Neurological, Metabolic, and Psychopathological Correlates of Lifetime Suicidal Behaviour in Major Depressive Disorder without Current Suicide Ideation.

INTRODUCTION: Suicidal behaviour (SB) has a complex aetiology. Although suicidal ideation (SI) is considered the most important risk factor for future attempts, many people who engage in SB do not report it. METHODS: We investigated neurological, metabolic, and psychopathological correlates of lifetime SB in two independent groups of patients with major depression (sample 1: n = 230; age: 18-65 years; sample 2: n = 258; age >60 years) who did not report SI during an index episode. RESULTS: Among adults (sample 1), SB was reported by 141 subjects (58.7%) and severe SB by 33 (15%). After controlling for interactions, four risk factors for SB emerged: male gender (OR 2.55; 95% CI: 1.06-6.12), negative self-perception (OR 1.76; 95% CI: 1.08-2.87), subthreshold hypomania (OR 4.50; 95% CI: 1.57-12.85), and sexual abuse (OR 3.09; 95% CI: 1.28-7.48). The presence of at least two of these factors had the best accuracy in predicting SB: sensitivity = 57.6% (39.2-74.5); specificity = 75.1% (68.5-82.0); PPV = 27.9% (20.9-37.2); NPV = 91.4% (87.6-94.1). In older patients (sample 2), 23 subjects (9%) reported previous suicide attempts, which were characterized by earlier onset (25 years: OR 0.95: 0.92-0.98), impaired verbal performance (verbal fluency: OR 0.95: 0.89-0.99), higher HDL cholesterol levels (OR 1.04: 1.00-1.07) and more dyskinesias (OR 2.86: 1.22-6.70). CONCLUSION: Our findings suggest that SB is common in major depressive disorder, even when SI is not reported. In these individuals it is feasible and recommended to investigate both psychiatric and organic risk factors. The predictive power of models excluding SI is comparable to that of models including SI.

Suicide ideation and male-female differences in major depressive disorder.

OBJECTIVE: This study aimed to explore male-female differences in suicide ideation (SI) and suicide risk factors in major depressive disorder (MDD). METHODS: We analysed 482 adults (sample 1) and 438 elderly outpatients (sample 2) with MDD. Sample 1 was treated with different antidepressant combinations (escitalopram; bupropion plus escitalopram; venlafaxine plus mirtazapine) and assessed by means of the Concise Health Risk Tracking (SI), Quick Inventory of Depressive Symptomatology, Altman Mania Rating Scale and Psychiatric Diagnostic Screening Questionnaire. Sample 2 was treated with venlafaxine and assessed using the Hamilton scale for depression, Anxiety Sensitivity Index and Penn State Worry Questionnaire for anxiety, Beck Scale for Suicide Ideation and Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: In sample 1, females had greater depression severity (O.R 0.961 99%CI: 0.929 - 0.995), males reported more alcohol abuse (O.R 1.299 99%CI: 1.118 - 1.509) and active SI (O.R 1.109 99%CI: 1.005 - 1.255). In sample 2 men showed more severe SI (O.R 1.067; 99%CI: 1.014 - 1.122) and weight loss (OR = 5.89 99%CI: 1.01 - 34.19), women more gastrointestinal symptoms. CONCLUSIONS: In these selected samples, although women had more severe depression, men had more suicide risk factors. Such differences might contribute to men's increased suicide risk.

In major depressive disorder sex differences affect the clinical expression of depressive episodes. In comparison to men, women endorse higher levels of overall depression in adult MDD and more somatic anxiety and gastrointestinal symptoms in late-life MDD.After controlling for confounding variables, males have more severe SI and a larger number of suicide risk factors (eg. alcohol abuse; weight loss). The association between male sex and SI is detectable in both adults and elderly patients with MDD.Further studies are necessary to elucidate how sex differences in suicide ideation and suicide risk factors are related to men's increased suicide risk.

Irritable Mood and Subthreshold Hypomanic Episodes Correlate with More Severe Major Depression.

INTRODUCTION: Irritable mood (IM) and subthreshold hypomanic symptoms are reported in half and two-fifths of major depressed subjects respectively, but their clinical and prognostic meanings remain unclear. The aim of this study was to test the clinical usefulness of 2 specifiers in DSM-IV major depressive disorder (MDD): IM occurring during an index episode (IM+) and lifetime episodes of elated mood or IM with at least 2 concurrent hypomanic symptoms (subthreshold hypomanic episodes [SHEs]). METHOD: We included 482 outpatients with MDD participating in the Combining Medications to Enhance Depression Outcome study (mean age 43.14 ± 12.46 years, 144 males - 30%). The main aim of the original study was to test whether 2 different medications when given in combination as the first treatment step, compared to 1 medication, would improve antidepressant response. RESULTS: IM + subjects (N = 349; 70%) were younger and more often females, with a more severe depression, a more marked social impairment, and more psychiatric comorbidities. The IM + group was also characterized by higher levels of suicidal ideation and more cases of emotional abuse. The combination of IM+ and SHEs was associated with an even more severe clinical picture. Limitations include the post hoc method, incomplete assessment of bipolar validators (e.g., family history of bipolar illness), personality disorders and suicide attempts. CONCLUSIONS: The presence of IM and SHEs in MDD correlate with an overall more severe clinical condition.

Persistent benefits of slow titration of paroxetine in a six-month follow-up.

OBJECTIVE: Paroxetine titration may be difficult in older individuals as they are more sensitive to side effects. The current study extends to 6 months our previously published report in which paroxetine was started at 2.5 mg/day and slowly increased by 2.5 mg on alternate days (slow titration) or rapidly titrated to target dose from 10 mg/day (standard titration) in a naturalistic setting. METHODS: Here, the follow-up period was extended to 26 weeks. We performed an intent-to-treat analysis of 47 subjects from the original sample (major depressive disorder and/or generalized anxiety disorder (GAD); >60 years of age). Missing evaluations were replaced by last observations carried forward. GAD was included as a stratification factor. RESULTS: Patients in whom paroxetine was slowly up-titrated were more likely to remit (84.0% vs 54.5%; p = 0.028) and had lower core depression (p = 0.0015) and psychic anxiety levels (p = 0.006) after 26 weeks. Dropout rate was 20% in the slow titration group compared with 77.3% in the standard titration arm (p < 0.001). Patients with GAD accounted for all significant associations. No substantial differences were reported between slow and standard titration groups in the subsample without GAD. CONCLUSIONS: Despite some limitations, these findings suggest that paroxetine treatment should be started at lower doses in older depressed patients and slowly up-titrated. This strategy would allow to increase antidepressant response and the likelihood of completing treatment cycle in patients with high anxiety levels and GAD comorbidity.

Benefit of slow titration of paroxetine to treat depression in the elderly.

OBJECTIVE: Paroxetine is commonly used to treat depression in the elderly; however, titration issues have been raised. Rapid titration may lead to increased anxiety and early dropout. The aim of this cost-utility analysis was to compare the potential benefit of standard (10 mg the first day) versus slow titration (2.5 mg gradually increased). METHODS: Clinical analysis was based on a naturalistic trial integrated with a decision-analytic model representing second treatments for those who initially did not respond and for dropout cases. Treatment setting was a public outpatient center for mental disorders in Italy. Service use data were estimated from best practice guidelines, whereas costs (Euros; 2012) were retrieved from Italian official sources. RESULTS: Slow titration approach produced 0.031 more quality-adjusted life years (remission rate: 57% vs 44% in standard titration group) at an incremental cost of €5.53 (generic paroxetine) and €54.54 (brand paroxetine syrup). Incremental cost-effectiveness ratio (ICER) values were €159 and €1768, respectively, in favor of slow titration approach. Cost-effectiveness threshold, defined as ICER < 1 GDP per capita according to World Health Organization criteria, is about €25 000 in Italy. CONCLUSIONS: Our results are consistent with a superiority of slow titration of paroxetine in older depressed patients. However, these findings, in part based on simulated data, need to be replicated in clinical trials.

Antidepressant emergent mood switch in major depressive disorder: onset, clinical correlates and impact on suicidality.

Antidepressant (AD)- emergent mood switch (AEMS) is a common complication of bipolar depression. This study aimed to investigate the prevalence and clinical correlates of subthreshold AEMS (i.e. not fulfilling DSM criteria for hypomanic episodes) in major depressive disorder (MDD) and, prognostically, its impact on AD treatment outcome and suicidality. The study involved 425 outpatients with MDD followed during the acute phase (12 weeks) and continuation (weeks 13-28) AD treatment. AEMS was assessed through the Altman Self-Rating Mania scale (ASRM ≥ 6). Several clinical features differentiated individuals with or without subthreshold AEMS (n = 204 vs. 221): negative self-perception [odds ratio (OR) 1.017-1.565]; panic disorder (OR 1.000-1.091); subthreshold hypomanic episodes (OR 1.466-13.352); childhood emotional abuse (OR 1.053-2.447); lifetime suicidal behaviour (OR 1.027-1.236); AD-related remission (χ 2  = 22.903 P  < 0.0001) and suicide ideation (χ 2  = 16.701 P  < 0.0001). In AEMS earlier onset showed a strong correlation with bipolar spectrum disorder (overall score: P  = 0.0053; mixed depression: P  = 0.0154; subthreshold hypomania: P  = 0.0150) whereas late-onset was associated with more severe suicidal behaviour ( P  < 0.001). In conclusion, our results demonstrate that subthreshold mood switches occur frequently in unipolar depression during acute AD treatment as well as in continuation phase. Time of switch onset seems to have the greatest diagnostic and prognostic value.

Clinical correlates and prognostic implications of severe suicidal ideation in major depressive disorder.

Suicidal ideation (SI) is a risk factor for suicidal behaviour. To ascertain the clinical correlates and prognostic impact of severe SI, we analysed 249 outpatients with major depressive disorder (MDD) and suicidal thoughts included in the COmbining Medications to Enhance Depression outcome (CO-MED) trial. Patients with severe SI (36%) were younger at disease onset ( P = 0.0033), more severely depressed ( P = 0.0029), had more lifetime suicidal behaviour ( P < 0.0001) and psychiatric comorbidities (panic disorder: P = 0.0025; post-traumatic stress disorder: P = 0.0216), and a history of childhood maltreatment (neglect: P = 0.0054; emotional abuse: P = 0.0230; physical abuse: P = 0.0076; sexual abuse: P = 0.0016) than those experiencing low-moderate SI. After controlling for depression score, severe SI was positively correlated with lifetime suicidal behaviour (OR [95% CI]: 1.26 [1.12-1.41]), panic disorder (1.05 [1.00-1.12]), and childhood maltreatment (neglect: 1.93 [1.13-3.30]; physical abuse: 2.00 [1.11-3.69]; sexual abuse: 2.13 [1.17-3.88]), and inversely correlated with age of onset (0.97 [0.95-0.99]) and sleep-onset insomnia (0.76 [0.61-0.96]). Finally, the occurrence of serious lifetime suicidal behaviour was predicted by SI severity (2.18 [1.11-4.27]), bipolar score (1.36 [1.02-1.81]), and childhood sexual abuse (2.35 [1.09-5.05]). These results emphasise the importance of assessing childhood maltreatment and bipolar liability in MDD to estimate suicidal behaviour risk.

Age or age of onset: which is the best criterion to classify late-life depression?

In late-life depression (LLD), several differences between patients whose first episode is reported after age 65 (late-onset depression, LOD) and those with early-onset depression (EOD) might reflect the effects of brain ageing. To test this hypothesis, we analysed the impact of current age and age at illness onset on a number of clinical and cognitive manifestations in 438 outpatients with major depressive disorder aged >60 years, treated with venlafaxine for 12 weeks. When compared to the EOD group, patients with LOD were older ( P < 0.00001) and associated with lower depression severity ( P = 0.0029), lower global cognitive functioning [Mini-Mental State Examination (MMSE): P = 0.0001; Repeatable Battery for the Assessment of Neuropsychological Status: immediate memory, P = 0.0009, and delayed memory, P < 0.00001; Delis-Kaplan Executive Function System measuring executive functions: Trail-Making Test (TMT) - P = 0.0004 and Colour-Word Interference Test, Inhibition - P = 0.0063], and more dyskinesias (Abnormal Involuntary Movement Scale: P = 0.0006). After controlling for its interactions with age of onset, current age was inversely correlated with Montgomery Åsberg Depression Rating Scale scores at baseline ( P < 0.00001) and week 12 ( P = 0.0066), MMSE ( P < 0.00001), delayed memory ( P < 0.00001), and TMT ( P = 0.0021). Age of onset predicted impairment in immediate ( P = 0.023) and delayed memory ( P = 0.0181), and dyskinesias ( P = 0.0006). Although most features of LLD are related to ageing rather than to late-onset, LOD is a possible separate diagnostic entity characterised by memory dysfunction and increased liability to movement disorders.

Persistence of suicidal ideation within acute phase treatment of major depressive disorder: analysis of clinical predictors.

Suicidal ideation (SI) is common in major depressive disorder (MDD), and it is a risk factor for suicidal behaviour. Antidepressants are effective in reducing SI, but in some subjects, SI may persist for weeks. This study aimed to disentangle the contribution of baseline clinical characteristics in SI nonremission at week 6. Research involved 198 outpatients with MDD and SI collected within the Combining Medications to Enhance Depression Outcomes trial and treated with different antidepressant combinations. Although SI decreased from baseline to week 6 ( P < 0.0001), 78 patients (39%) failed to achieve SI remission. Insomnia [OR, 0.72; 95% confidence interval (CI), 0.52-0.99], reduced need for sleep (OR, 0.75; 95% CI, 0.58-0.99), self-confidence (OR, 0.52; 95% CI, 0.32-0.82), cheerfulness (OR, 0.57; 95% CI, 0.33-0.98), and comorbid panic disorder (OR, 0.93; 95% CI, 0.87-0.99) at baseline were associated with lack of SI remission after controlling for baseline depression and SI scores. The combination of baseline SI and insomnia was moderately effective in predicting the lack of SI remission, with a specificity of 80% (95% CI, 72-87%) and an NPV of 68% (95% CI, 63-72%). In individuals with MDD and SI, the presence of insomnia and bipolar features should prompt a search for more effective treatment solutions in order to favour SI remission and prevent suicidal behaviour.

Post-traumatic stress disorder and childhood emotional abuse are markers of subthreshold bipolarity and worse treatment outcome in major depressive disorder.

Post-traumatic stress disorder (PTSD) and childhood maltreatment (CMT: parental neglect; emotional, physical and sexual abuse) have been linked to bipolar disorder but they are also common in major depressive disorder (MDD). Our objective was to investigate their association with the bipolar spectrum and antidepressant treatment outcome in 482 outpatients with DSM-IV MDD treated in the Combining Medications to Enhance Depression Outcomes trial for 28 weeks Bipolar spectrum score included age of onset <21 years, subthreshold hypomania (a period of elated or irritable mood with at least two concurrent hypomanic symptoms, which did not fulfill DSM criteria for hypomanic/manic episode) and depressive mixed state (DMX). PTSD subjects (n = 107; 22%) had more severe depression (P < 0.0001), work and social impairment (P = 0.0031), comorbid anxiety disorders (P < 0.0001) and increased suicidality (P = 0.0003). Bipolar spectrum score was higher with PTSD comorbidity (P = 0.0063) and childhood emotional abuse (P = 0.0001). PTSD comorbidity was associated with residual suicidality (P = 0.0218) after 6 weeks of antidepressant use whereas childhood emotional abuse [odds ratio (OR), 1.01-2.22], subthreshold hypomania (OR, 1.04-4.09) and DMX (OR, 1.00-4.19) were predictors of mood switch. These results corroborate the role of PTSD and childhood emotional abuse as markers of bipolar spectrum and prognostic factors during antidepressant treatment.

Obsessive-compulsive symptoms in major depressive disorder correlate with clinical severity and mixed features.

Obsessive-compulsive symptoms (OCS) are often reported in patients with bipolar disorder. The aim of this study was to investigate OCS and their related clinical features in major depressive disorder (MDD). The analysis involved 482 outpatients with MDD collected within the Combining Medications to Enhance Depression outcomes trial, who were assessed with scales for depression, suicidality, irritability, hypomanic symptomatology, and other comorbid psychiatric manifestations. OCS were reported in 27% of the sample. Patients with MDD experiencing OCS were found to differ from those not experiencing OCS by a greater severity of depression (d = 0.41, P = 0.0001), more hypomanic symptoms (d = 0.48, P < 0.0001) and mixed features (22% vs. 10%, P = 0.001), increased levels of suicidal thoughts (d = 0.40, P = 0.0001), a lower likelihood of achieving remission after antidepressant treatment (19% vs. 33%, P = 0.0109), as well as more comorbid anxiety disorders (i.e. panic disorder: d = 0.98, P < 0.0001; generalized anxiety disorder: d = 0.74, P < 0.0001; social phobia: d = 0.71, P < 0.0001), and post-traumatic stress disorder (d = 0.81, P < 0.0001). In light of these findings, clinicians should pay more attention to the occurrence of OCS in MDD, as these symptoms may reflect greater clinical severity, poorer treatment outcome, and increased risk for bipolarity.

Clinical correlates and prognostic impact of binge-eating symptoms in major depressive disorder.

Binge-eating (BE) symptoms are relatively common in major depressive disorder (MDD), but their prognostic role is not fully understood. This study compared two groups of patients with MDD experiencing or not BE symptoms to ascertain differences in terms of clinical manifestations, presence of bipolar features, and antidepressant treatment outcomes. The study involved 482 outpatients collected within the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, who were assessed with scales for depressive and hypomanic symptomatology, suicidality, comorbid mental disorders, and childhood traumas. BE symptoms were reported in 95 patients (20%). Patients with MDD experiencing BE symptoms were characterized by higher scores of negative self-outlook ( P = 0.0018), negative outlook of future ( P = 0.0014), irritability ( P = 0.0043), comorbid anxiety disorders (generalized anxiety disorder: P = 0.0006; panic disorder: P < 0.0001; social phobia: P < 0.0001), obsessive-compulsive disorder ( P = 0.0053), hypomanic symptoms (increased talkativeness: P = 0.0029; reduced need for sleep: P = 0.0171), and suicidality (suicidal propensity: P = 0.0013; suicidal risk: P = 0.0148; lifetime suicidal behavior: P = 0.0052). BE symptoms (OR = 2.02; 95% CI = 1.06-3.84) and depression severity (OR = 1.04; 95% CI = 1.00-1.08) were independently associated with lifetime attempted suicide. The presence of BE symptoms might indicate higher severity of depressive disorder. Suicidal risk is a major issue in these patients, whereas the association between BE and bipolar features needs further research.

APOE epsilon-4 allele and cytokine production in Alzheimer's disease.

OBJECTIVE: The APOE epsilon-4 allele has consistently emerged as a susceptibility factor for Alzheimer's disease (AD). Pro-inflammatory cytokines are detectable at abnormal levels in AD, and are thought to play a pathophysiological role. Animal studies have shown dose-dependent correlations between the number of APOE epsilon-4 alleles and the levels of pro-inflammatory cytokines. The aims of this study were to investigate the influence of APOE genotypes on TNF-alpha, IL-6, and IL-1beta secreted by peripheral blood mononuclear cells (PBMC) from human patients with AD and to analyze the correlation between cytokine production and AD clinical features. METHODS: Outpatients with AD (n = 40) were clinically evaluated for cognitive decline (MMSE) and psychiatric symptoms (Cornell Scale for Depression in Dementia; Neuropsychiatric Inventory) and genotyped for APOE variants. PBMCs were isolated from the donors and used to assess spontaneous and PMA-stimulated secretion of TNF-alpha, IL-6, and IL-1beta. Cytokine production was determined by immuno-enzymatic assays (ELISA). RESULTS: In comparison with their counterparts without APOE4, patients with at least one copy of the APOE epsilon-4 allele showed higher spontaneous (p = 0.037) and PMA-induced (p = 0.039) production of IL-1beta after controlling for clinical variables. Significant correlations were reported between NPI scores (psychotic symptoms) and IL-6 production. CONCLUSION: These preliminary findings suggest the involvement of inflammatory response in the pathogenic effect of the APOE epsilon-4 allele in AD, although their replication in larger samples is mandatory. The modest correlations between pro-inflammatory cytokines released at peripheral level and AD features emphasizes the need for further research to elucidate the role of neuroinflammation in pathophysiology of AD.

Lack of association between interleukin-1 alpha rs1800587 polymorphism and Alzheimer's disease in two Independent European samples.

Interleukin-1 (IL1) can contribute to pathophysiology of Alzheimer's disease (AD) by promoting deposition of amyloid-beta in the brain. The gene encoding IL1 alpha (IL1A) has a common polymorphism in its 5' regulatory region (rs1800587) with possible functional effects. IL1A T/T genotype has been associated with AD but the overall effect is modest and negative studies have been published. The aim of this study was to investigate the association of the IL1A rs1800587 polymorphism with AD in two independent case-control groups from Greece (Athens) and Italy (Faenza and Granarolo). Preliminary results from the ongoing sample (110 patients with sporadic AD and 130 nonpsychiatric controls) showed no association between IL1A variants and AD, however C/T heterozygotes had more severe depression in AD (Cornell Scale for Depression in Dementia) compared to other genotypes (F = 4.56, d.f = 1, p = 0.037) after controlling for age, illness duration and cognitive impairment (MMSE). Despite the small sample size and the possibility of a false negative finding, our preliminary data support the hypothesis the IL1A rs1800587 variants are not associated with AD. The effect of the IL1A on depressive symptomatology warrants further investigations, however the lack of a gene-dose relationship would suggest a false positive.

Attrition in treatment-resistant depression: predictors and clinical impact.

The aim of this study was to investigate attrition (dropout) during a second antidepressant trial in treatment-resistant depression. Three hundred forty-two outpatients with major depressive disorder and lack of response to a prior antidepressant were treated with venlafaxine for 6 weeks. Sociodemographic and clinical characteristics were compared between the attrition and non-attrition groups. Attrition was reported in 65 patients (19%), of whom 30 patients (46%) dropped out within week 4. The characteristics of dropout patients included a longer duration of depressive episode (P = 0.011) and lower antidepressant doses (P < 0.0001) as a consequence of a faster decrease (week 2) in depressive symptoms (P = 0.028). However, by controlling for early improvement, dropout subjects were associated with a smaller probability of antidepressant response (odds ratio = 0.16▪.83). A decrease of at least 30% in Montgomery Asberg Depression Rating Scale on day 14 predicted subsequent dropout with high specificity (81.9%▪1.0%) but lower sensitivity (19.6%▪2.8%) for clinical use. Patients who have been depressed for a longer period and show an initial improvement of symptoms after changing their antidepressant may be at increased risk for drop out. Further studies are necessary to ascertain the usefulness of these characteristics for predicting attrition.

Early improvement and response to antidepressant medications in adults with major depressive disorder. Meta-analysis and study of a sample with treatment-resistant depression.

BACKGROUND: Initial improvement in the first weeks of antidepressant (AD) treatment is a useful early predictor of complete AD response. We performed a meta-analysis of AD studies to investigate whether a partial decrease in depressive symptoms by week 4 was associated with response and remission by weeks 6-14 in major depressive disorder (MDD). Finally, we focused on treatment-resistant depression (TRD: lack of response to prior AD) to test the impact of early improvement on a second AD treatment outcome and to compare different switching strategies. METHODS: Meta-analysis was conducted on AD naturalistic studies published between 01.01.2000 and 06.30.2017. TRD was an exclusion criterion. TRD was analyzed in 407 MDD patients treated with venlafaxine for 6 weeks. The MADRS was used to define very early improvement (VEI: > 20% decrease at week 2), early improvement (EI: > 30% decrease at week 4) and remission (week 6 MADRS < 10). A theoretical model was used to simulate AD switch in TRD patients who failed to achieve remission (Algorithm A), VEI (Algorithm B) or EI (Algorithm C). RESULTS: Our meta-analysis (9 studies; N = 6185) showed significant associations between early improvement, response (OR: 3.28 95% C.I: 2.06-5.20) and remission (OR: 2.10 95% C.I: 1.53-2.87). 24.6% of TRD sample remitted. VEI was a poor outcome predictor: sensitivity = 0.52 (0.40-0.63); specificity = 0.82 (0.76-0.86); AUC = 0.67 (0.62-0.71). EI had a moderate predictive power: sensitivity = 0.87 (0.77-0.93); specificity = 0.71 (0.66-0.77); AUC = 0.76 (0.71-0.80). The best treatment scenario was Algorithm C (switch after 4 weeks) in which remission rate was marginally increased (35.1% vs 33.7% of Algorithm A). Algorithm B (switch after 2 weeks) led to a 4.3% decrease in remission compared to Algorithm A. LIMITATIONS: Inclusion of a naturalistic sample without a control arm; simulation of treatments. CONCLUSION: Although literature data suggest a correlation between an initial improvement of depressive symptoms and later response and remission during AD treatment, our analysis shows that such an early improvement is not a reliable outcome predictor in TRD. The nature of TRD is complex and different biological mechanisms and treatments might be necessary for TRD patients.

Genetics of Alzheimer's disease. A rapidly evolving field.

Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). Genome-wide analyses, transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs.

Depression and social phobia secondary to alcohol dependence.

BACKGROUND: According to the self-medication hypothesis, individuals with depression and anxiety disorders use alcohol to control their symptoms and subsequently become dependent. Conversely, alcohol dependence disorder (ADD) can cause or exacerbate psychiatric disorders. This study analyzed the characteristics of depression and social phobia secondary to ADD. (1) What is their functional impact? (2) Are they independent or associated conditions? (3) Do they completely remit in abstinent individuals? (4) Is the remission of one disorder associated with the remission of the other disorder? METHODS: Sixty-four inpatients with ADD were evaluated with depression and anxiety disorder scales upon admission to hospital and after 5 weeks of detoxification. RESULTS: Baseline comparisons differentiated patients with a Hamilton Rating Scale for Depression (HDRS) score > 35 (n = 50; 78%) from those with an HDRS score < or = 35 by higher levels of generalized anxiety and lower global functioning. Patients with generalized social phobia [Leibowitz Social Anxiety Scale (LSAS) score > 60: n = 20; 31.2%] were not distinguishable from those with an LSAS score < or = 60 by depressive and anxiety disorder symptoms. In postdetoxification assessment, patients who remitted from depression (HDRS score < 7: n = 35; 54.6%) had a lower generalized anxiety and marginally higher levels of hypochondriasis compared to nonremitter subjects (HDRS score > or = 7). Patients who remitted from social phobia (LSAS score < 30: n = 32; 50%) did not significantly differ from nonremitter subjects in depressive and anxiety disorder symptoms. Generalized anxiety (Hamilton Rating Scale for Anxiety) and hypochondriasis (Whiteley Index) were the significant predictors of global functioning (Global Assessment Scale). CONCLUSIONS: Depression and social phobia secondary to ADD are independent conditions that do not completely remit after cessation of drinking. Specific treatments are needed to reduce residual depressive and anxiety symptoms in abstinent alcoholics.

Clinical prediction of antidepressant response in mood disorders: linear multivariate vs. neural network models.

Predicting the outcome of antidepressant treatment by pre-treatment features would be of great usefulness for clinicians as up to 50% of major depressives may not have a satisfactory response in spite of adequate trials of antidepressant drugs. In the present article we compared a linear multivariate model of predictors with a few artificial neural network (ANN) models differing from one another by outcome definition and validation procedure. The sample consisted of a reanalysis of 116 inpatients with a major depressive episode included in a 6-week open-label trial with fluvoxamine. With the original outcome definition (responders/non-responders), ANN performed better than logistic regression (90% of correct classifications in the training sample vs. 77%). However only 62% of new patients were correctly predicted by ANN for their outcome class. Length of the index episode, psychotic features and suicidal behavior emerged as outcome predictors in both models, while demographic characteristics, personality disorders and concomitant somatic morbidity were pointed to only by ANN analysis. Increase of classes in the outcome field resulted in a more elevated error: 46.4% for three classes, 60.4% for four classes and 70.3% for five classes. Overall, our findings suggest that antidepressant outcome prediction based on clinical variables is poor. The ANN approach is as valid as traditional multivariate techniques for the analysis of psychopharmacology studies. The complex interactions modelled through ANN may eventually be applied at the clinical level for individualized therapy. However, the accuracy of prediction is still far from satisfactory from a clinical point of view.