Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial.

IMPORTANCE: Patients with treatment-resistant depression (TRD) do not respond sufficiently to several consecutive treatments for major depressive disorder. Deep brain stimulation (DBS) is a promising treatment for these patients, but presently placebo effects cannot be ruled out. OBJECTIVE: To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014. Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved. A randomized, double-blind, 12-week crossover phase was then conducted with patients receiving active treatment followed by sham or vice versa. Response and nonresponse to treatment were determined using intention-to-treat analyses. INTERVENTIONS: Deep brain stimulation targeted to the vALIC. MAIN OUTCOMES AND MEASURES: The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase. The primary outcome of the crossover phase was the difference in the HAM-D-17 scores between active and sham DBS. The score range of this tool is 0 to 52, with higher scores representing more severe symptoms. Patients were classified as responders to treatment (≥50% decrease of the HAM-D-17 score compared with baseline) and partial responders (≥25 but <50% decrease of the HAM-D-17 score). RESULTS: Of 25 patients included in the study, 8 (32%) were men; the mean (SD) age at inclusion was 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (95% CI, 20.3-24.1) at baseline to 15.9 (95% CI, 12.3-19.5) (P = .001), Montgomery-Åsberg Depression Rating Scale scores from 34.0 (95% CI, 31.8-36.3) to 23.8 (95% CI, 18.4-29.1) (P < .001), and Inventory of Depressive Symptomatology-Self-report scores from from 49.3 (95% CI, 45.4-53.2) to 38.8 (95% CI, 31.6-46.0) (P = .005) in the optimization phase. Following the optimization phase, which lasted 51.6 (22.0) weeks, 10 patients (40%) were classified as responders and 15 individuals (60%) as nonresponders. Sixteen patients entered the randomized crossover phase (9 responders [56%], 7 nonresponders [44%]). During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95% CI, 9.8-17.4]) than during sham DBS (23.1 [95% CI, 20.6-25.6]) (P < .001). Serious adverse events included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients). CONCLUSIONS AND RELEVANCE: Deep brain stimulation of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients and was tolerated well. The randomized crossover design corroborates that vALIC DBS causes symptom reduction rather than sham. TRIAL REGISTRATION: trialregister.nl Identifier: NTR2118.

Erythrocyte fatty acid profiles and plasma homocysteine, folate and vitamin B6 and B12 in recurrent depression: Implications for co-morbidity with cardiovascular disease.

Oxidative stress induced interactions between fatty acid (FA) and one-carbon metabolism may be involved in co-occurrence of major depressive disorder (MDD) and cardiovascular disease (CVD), which have been scarcely studied together. In 137 recurrent MDD-patients vs. 73 age- and sex-matched healthy controls, we simultaneously measured key components of one-carbon metabolism in plasma (homocysteine, folate, vitamins B6 and B12), and of FA-metabolism in red blood cell membranes [main polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA) and structural FA-indices (chain length, unsaturation, peroxidation)]. Results show significant positive associations of folate with EPA, DHA, and the peroxidation index, which were similar in patients and controls. After correction for confounders, these associations were lost except for EPA. Associations between B-vitamins and FA-parameters were non-significant, but also similar in patients and controls. Homocysteine and DHA were significantly less negatively associated in patients than in controls. In conclusion, these data indicate similarities but also differences in associations between parameters of one-carbon and FA-metabolism in recurrent MDD patients vs. controls, which may reflect differences in handling of oxidative stress. Further research should test the consequences of these differences, particularly the premature development of CVD in MDD.

Ala54Thr fatty acid-binding protein 2 (FABP2) polymorphism in recurrent depression: associations with fatty acid concentrations and waist circumference.

BACKGROUND: Fatty acid (FA)-alterations may mediate the mutual association between Major Depressive Disorder (MDD) and cardiovascular disease (CVD). However, etiology of observed FA-alterations in MDD and CVD remains largely unclear. An interesting candidate may be a mutation in the fatty acid-binding protein 2 (FABP2)-gene, because it regulates dietary FA-uptake. Therefore, we aimed to test the hypotheses that in MDD-patients the FABP2 Ala54Thr-polymorphism would be (I) more prevalent than in sex- and age-matched controls, (II) associated with observed alterations in FA-metabolism, and (III) associated with CVD-risk factor waist circumference. METHODS: We measured concentrations of 29 different erythrocyte FAs, FABP2-genotype, and waist circumference in recurrent MDD-patients and matched never-depressed controls. RESULTS: FABP2-genotype distribution did not significantly differ between the 137 MDD-patients and 73 matched controls. However, patients with the Ala54Thr-polymorphism had (I) higher concentrations of especially eicosadienoic acid (C20:2ω6; P=.009) and other 20-carbon FAs, and associated (II) lower waist circumference (P=.019). In addition, FABP2-genotype effects on waist circumference in patients seemed (I) mediated by its effect on C20:2ω6, and (II) different from controls. CONCLUSIONS: Although Ala54Thr-polymorphism distribution was not associated with recurrent MDD, our results indicate that FABP2 may play a role in the explanation of observed FA-alterations in MDD. For Ala54Thr-polymorphism patients, potentially adaptive conversion of increased bioavailable dietary precursors into eicosadienoic acid instead of arachidonic acid might be related to a low waist circumference. Because this is the first investigation of these associations, replication is warranted, preferably by nutrigenetic studies applying lipidomics and detailed dietary assessment.

Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression.

Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity and fatty acid (FA)-metabolism have been observed in (recurrent) major depressive disorder (MDD). Through the pathophysiological roles of FAs in the brain and cardiovascular system, a hypothesized relationship between HPA-axis activity and FA-metabolism could form a possible missing link accounting for the association of HPA-axis hyperactivity with recurrence and cardiovascular disease in MDD. In 137 recurrent MDD-patients and 73 age- and sex-matched controls, we therefore investigated associations between salivary cortisol (morning and evening) and the following indicators of FA-metabolism measured in the red blood cell membrane: (I) three main FAs [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)], and (II) structural FA indices (unsaturation, chain length, peroxidation) calculated from concentrations of 29 FAs to delineate overall FA-characteristics. In addition, we compared these associations in patients with those in controls. In patients, evening cortisol concentrations were significantly negatively associated with DHA (B=-1.358; SE=0.499; t=-2.72; p=.006), the unsaturation index (B=-0.021; SE=0.009; t=-2.42; p=.018), chain length index (B=-0.060; SE=0.025; t=-2.41; p=.019), and peroxidation index (B=-0.029; SE=0.012; t=-2.48; p=.015). The relations between cortisol and the latter three variables were significantly negative in patients relative to controls. Significance remained after correction for confounders. Our results suggest a relationship between HPA-axis activity and FA-metabolism in recurrent MDD. Future randomized experimental intervention studies using clinical outcome measures could help to further elucidate the suggested effects of hypercortisolemia in the brain and cardiovascular system in recurrent MDD.

The Coping with Attention and Memory Complaints Questionnaire (CAMQ): psychometric evaluation of an instrument in suspected chronic solvent-induced encephalopathy (CSE).

Long-term occupational exposure to organic solvents may induce chronic solvent-induced encephalopathy (CSE), leading to neuropsychological impairments. We developed the Coping with Attention and Memory Complaints Questionnaire (CAMQ), an instrument for the assessment of coping strategies in patients suspected of CSE with neuropsychological complaints. Items for the CAMQ were based on existing coping dimensions and constructed by experts. The psychometric properties of the CAMQ were evaluated in a sample of 307 workers suspected of CSE. Factor analysis revealed four coping subscales: active coping, avoidance, acceptance, and seeking social support, all with good internal consistency (alphas .71-.78) and good test-retest reliability (ICCs .67-.82). The subscales demonstrated moderate correlations with related external constructs such as anxiety and depression, locus of control, meta-memory, mastery and generic coping styles. In conclusion, this study: (1) shows that the newly developed CAMQ is a reliable instrument, and (2) provides evidence for its validity in assessing coping with complaints of memory and attention in CSE-suspected patients. These results may serve for further study on coping with complaints of memory and attention, psychological adjustment and well-being in CSE patients.

Lower cortisol levels predict recurrence in remitted patients with recurrent depression: a 5.5 year prospective study.

Major Depressive Disorder (MDD) is a highly recurrent disease. Stress-responsive system dysfunction seems to persist after remission. In patients with more chronic and recurrent depressive episodes, state related HPA-axis dysregulation might be a risk factor for prospective recurrence. This study examines the predictive effect of cortisol on consecutive episodes in remitted recurrently depressed patients. Cortisol was assessed in saliva in remitted recurrently depressed patients (n=55) that were followed up prospectively for 5.5 years after remission. Recurrence was assessed using a well validated structured interview. Lower mean morning cortisol levels predicted earlier time to recurrence over 5.5 year after correction for residual symptoms (p=0.015). Residual symptoms and childhood trauma slightly confounded the association between cortisol and recurrence. Lower cortisol levels were associated with having experienced traumatic childhood life events (42.3% in patients with lower cortisol versus 19.2% in patients with higher cortisol). Our study provides further support for the predictive role over 5.5 year of HPA axis dysregulation, i.e. lower morning cortisol levels, of recurrence in recurrently depressed patients. Childhood trauma is associated to having lower cortisol levels. It might have long term consequences for dealing with stress and the HPA-axis.

Statistical methodological issues in handling of fatty acid data: percentage or concentration, imputation and indices.

Basic aspects in the handling of fatty acid-data have remained largely underexposed. Of these, we aimed to address three statistical methodological issues, by quantitatively exemplifying their imminent confounding impact on analytical outcomes: (1) presenting results as relative percentages or absolute concentrations, (2) handling of missing/non-detectable values, and (3) using structural indices for data-reduction. Therefore, we reanalyzed an example dataset containing erythrocyte fatty acid-concentrations of 137 recurrently depressed patients and 73 controls. First, correlations between data presented as percentages and concentrations varied for different fatty acids, depending on their correlation with the total fatty acid-concentration. Second, multiple imputation of non-detects resulted in differences in significance compared to zero-substitution or omission of non-detects. Third, patients' chain length-, unsaturation-, and peroxidation-indices were significantly lower compared to controls, which corresponded with patterns interpreted from individual fatty acid tests. In conclusion, results from our example dataset show that statistical methodological choices can have a significant influence on outcomes of fatty acid analysis, which emphasizes the relevance of: (1) hypothesis-based fatty acid-presentation (percentages or concentrations), (2) multiple imputation, preventing bias introduced by non-detects; and (3) the possibility of using (structural) indices, to delineate fatty acid-patterns thereby preventing multiple testing.

Longitudinal hypothalamic-pituitary-adrenal axis trait and state effects in recurrent depression.

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity has been observed in (recurrent) major depressive disorder (MDD), although inconsistently and mainly cross-sectional. Longitudinal studies clarifying state-trait issues are lacking. We aimed to determine whether HPA-axis (hyper)activity in recurrent MDD is: (I) reflecting a persistent trait; (II) influenced by depressive state; (III) associated with stress or previous episodes; (IV) associated with recurrence; and (V) influenced by cognitive therapy. METHODS: We included 187 remitted highly recurrent MDD-patients (mean number of previous episodes: 6.3), participating in a randomized-controlled-trial investigating the preventive effect of additional cognitive therapy on recurrence. In an add-on two-staged patient-control and prospective-cohort design, we first cross-sectionally compared patients' salivary morning and evening cortisol concentrations with 72 age- and sex-matched controls, and subsequently longitudinally followed-up the patients with repeated measures after three months and two years. RESULTS: Patients had higher cortisol concentrations than controls (p<.001), which did not change by MDD-episodes during follow-up. HPA-axis activity had no relation with daily hassles or childhood life events. Cortisol concentrations were lower in patients with more previous episodes (p=.047), but not associated with recurrence(s) during follow-up. Finally, randomly assigned cognitive therapy at study-entry enhanced cortisol declines over the day throughout the two-year follow-up (p=.052). CONCLUSIONS: Our results indicate that remitted recurrent MDD-patients have a persistent trait of increased cortisol concentrations, irrespective of stress. In combination with our finding that patients' cortisol concentrations do not change during new MDD-episodes (and thus not represent epiphenomenal or state-effects), our results support that hypercortisolemia fulfills the state-independence criterion for an endophenotype for recurrent depression.

Prevalence of psychiatric disorders in patients with chronic solvent induced encephalopathy (CSE).

INTRODUCTION: Long term occupational exposure to organic solvents may induce chronic solvent-induced encephalopathy (CSE), characterized by mild to severe cognitive impairment, generally seen as the key diagnostic feature. Psychiatric disorders are often diagnosed in subjects with CSE, but were never studied in more detail. This study was designed to establish the prevalence rates of DSM IV mood, anxiety, and alcohol and substance related disorders in patients with CSE. MATERIALS AND METHODS: In CSE, n=203 (consecutively recruited between 2002 and 2005), defined according to the criteria of the World Health Organisation (WHO), one month prevalence rates of DSM IV mood, anxiety, and life time alcohol/substance related disorders were assessed using the Structured Clinical Interview for DSM IV disorders (SCID). These prevalences were compared with those from an age and gender matched community sample (n=3212) while controlling for insufficient neuropsychological test effort. RESULTS: In CSE, prevalence rates for major depressive disorder (n=36, relative risk (RR)=7.4), dysthymia (n=15, RR=6.0), panic disorders (n=18, RR=7.1), agoraphobia (n=7, RR=5.5) and generalized anxiety disorder (n=19, RR=15.8) were increased. Reduced prevalence rates were found for alcohol related disorders (n=21, RR=0.3). Insufficient neuropsychological test effort was not associated with increased prevalence rates of DSM IV disorders in subjects suspected of CSE. DISCUSSION AND CONCLUSIONS: In conclusion, in this first large scale study in patients with CSE, prevalence rates of DSM IV mood and anxiety disorders were elevated as compared with those in the general community, while the prevalence rates of alcohol related disorders were reduced. Further study must determine whether CSE, and mood and anxiety disorders, share a same, solvent induced, neurobiological pathway, supporting the use of a more inclusive diagnostic approach. Additionally, randomised controlled trials are needed for the urgent issue of how to treat mood and anxiety disorders in CSE patients effectively.

Plasma and erythrocyte fatty acid patterns in patients with recurrent depression: a matched case-control study.

BACKGROUND: The polyunsaturated fatty acid (PUFA) composition of (nerve) cell membranes may be involved in the pathophysiology of depression. Studies so far, focussed mainly on omega-3 and omega-6 PUFAs. In the present study, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and PUFAs of the omega-3, -6 and -9 series in plasma and erythrocytes of patients with recurrent major depressive disorder (MDD-R) were compared with controls. METHODOLOGY AND PRINCIPAL FINDINGS: We carried out a case-control study. The sample consisted of 137 patients with MDD-R and 65 matched non-depressed controls. In plasma and erythrocytes of patients with MDD-R the concentrations of most of the SFAs and MUFAs, and additionally erythrocyte PUFAs, all with a chain length > 20 carbon (C) atoms, were significantly lower than in the controls. In contrast, the concentrations of most of the shorter chain members (< or = 18C) of the SFAs and MUFAs were significantly higher in the patients. Estimated activities of several elongases in plasma of patients were significantly altered, whereas delta-9 desaturase activity for C14:0 and C18:0 was significantly higher. CONCLUSIONS/SIGNIFICANCE: The fatty acid status of patients with MDD-R not only differs with regard to omega-3 and omega-6 PUFAs, but also concerns other fatty acids. These alterations may be due to: differences in diet, changes in synthesizing enzyme activities, higher levels of chronic (oxidative) stress but may also result from adaptive strategies by providing protection against enhanced oxidative stress and production of free radicals.

Cerebral impairment in chronic solvent-induced encephalopathy.

OBJECTIVE: Worldwide, many workers experience occupational exposure to organic solvents, which may induce chronic solvent-induced encephalopathy (CSE). Disturbances within the frontostriatothalamic (FST) circuitry might explain the symptomatology of CSE. We tested the hypothesis of FST circuitry abnormalities in CSE, as well as associations with performance of psychomotor speed, attention, and solvent exposure. To detect preclinical, solvent-related effects, we also studied the FST circuitry in solvent-exposed, but asymptomatic workers. METHODS: Ten CSE patients, 10 asymptomatic but solvent-exposed house painters (EC), and 11 nonexposed asymptomatic carpenters were included. Dopamine D(2) receptor (D2R) binding, central nervous system tissue metabolites, and fractional anisotropy were measured within the FST circuitry, using single-photon emission computed tomography, magnetic resonance spectroscopy, and diffusion tensor imaging. Performance of psychomotor speed and attention, and severity of solvent exposure were assessed. RESULTS: Striatal D2R binding was reduced in CSE. In the solvent-exposed asymptomatic patients, striatal D2R binding and levels of N-acetylaspartate + N-acetylaspartyl-glutamate in frontal gray matter were reduced. In both exposed groups, a trend was seen for reduced choline in frontal gray matter. In CSE, the fractional anisotropy in the thalamus, caudate nucleus, and striatal D2R binding significantly predicted reduced performance of attention and psychomotor speed. In CSE, striatal D2R binding showed a negative correlation with solvent exposure. INTERPRETATION: This is the first study in CSE showing pronounced disturbances within the FST circuitry that are related to the clinical findings and to exposure severity to solvents. The comparable, but milder, abnormalities within the FST circuitry in the exposed asymptomatic workers may imply a presymptomatic phase of CSE.

Differential predictors of response to preventive cognitive therapy in recurrent depression: a 2-year prospective study.

BACKGROUND: Major depressive disorder is a recurrent disease. Brief cognitive therapy (CT), added to either regular care or medication, is helpful in preventing relapse/recurrence. Little is known which type of persons benefit from preventive CT, the so called 'aptitude treatment interaction' effect. METHOD: The present cohort included exclusively patients with at least two previous episodes remitted on various types of treatments (n = 172). They were assessed within a clinical trial comparing treatment as usual (TAU) with preventive CT added to TAU. Differential demographic, illness-related, psychological and biological risk factors in postponing recurrence by preventive CT were examined. RESULTS: Significant aptitude-treatment-interaction effects were found for the number of previous episodes, daily hassles and life events, avoidant coping, gender, and morning cortisol levels. Preventive CT seemed ineffective in patients with life events (as more frequently reported by women in our study) and in patients with high episode number characterized by higher levels of avoidant coping. Generic predictors indicate that in CT, as in TAU, patients with more residual depressive symptomatology and higher levels of dysfunctional attitudes profit less from preventive CT. CONCLUSION: The finding that preventive CT protects against the influence of a consistently found risk factor of relapse/recurrence, i.e. the number of depressive episodes, underlines the potential of psychological preventive interventions. Preventive CT seemed to be especially effective in reducing presumably internally provoked, relapse/recurrence but may be quite ineffective in reducing externally provoked relapse/recurrence. CT possibly prevents either stress generation or disrupts kindling effects. Kindling effects probably cannot be disrupted in patients with higher levels of avoidant coping who experienced a high number of episodes, and patients who experienced life events.

Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: preliminary findings.

Major depression is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In contrast to cortisol, dehydroepiandrosterone-sulfate (DHEA-S) has been less extensively studied in depressed patients. This study examined salivary morning and evening levels of cortisol and DHEA-S in 13 medicated, unipolar, non-psychotic depressed patients and 13 healthy volunteers. Diurnal declines in cortisol and DHEA-S levels were found in both depressed and control groups. In patients compared with controls, DHEA-S was significantly elevated, in conjunction with normal cortisol levels. Based on DHEA-S at 22:00 h only, 77% of the subjects were correctly classified in a discriminant analysis as depressed or control. When simultaneously entered in a multiple regression analysis, DHEA-S (morning and evening) and cortisol (evening only) predicted symptom severity in depressed patients. These preliminary results suggest that DHEA-S may be a more sensitive indicator of depression and symptom severity than cortisol in medicated but still clinically depressed patients.