Prevalence and prediction of dropout during depression treatment in routine outpatient care: an observational study.

Efficacious treatments are available for major depressive disorder (MDD), but treatment dropout is common and decreases their effectiveness. However, knowledge about prevalence of treatment dropout and its risk factors in routine care is limited. The objective of this study was to determine the prevalence of and risk factors for dropout in a large outpatient sample. In this retrospective cohort analysis, routinely collected data from 2235 outpatients with MDD who had a diagnostic work-up between 2014 and 2016 were examined. Dropout was defined as treatment termination without achieving remission before the fourth session within six months after its start. Total and item scores on the Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD) at baseline, and demographic variables were analyzed for their association with dropout using logistic regression and elastic net analyses. Data of 987 subjects who started routine outpatient depression treatment were included in the analyses of which 143 (14.5%) dropped out. Higher DM-TRD-scores were predictive for lower dropout odds [OR = 0.78, 95% CI = (0.70-0.86), p < 0.001]. The elastic net analysis revealed several clinical variables predictive for dropout. Higher SES, higher depression severity, comorbid personality pathology and a comorbid anxiety disorder were significantly associated with less dropout in the sample. In this observational study, treatment dropout was relatively low. The DM-TRD, an easy-to-use clinical instrument, revealed several variables associated with less dropout. When applied in daily practice and combined with demographical information, this instrument may help to reduce dropout and increase treatment effectiveness.

Fatty acids and recurrence of major depressive disorder: combined analysis of two Dutch clinical cohorts.

OBJECTIVE: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) alterations in patients with major depressive disorder (MDD) have been shown to persist after remission. Whether these alterations are risk factors for MDD recurrence remains unknown. Here, we examined whether fatty acids predict time until MDD recurrence in remitted MDD patients. METHODS: Data were used from remitted MDD patients of the Netherlands Study of Depression and Anxiety (n = 356) and the Depression Evaluation Longitudinal Therapy Assessment studies (n = 118). Associations of FAs with time until MDD recurrence up to 8-year follow-up were analyzed using Cox regression analyses. Study-specific estimates were pooled using mega- and meta-analysis techniques. RESULTS: 27.5% (NESDA) and 56.8% (DELTA) participants had an MDD recurrence. Pooled results showed that no FA was significantly associated with time until MDD recurrence (n-3 PUFAs: hazard ratio (HR) = 1.17, 95% confidence interval (CI) = 0.98-1.41, P = 0.082; n-6 PUFAs: HR = 1.08, 95% CI = 0.84-1.38, P = 0.55). CONCLUSION: In remitted MDD patients, circulating PUFAs were not associated with prospective risk of MDD recurrence. Consequently, circulating PUFAs are unlikely to reflect a vulnerability marker for recurrence, so correcting n-3 PUFA 'deficits' through supplementation does not seem a promising option to prevent MDD recurrence.

[Antidepressants are frequently prescribed but still critized; a perspective on causes and solutions]. / Antidepressiva: al decennia voor­geschreven én toch nog steeds bekritiseerd; een perspectief op oorzaken en oplossingen.

BACKGROUND: From around 1980, antidepressants (ad) have increasingly been prescribed, for longer periods of time, especially selective serotonin reuptake inhibitors (ssris). Paradoxically, their effectiveness is still doubted, especially outside the psychiatric profession.
AIM: To explain increase and offer a perspective on causes and solutions, and to indicate how to reach consensus.
METHOD: Position paper with critical analysis and synthesis of relevant literature.
RESULTS: The rise in AD prescriptions results from: 1. increased safety and ease of prescribing, 2. increased presentation and recognition of depression in primary care, 3. extension of indication criteria, 4. effective marketing strategies, and 5. effectiveness in acute phase (aad) and of relapse/recurrence prevention in continuation/maintenance phases (coad).Critics point to: 1. low added value of aad relative to placebo, 2. many drop-outs and non-responders, 3. relapse/recurrence prevention with coad works only for responders to aad, 4. relapse/recurrence after AD discontinuation often involves withdrawal symptoms, and 5. publication bias, selective reporting, selective patient selection, and suboptimal blinding, resulting in overestimated effectiveness and underestimated disadvantages.Factors that keep fueling the controversy are: 1. critics stress the net effectiveness of AD whereas proponents point at gross effectiveness which includes spontaneous recovery and placebo effect; 2. persistence of distrust in industry-funded rcts; 3. ideological positions, reinforced by conflicts of interest and selective citations; 4. lack of rcts with relevant long-term outcome measurements.
CONCLUSION: Although consensus is difficult to achieve given the ideological component, there are options. Three factors are critically important: confer to establish which data convince the opposition, response prediction (what works for whom), and rcts with long-term functional outcomes.

Predicting clinical course in major depressive disorder: The association between DM-TRD score and symptom severity over time in 1115 outpatients.

BACKGROUND: The Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD) is a promising prediction tool for major depressive disorder (MDD) based on variables associated with treatment outcome. The objective of our study was to examine the association between the DM-TRD and clinical course in a large cohort of MDD outpatients receiving treatment as usual. Furthermore, we examined whether the addition of an item measuring the presence of childhood adversity improved this association. METHODS: We included 1115 subjects with MDD (according to the DSM-IV) who were naturalistically treated at seven outpatient departments of a secondary mental healthcare center in the Netherlands. Data on subjects who had a diagnostic work-up between June 2014 and June 2016 were analyzed. Multilevel analyses were performed to examine the association between the DM-TRD score at baseline and clinical course, defined by symptom severity according to scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) over time. We also investigated whether an extra item measuring childhood adversity improved the model. RESULTS: The model including the DM-TRD and its interaction with time was superior to previous models. The addition of childhood adversity and its interaction with time did not improve the model. CONCLUSIONS: In depressed outpatients receiving treatment as usual, the solid longer-term association between higher DM-TRD scores and worse clinical course supports its usefulness in clinical practice. Childhood adversity did not improve the model value indicating that-counterintuitively-this parameter offers no additional predictive power to the variables included.

[The care standard 'Depressive disorders']. / De zorgstandaard Depressieve stoornissen.

BACKGROUND: The care standard 'Depressive disorders' describes the complete patient journey for patients with depressive symptoms and disorders from the age of 8 years onwards.
AIM: To describe the most important recommendations in this care standard.
METHOD: The care standard is an adaptation of the existing guidelines for depression, supplemented with practical knowledge from professionals and patients' values and preferences.
RESULTS: Core elements in the care for depression are an appropriate use of care and a focus on relapse prevention. A combination of psychotherapy and medication is indicated for persistent depression and more sessions of psychotherapy might be required. There is some evidence for the use of repetitive transcranial magnetic stimulation in treatment-resistant depression.
CONCLUSION: The care standard is an important instrument to improve the quality of care for depression at both the organisational and the regional level.

[Electroconvulsion therapy for persistent depression in the Netherlands; very low application rate]. / Elektroconvulsietherapie bij persisterende depressie in Nederland; zeer lage toepassingsgraad.

BACKGROUND: Of all depressive disorders, 20% has a persistent course. For persistent depressive patients, electroconvulsive therapy (ect) is recommended for this patient population, since it is the most potent treatment for depression. The Dutch depression guideline advises the use of ect for persistent depressive disorder at approximately 12 months after inadequate efficacy of psychotherapy and/or pharmacological treatment.
AIM: To quantify the use of electroconvulsive therapy in persistent depressive patients in the Netherlands.
METHOD: Quantitative research using the Dutch registration system (diagnosis-treatment-combination; dbc) information system (dis) of the Dutch Healthcare Authority (nza).
RESULTS: Of the patients within the dbc system (in 2014) with the main diagnosis of unipolar depression, 23,597 (26%) were registered for more than two years and could be classified as having a persistent depressive episode. Of these latter patients, only 278 (1.2%) received ect.
CONCLUSION: In the Netherlands, only 1.2% of patients with a persistent depression received ect, whereas this treatment could have been considered for 26% of this group. The low application rate might be caused by professionals' inadequate knowledge about ect and the premature use of the handicap model.

[Reaction on 'Persistant underuse of ECT for persistant depressive disorder?'] / Reactie op 'Persisterend ondergebruik van ECT bij persisterende depressieve stoornis?'.

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Focus on fatty acids in the neurometabolic pathophysiology of psychiatric disorders.

Continuous research into the pathophysiology of psychiatric disorders, such as major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and schizophrenia, suggests an important role for metabolism. This narrative review will provide an up-to-date summary of how metabolism is thought to be involved in the pathophysiology of these psychiatric disorders. We will focus on (I) the important role of fatty acids in these metabolic alterations, (II) whether fatty acid alterations represent epiphenomena or risk factors, and (III) similarities and dissociations in fatty acid alterations between different psychiatric disorders. (Historical) epidemiological evidence links fatty acid intake to psychiatric disorder prevalence, corroborated by altered fatty acid concentrations measured in psychiatric patients. These fatty acid alterations are connected with other concomitant pathophysiological mechanisms, including biological stress (hypothalamic-pituitary-adrenal (HPA)-axis and oxidative stress), inflammation, and brain network structure and function. Metabolomics and lipidomics studies are underway to more deeply investigate this complex network of associated neurometabolic alterations. Supplementation of fatty acids as disease-modifying nutraceuticals has clinical potential, particularly add-on eicosapentaenoic acid (EPA) in depressed patients with markers of increased inflammation. However, by interpreting the observed fatty acid alterations as partly (mal)adaptive phenomena, we attempt to nuance translational expectations and provide new clinical applications for these novel neurometabolic insights, e.g., to predict treatment response or depression recurrence. In conclusion, placing fatty acids in context can contribute to further understanding and optimized treatment of psychiatric disorders, in order to diminish their overwhelming burden of disease.

[The diagnosis of unipolar versus bipolar disorders using neuroimaging]. / Diagnostiek van uni- versus bipolaire stoornissen middels neuro-imaging.

BACKGROUND: Clinical differentiation between unipolar and bipolar depression can be a challenge. Additional diagnostic tools based on biomarkers could help resolve ambiguous cases. In this article we discuss studies from the dissertation 'Bipolar or unipolar? A brain teasing question', investigating to which extent neuroimaging could contribute to such detection.
AIM: To investigate whether neuroimaging can aid in differentiating between uni- and bipolar disorder.
METHOD: An analysis of the brain anatomy and functioning in medication-free uni- and bipolar participants and healthy controls using magnetic resonance imaging (MRI).
RESULTS: The results indicate that there are differences regarding both brain structure and functioning when comparing unipolar and bipolar patients. The nature of these differences corresponded with the present mood state. Diagnosis could also be predicted on an individual level. However, direct implementation during clinical practice is currently not possible, in part due to the heterogeneity of the findings and the limitations inherent to MRI-research.
CONCLUSION: Neuroimaging may be a promising technique for development of additional diagnostic tools to differentiate between unipolar and bipolar disorder.

Impact of deep brain stimulation of the ventral anterior limb of the internal capsule on cognition in depression.

BACKGROUND: Preliminary studies report no negative and a possible positive impact of deep brain stimulation (DBS) on cognition of patients with treatment-resistant depression (TRD). However, these studies neither controlled for practice effects nor compared active with sham stimulation. METHOD: To address these limitations, we compared 25 TRD patients, who underwent DBS of the ventral anterior limb of the internal capsule (vALIC), with 21 healthy controls (HCs) matched on gender, age and education level. Both groups did subtests of the Cambridge Neuropsychological Test Automated Battery assessing verbal and visuospatial memory, attention, cognitive flexibility, psychomotor functioning, planning and object naming. TRD patients were tested 3 weeks prior to DBS surgery (baseline), 3 weeks following surgery (T1) and following 52 weeks of DBS optimization (T2). HCs were tested at baseline, 6 weeks following baseline (T1) and 20-24 weeks following baseline (T2). Subsequently, TRD patients entered a randomized, double-blind crossover phase, in which they were tested in an active and a sham stimulation phase. RESULTS: TRD patients did not improve on a test of immediate verbal recognition from baseline to T1, whereas HCs did (group x time: p = 0.001). Both TRD patients and HCs improved over sessions on tests measuring delayed verbal recall, visuospatial memory, planning and object naming (all p < 0.01). Active and sham stimulation did not have an impact on any of the tests differentially. CONCLUSIONS: vALIC DBS neither has a lasting positive nor negative impact on cognition in TRD patients. DBS surgery might have a temporary negative effect on verbal memory.

Visuospatial planning in unmedicated major depressive disorder and bipolar disorder: distinct and common neural correlates.

BACKGROUND: Cognitive impairments are an important feature of both remitted and depressed major depressive disorder (MDD) and bipolar disorder (BD). In particular, deficits in executive functioning may hamper everyday functioning. Identifying the neural substrates of impaired executive functioning would improve our understanding of the pathophysiology underlying these disorders, and may eventually aid in discriminating between MDD and BD, which is often difficult during depression and remission. To date, mostly medicated MDD and BD subjects have been investigated, which may have influenced results. Therefore, we investigated executive functioning in medication-free depressed and remitted MDD and BD subjects. METHOD: We used the Tower of London (ToL) visuospatial planning task to assess behavioural performance and blood oxygen-level dependent responses in 35 healthy controls, 21 remitted MDD, 23 remitted BD, 19 depressed MDD and nine depressed BD subjects. RESULTS: Visuospatial planning per se was associated with increased frontostriatal activity in depressed BD compared to depressed MDD. In addition, post-hoc analyses indicated that visuospatial planning load was associated with increased parietal activity in depressed compared to remitted subjects, and BD compared to MDD subjects. Task performance did not significantly differ between groups. CONCLUSIONS: More severely affected, medication-free mood disorder patients require greater parietal activity to perform in visuospatial planning, which may be compensatory to maintain relatively normal performance. State-dependent frontostriatal hyperactivity during planning may be a specific BD characteristic, providing clues for further characterization of differential pathophysiology in MDD v. BD. This could potentially provide a biomarker to aid in the differentiation of these disorders.

[Reasons for including the Inventory of Depressive Symptomatology (IDS) and its shortened version (QIDS) in routine outcome monitoring by the Foundation Benchmark Mental Health (SBG)]. / Inventory of Depressive Symptomatology en verkorte versie in routine outcome monitoring van Stichting Benchmark GGZ.

BACKGROUND: Increasingly, health insurance companies are asking for treatment results in mental health care to be expressed in actual numbers. They base their request on the data supplied by sbg (Stichting Benchmark ggz) and the procedures that sbg has followed. For the purpose of benchmarking, the sbg has accepted a limited number of questionnaires. These tools are not suitable for performing routine outcome monitoring (rom) in clinical practice. There is a urgent need for these questionnaires to be replaced by a widely-used depression questionnaire, namely the ids. AIM: To present arguments supporting the view that the ids is an excellent and useful instrument that the sbg should accept as a measuring tool. METHOD: We discuss the quality of the ids by reviewing the literature. RESULTS: The ids is a high quality instrument well suited for measuring the severity of depressions and also is sufficiently sensitive for measuring mood improvements.
CONCLUSION: The ids is an excellent tool for performing rom measurements and is available free of charge. The authors argue that the sbg should accept this questionnaire as a suitable instrument for benchmarking.

Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans.

AIM: To test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. METHODS: As part of a larger study, we determined the effects of GLP-1 receptor activation on brain responses to anticipation and receipt of chocolate milk versus a tasteless solution, using functional MRI (fMRI). Obese subjects with type 2 diabetes, and obese and lean subjects with normoglycaemia (n = 48) underwent three fMRI sessions at separate visits with intravenous infusion of the GLP-1 receptor agonist exenatide, exenatide with prior GLP-1 receptor blockade by exendin-9-39 or placebo, during somatostatin pituitary-pancreatic clamps. RESULTS: Body mass index negatively correlated with brain responses to receipt of chocolate milk and positively correlated with anticipation of receipt of chocolate milk in brain areas regulating reward, appetite and motivation. Exenatide increased brain responses to receipt of chocolate milk and decreased anticipation of receipt of chocolate milk compared with placebo, paralleled by reductions in food intake. Exendin-9-39 largely prevented these effects. CONCLUSIONS: Our findings show that GLP-1 receptor activation decreases anticipatory food reward, which may reduce cravings for food and increases consummatory food reward, which may prevent overeating.

Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular disease comorbidity.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death in severe psychiatric disorders (depression, schizophrenia). Here, we provide evidence of how the effects of oxidative stress on fatty acid (FA) and one-carbon (1-C) cycle metabolism, which may initially represent adaptive responses, might underlie comorbidity between CVD and psychiatric disorders. METHOD: We conducted a literature search and integrated data in a narrative review. RESULTS: Oxidative stress, mainly generated in mitochondria, is implicated in both psychiatric and cardiovascular pathophysiology. Oxidative stress affects the intrinsically linked FA and 1-C cycle metabolism: FAs decrease in chain length and unsaturation (particularly omega-3 polyunsaturated FAs), and lipid peroxidation products increase; the 1-C cycle shifts from the methylation to transsulfuration pathway (lower folate and higher homocysteine and antioxidant glutathione). Interestingly, corresponding alterations were reported in psychiatric disorders and CVD. Potential mechanisms through which FA and 1-C cycle metabolism may be involved in brain (neurocognition, mood regulation) and cardiovascular system functioning (inflammation, thrombosis) include membrane peroxidizability and fluidity, eicosanoid synthesis, neuroprotection and epigenetics. CONCLUSION: While oxidative-stress-induced alterations in FA and 1-C metabolism may initially enhance oxidative stress resistance, persisting chronically, they may cause damage possibly underlying (co-occurrence of) psychiatric disorders and CVD. This might have implications for research into diagnosis and (preventive) treatment of (CVD in) psychiatric patients.

Worse off by waiting for treatment? The impact of waiting time on clinical course and treatment outcome for depression in routine care.

BACKGROUND: Long-term untreated major depressive disorder (MDD) is associated with a less favorable clinical course. Waiting time, defined as the interval between diagnostic workup and treatment initiation, may be clinically relevant given the prolongation of the pre-existing duration of untreated MDD. However, it is currently unknown whether and to what extent waiting time affects treatment course in routine outpatient care. METHODS: Retrospectively extracted data from 715 outpatients with MDD who received naturalistic outpatient MDD treatment were examined. Treatment outcome was defined as the difference in depression severity at the start of treatment and six months thereafter. Clinical course during waiting time was defined by the difference in severity at diagnostic workup and at treatment initiation. We analyzed the association between waiting time and treatment outcome and between waiting time and clinical course during this waiting time using multivariable regression analyses. We adjusted for severity and suicidality as potential confounders. RESULTS: An increased duration of the waiting time was associated with a less favorable treatment outcome (B = 0.049, SE = 0.019, p = 0.01). This association persisted after adjustment for potential confounders (B = 0.053, SE = 0.02, p = 0.01). No association was found between length of waiting time and clinical course during waiting time. LIMITATIONS: Strict definitions resulted in smaller sample sizes for the final analyses. The uncontrolled design may be questionable to definitively establish the impact of waiting time on treatment outcome. CONCLUSIONS: A prolonged waiting time is significantly associated with less favorable treatment outcome. Reduction of waiting time deserves priority in depression treatment planning to improve clinical outcomes.

Polyunsaturated fatty acids changes during electroconvulsive therapy in major depressive disorder.

Polyunsaturated fatty acids (PUFAs) have important electrochemical properties and have been implicated in the pathophysiology of major depressive disorder (MDD) and its treatment. However, the relation of PUFAs with electroconvulsive therapy (ECT) has never been investigated. Therefore, we aimed to explore the associations between PUFA concentrations and response to ECT in patients with MDD. We included 45 patients with unipolar MDD in a multicentre study. To determine PUFA concentrations, we collected blood samples at the first (T0) and twelfth (T12) ECT-session. We assessed depression severity using the Hamilton Rating Scale for Depression (HAM-D) at T0, T12 and at the end of the ECT-course. ECT-response was defined as 'early response' (at T12), 'late response' (after ECT-course) and 'no' response (after the ECT-course). The PUFA chain length index (CLI), unsaturation index (UI) and peroxidation index (PI) and three individual PUFAs (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA] and nervonic acid [NA]) were associated with response to ECT using linear mixed models. Results showed a significant higher CLI in 'late responders' compared to 'non responders'. For NA, 'late responders' showed significantly higher concentrations compared to 'early'- and 'non responders'. In conclusion, this study provides the first indication that PUFAs are associated with the efficacy of ECT. This indicates that PUFAs' influence on neuronal electrochemical properties and neurogenesis may affect ECT outcomes. Thereby, PUFAs form a potentially modifiable factor predicting ECT outcomes, that warrants further investigation in other ECT-cohorts.

[Staging and profiling of unipolar depression]. / Stagering en profilering van unipolaire depressies.

BACKGROUND: Not only is the heterogeneous concept of depression too comprehensive, it is also insufficiently differentiated. This serves as a barrier to scientific research and obscures the symptoms that should indicate what treatment is required. AIM: To describe an accurate model for staging and profiling depression. METHOD: We placed depressive disorders in the context of the entire course of the disorder and we regarded the course as a continuum of psychopathology. RESULTS: First of all we distinguish five stages: (1) the prodromal phase, (2) the first depressive episode, (3) residual symptoms following an episode, (4) the relapse episode and (5) the chronic and/or treatment-resistant depression. The higher the stage, the greater the need for complex and specialised treatment. As characteristics for profiling we distinguish (a) aetiological and pathophysiological variables and (b) clinical factors. The latter are the ones that mainly influence treatment from stage 2 onwards. CONCLUSION: In our article we give a tentative overview of possible characteristics for profiling. At the moment the clinical factors are the ones used most for assessment. Current research into the value of aetiological characteristics for profiling will increase the applicability of a staging and profiling model.

Robustness of radiomics to variations in segmentation methods in multimodal brain MRI.

Radiomics in neuroimaging uses fully automatic segmentation to delineate the anatomical areas for which radiomic features are computed. However, differences among these segmentation methods affect radiomic features to an unknown extent. A scan-rescan dataset (n = 46) of T1-weighted and diffusion tensor images was used. Subjects were split into a sleep-deprivation and a control group. Scans were segmented using four segmentation methods from which radiomic features were computed. First, we measured segmentation agreement using the Dice-coefficient. Second, robustness and reproducibility of radiomic features were measured using the intraclass correlation coefficient (ICC). Last, difference in predictive power was assessed using the Friedman-test on performance in a radiomics-based sleep deprivation classification application. Segmentation agreement was generally high (interquartile range = 0.77-0.90) and median feature robustness to segmentation method variation was higher (ICC > 0.7) than scan-rescan reproducibility (ICC 0.3-0.8). However, classification performance differed significantly among segmentation methods (p < 0.001) ranging from 77 to 84%. Accuracy was higher for more recent deep learning-based segmentation methods. Despite high agreement among segmentation methods, subtle differences significantly affected radiomic features and their predictive power. Consequently, the effect of differences in segmentation methods should be taken into account when designing and evaluating radiomics-based research methods.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

[Dose-escalation of SSRIS in major depressive disorder. Should not be recommended in current guidelines]. / Dosisverhoging van SSRI'S bij depressie; niet aan te bevelen in richtlijnen.

BACKGROUND: In cases where patients with unipolar depression do not respond to a standard dose of selective serotonin reuptake inhibitors (SSRIS), treatment guidelines often recommend a higher dose. A systematic review of the literature revealed uncertainty about the efficacy of dose escalation and pointed to methodological weaknesses in earlier research. AIM: To review current practice and results concerning dose-escalation of SSRIS. METHOD: We made a summary of previously published English articles that systematically reviewed previous SSRI-dose-escalation studies in depressed patients and present the results of a recent double-blind randomised dose-escalation study of paroxetine. By means of a 123I-ß-cit-spect study in a subgroup of the patients in the recent dose-escalation study it was possible to measure the amount of paroxetine bound to serotonin transporters. This provided combined clinical and pharmacological outcomes. RESULTS: The study with paroxetine provided clinical evidence that dose-escalation of paroxetine in depression was not effective and that adverse effects increased. The occupancy of the serotonin-transporters did not increase significantly after dose-escalation, despite increases in paroxetine serum levels. CONCLUSION: Dose-escalation of ssris for patients with unipolar depression who did not respond to a standard dose, does not improve response or the chance of remission. The pharmacological explanation for this is that the occupancy of the serotonin-transporters does not increase following dose-escalation.