[Farmacogenetica in de psychiatrie; de huidige status quo]. / Farmacogenetica in de psychiatrie; de huidige status quo.

BACKGROUND: Medication side effects and limited efficacy are substantial problems in general and also in psychopharmaceuticals. Previous studies have shown that pharmacogenetic individual characteristics can be relevant. AIM: To arrive at a responsible use of pharmacogenetics, exploiting its potential but also avoiding overdiagnosis. METHOD: To provide an overview of the current status quo in the field of pharmacogenetics in psychiatry. RESULTS: The Dutch Association for Psychiatrists (NVvP) authorized a guideline ‘Pharmacogenetics in Psychiatry’ that is summarized. Also the current international guidelines and clinical implementation of pharmacogenetics are discussed. CONCLUSION: For the time being, pharmacogenetics seems to be indicated only when patients have already experienced problems with psychopharmaca use, such as side effects and/or inefficacy. If genotyping is requested then generally CYP2C19 and CYP2D6 can be useful, as dosage recommendations are available in case of genetic variants.

Understanding personalized dynamics to inform precision medicine: a dynamic time warp analysis of 255 depressed inpatients.

BACKGROUND: Major depressive disorder (MDD) shows large heterogeneity of symptoms between patients, but within patients, particular symptom clusters may show similar trajectories. While symptom clusters and networks have mostly been studied using cross-sectional designs, temporal dynamics of symptoms within patients may yield information that facilitates personalized medicine. Here, we aim to cluster depressive symptom dynamics through dynamic time warping (DTW) analysis. METHODS: The 17-item Hamilton Rating Scale for Depression (HRSD-17) was administered every 2 weeks for a median of 11 weeks in 255 depressed inpatients. The DTW analysis modeled the temporal dynamics of each pair of individual HRSD-17 items within each patient (i.e., 69,360 calculated "DTW distances"). Subsequently, hierarchical clustering and network models were estimated based on similarities in symptom dynamics both within each patient and at the group level. RESULTS: The sample had a mean age of 51 (SD 15.4), and 64.7% were female. Clusters and networks based on symptom dynamics markedly differed across patients. At the group level, five dynamic symptom clusters emerged, which differed from a previously published cross-sectional network. Patients who showed treatment response or remission had the shortest average DTW distance, indicating denser networks with more synchronous symptom trajectories. CONCLUSIONS: Symptom dynamics over time can be clustered and visualized using DTW. DTW represents a promising new approach for studying symptom dynamics with the potential to facilitate personalized psychiatric care.

Cognitive change after electroconvulsive therapy in mood disorders measured with the Montreal Cognitive Assessment.

OBJECTIVE: The Montreal Cognitive Assessment (MoCA) is a sensitive and clinically practical test but its usefulness in measuring long-term cognitive effects of ECT is unclear. Using the MoCA, we investigated short- and long-term global cognitive change in ECT-treated patients with a Major Depressive Episode (MDE). METHOD: We included 65 consecutive ECT-treated patients with MDE, in whom global cognitive functioning was assessed at baseline (T0); during ECT (before the third session; T1); and 1 week (T2), 3 months (T3), and 6 months (T4) after completion of the index course. Changes in MoCA (sub)scores were analyzed using linear mixed models and reliable change indices were computed to investigate individual changes in MoCA total scores. RESULTS: There was a significant effect of time on MoCA scores (F(4, 230.5) = 4.14, P = 0.003), with an improvement in global cognitive functioning from T3 compared to T1 and T2. At the individual level, 26% (n = 17) of patients showed a significantly worse cognitive functioning at T2 and 12% (n = 8) an improved cognitive functioning compared to T0. For T4, these percentages ameliorated to 8% and 18% respectively. CONCLUSION: No persistent global cognitive impairment induced by ECT was found at the group level using the MoCA. At the individual level, however, there was clear heterogeneity in the effects of ECT on cognitive functioning. The MoCA is a suitable tool to monitor short- and long-term global cognitive functioning in ECT-treated patients with MDE but in younger patients, potential ceiling effects must be taken into account.

Improvement after two sessions of electroconvulsive therapy predicts final remission in in-patients with major depression.

OBJECTIVE: To investigate whether early improvement, measured after two electroconvulsive therapy (ECT) sessions, is a good predictor of eventual remission in severely depressed in-patients receiving ECT. METHOD: A prospective cohort study was performed that included 89 major depressive disorder in-patients treated with bilateral ECT. Sensitivity, specificity, and predictive values were computed for various definitions of early improvement (15%, 20%, 25%, and 30% reduction on the Montgomery Asberg depression rating scale (MADRS) score) after 1 week (i.e. two sessions) of ECT regarding prediction of remission (final MADRS score ≤ 9). RESULTS: A 15% reduction in MADRS score appeared to be the best definition of early improvement, with modest sensitivity (51%) and relatively good specificity (79%). Kaplan-Meier analysis showed a more than 2-week shorter time to remission in patients with early improvement compared with patients lacking early improvement. CONCLUSION: Early improvement during an ECT course may be assessed after two ECT sessions. Such improvement, defined as a 15% reduction in the MADRS score, is a moderately sensitive predictor for eventual remission in an in-patient population with severe major depression.

Van oude pillen, de dingen die voorbijgaan.

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A randomized clinical trial comparing two two-phase treatment strategies for in-patients with severe depression.

OBJECTIVE: To compare the efficacy of two antidepressant treatment strategies in severely depressed in-patients, that is, imipramine vs. venlafaxine, both with subsequent lithium addition in non-responders. METHOD: In-patients (n = 88) with major depressive disorder were randomized to 7-week treatment with imipramine or venlafaxine (phase I). All non-responders (n = 44) received 4-week plasma level-targeted dose lithium addition (phase II). Efficacy was evaluated after 11 weeks of treatment. RESULTS: Analyzing phases I and II combined, non-inferiority was established and the difference in the proportion of responders (HAM-D score reduction ≥50%) by the end of phase II demonstrated the venlafaxine-lithium treatment strategy to be significantly superior to the imipramine-lithium treatment strategy (77% vs. 52%) (χ2 (1) = 6.03; P = 0.01). Regarding remission (HAM-D score ≤ 7), 15 of 44 (34%) patients in the imipramine-lithium treatment group were remitters compared to 22 of 44 (50%) patients in the venlafaxine-lithium treatment group, a non-significant difference. Patients in the venlafaxine-lithium treatment group had a non-significant larger mean HAM-D score reduction compared with patients in the imipramine-lithium treatment group (16.1 vs. 13.5 points, respectively; Cohen's d = 0.30). CONCLUSION: The venlafaxine-lithium treatment strategy can be considered a valuable alternative for the imipramine-lithium treatment strategy in the treatment of severely depressed in-patients.

[Hypertension en orthostatic hypotension during use of monoamine oxidase (MAO) inhibitors]. / Hypertensie en orthostatische hypotensie bij gebruik van monoamine-oxidase(MAO)-remmers1.

Monoamine oxidase (mao) inhibitors are antidepressants with potentially severe side-effects. For this reason, the registration of this drug was suspended for some time when safer alternatives became available. However, mao inhibitors can be very effective in cases where depression has proved to be treatment resistant. Consequently, last year tranylcypromine was re-registered for use in the Netherlands. Since mao inhibitors have been used only sporadically in the Netherlands over the last few years, health professionals have only limited knowledge about the side-effects. On the basis of a recent case, we discuss the two most important side-effects of using mao inhibitors, namely hypertension and orthostatic hypotension. We discuss the possible causes and suggest ways on which these two side-effects can be prevented, or treated, should they arise.

Beta-blocking agents during electroconvulsive therapy: a review.

Electroconvulsive therapy (ECT) is associated with at least transient episodes of hypertension and tachycardia. Beta-blocking agents may be indicated to prevent cardiovascular complications and may shorten seizure duration. This review evaluates studies that used beta-blocking agents during ECT to determine which agent has the most favourable outcomes on cardiovascular variables and seizure duration. A Medline database search was made using the combined keywords 'adrenergic beta-antagonists' and 'electroconvulsive therapy'. The search was restricted to double-blind randomized controlled trials and yielded 29 original studies. With the use of esmolol, significant attenuating effects were found on cardiovascular parameters in the first 5 min after stimulation; its shortening effects on seizure duration may be dose-related. With the use of labetalol, findings on cardiovascular effects were inconsistent during the first minutes after stimulation but were significant after 5 min and thereafter; seizure duration was scarcely studied. Landiolol attenuates heart rate but with inconsistent findings regarding arterial pressure (AP); seizure duration was mostly unaffected. Esmolol appears to be effective in reducing the cardiovascular response, although seizure duration may be affected with higher dosages. Landiolol can be considered a suitable alternative, but effects on AP need further investigation. Labetalol has been studied to a lesser extent and may have prolonged cardiovascular effects. The included studies varied in design, methodology, and the amount of exact data provided in the publications. Further study of beta-blocking agents in ECT is clearly necessary.

Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Drug-free patients with major depression show an increased electrophysiological response to valid and invalid feedback.

BACKGROUND: Depressed patients are biased in their response to negative information. They have been found to show a maladaptive behavioral and aberrant electrophysiological response to negative feedback. The aim of this study was to investigate the behavioral and electrophysiological response to feedback validity in drug-free depressed patients. METHOD: Fifteen drug-free in-patients with unipolar major depression disorder (MDD) and 30 demographically matched controls performed a time-estimation task in which they received valid and invalid (i.e. related and unrelated to performance) positive and negative feedback. The number of behavioral adjustments to the feedback and the feedback-related negativity (FRN) were measured. RESULTS: Patients made fewer correct adjustments after valid negative feedback than controls, and their FRNs were larger. Neither patients nor controls adjusted their time estimates following invalid negative feedback. CONCLUSIONS: The FRN results suggest that depressed drug-free in-patients have an atypical rostral anterior cingulate response to feedback that is independent of feedback validity. Their behavioral response to invalid negative feedback, however, is not impaired. This study confirms the notion that the behavioral responses of depressed individuals to negative feedback are context dependent.

Policy and Practice Review: A First Guideline on the Use of Pharmacogenetics in Clinical Psychiatric Practice.

Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient.

Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

OBJECTIVE: It remains unclear whether unipolar psychotic depression should be treated with an antidepressant and an antipsychotic or with an antidepressant alone. METHOD: In a multi-center RCT, 122 patients (18-65 years) with DSM-IV-TR psychotic major depression and HAM-D-17 > or = 18 were randomized to 7 weeks imipramine (plasma-levels 200-300 microg/l), venlafaxine (375 mg/day) or venlafaxine-quetiapine (375 mg/day, 600 mg/day). Primary outcome was response on HAM-D-17. Secondary outcomes were response on CGI and remission (HAM-D-17). RESULTS: Venlafaxine-quetiapine was more effective than venlafaxine with no significant differences between venlafaxine-quetiapine and imipramine, or between imipramine and venlafaxine. Secondary outcomes followed the same pattern. CONCLUSION: That unipolar psychotic depression should be treated with a combination of an antidepressant and an antipsychotic and not with an antidepressant alone, can be considered evidence based with regard to venlafaxine-quetiapine vs. venlafaxine monotherapy. Whether this is also the case for imipramine monotherapy is likely, but cannot be concluded from the data.

Hair cortisol in patients with a depressive episode treated with electroconvulsive therapy.

BACKGROUND: There is substantial evidence showing changes in hypothalamic pituitary adrenal (HPA)-axis activity in patients with major depressive disorder (MDD). Also, there seem to be differences in HPA-axis functioning between MDD subgroups. It is however unclear whether hair cortisol concentrations (HCC), which are a stable marker of long-term cortisol levels, are suitable as a biomarker for identifying subgroups in MDD. METHODS: We were able to attain valid HCC from a scalp hair sample of sixty-two patients with a major depressive episode right before electroconvulsive therapy (ECT). HCC were our main biological outcome measure. We created subgroups using depression severity as defined by the Hamilton Depression Rating Scale, the presence/absence of psychotic symptoms, the presence of melancholia as defined by the CORE and catatonia as defined by the Bush-Francis Catatonia Rating Scale. RESULTS: Our analyses of the total group showed a median HCC of 4.4 pg/mg. We found patients with catatonia (N = 10) to have substantially higher median HCC (8.3 pg/mg) than patients without catatonia (3.8 pg/mg). Although presence of melancholia and depression severity were not significantly associated with HCC, more severe psychomotor agitation was associated with higher HCC. Pre-treatment HCC was not associated with ECT outcome. STRENGTHS AND LIMITATIONS: A complicating factor in interpretation of our results was the large variability in HCC. This could be related to potential confounders such as cardiometabolic and other comorbidities, that were however addressed to the extent possible. CONCLUSIONS: HCC is a potential biomarker for MDD patients with severe agitation and/or catatonia. CLINICALTRIALS.GOV: Identifier: NCT02562846.

Efficacy of venlafaxine compared with tricyclic antidepressants in depressive disorder: a meta-analysis.

With respect to the pharmacological characteristic, venlafaxine is comparable with tricyclic antidepressants (TCAs), and venlafaxine might be comparable in efficacy. We performed a systematic review investigating the relative efficacy and tolerability of venlafaxine compared with TCAs (imipramine, clomipramine, amitriptyline, nortriptyline and desipramine). Relevant double-blind randomised trials were identified from systematic searches of electronic databases. An exact analysis of the estimated odds ratios of response of the TCA relative to venlafaxine showed no overall significance of treatment effect (P = 0.38). The odds ratios were not homogenous across studies (P = 0.0213). The average dose of venlafaxine was 103.5 mg/day and for the TCA 106.1 mg/day. An exact analysis of the estimated odds ratios of the withdrawals and side effects in the trials with a TCA relative to venlafaxine showed no overall significance of withdrawal. From our review, no significant difference in treatment effect between low dose of both venlafaxine and the TCAs could be found. In our opinion, because of the heterogeneity of the odds ratios, one cannot conclude that they are of equal efficacy.

[Symptoms of depression in strict Calvinist patients and in patients without religious affiliations: a comparison]. / Symptomen bij een depressie; bevindelijk gereformeerde versus niet-kerkelijke patiënten.

BACKGROUND: Culture can have a considerable influence on the way in which a depression is experienced, expressed or presented. Strict Calvinists or reformed pietists form an orthodox protestant cultural minority in the Netherlands. This orthodox wing of the Dutch Reformed Churches places a strong emphasis on personal religious experience of God's work of conversion. It is possible that symptoms of depression in this group differ somewhat from such symptoms in nonaffiliated depressed patients. AIM: To determine whether depressive symptoms in strict Calvinistic patients differ from those in non-affiliated patients. METHOD: Seventy depressed adult Dutch nationals receiving treatment as outpatients under the mental health service were asked to fill in a depression self-scoring list (Beck Depression Inventory II (bdi-ii)). A comparison was made between the total scores and scores of symptom clusters of strict Calvinists and the corresponding scores of non-affiliated patients. results The strict Calvinists had a lower total score than the non-affiliated patients on the bdi-ii and their scores were particularly lower for the symptom clusters suicidality and restrictions in functioning. CONCLUSION: Strict Calvinists differed from the non-affiliated patients in the way in which they presented on a depression self scoring list during depression. Perhaps strict Calvinists have less chance of being diagnosed and treated at an early stage because they conceal their depression and struggle on for a longer time. The study shows that insight into the religious background of Dutch national patients can be important for accurate psychiatric diagnostics.