptyline) are substrates for P-gp, and in mice lacking P-gp, penetration of amitriptyline, but not fluoxetine, into the brain is enhanced. We reasoned that polymorphic variation of P-gp may contribute to differing responses of patients to antidepressant drugs. A single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) was recently correlated with expression levels and in vivo function of P-gp. We examined this SNP in patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine, and observed a significant association between nortriptyline-induced postural hypotension and 3435C>T (chi(2) = 6.78, df = 2, P = 0.034). Our results suggest that homozygosity for 3435T alleles of ABCB1 is a risk factor for occurrence of nortriptyline-induced postural hypotension (OR = 1.37, P = 0.042, 95% CI 1.01-1.86).

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 contribution of temperament, childhood neglect, and abuse to the development of personality dysfunction: a comparison of three models.

We examined the contribution of temperament, childhood neglect, and abuse to the development of personality dysfunction as postulated in three different but correlated models of personality: the psychobiological, Vaillant's psychoanalytic, and DSM psychopathology models. Character, defense style, and personality disorder symptomatology (the dependent variables), and temperament, childhood neglect, and abuse (the independent variables) were assessed in 168 depressed outpatients. High harm avoidance (temperament) tended to be the strongest and most consistent risk factor across the three models. Deficient parental care predicted personality dysfunction, however low care was not consistently predictive across all three models. Emotional/psychological abuse and actual physical abuse were risk factors for increasing personality disorder symptomatology only. Childhood sexual abuse was not as predictive of personality dysfunction as might be expected, thereby raising questions as to the importance placed on child sexual abuse as a general risk factor for personality psychopathology.