Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

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.

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.

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.

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.

[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.

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.

Decreased functional connectivity of the insula within the salience network as an indicator for prospective insufficient response to antidepressants.

Insufficient response to treatment is the main cause of prolonged suffering from major depressive disorder (MDD). Early identification of insufficient response could result in faster and more targeted treatment strategies to reduce suffering. We therefore explored whether baseline alterations within and between resting state functional connectivity networks could serve as markers of insufficient response to antidepressant treatment in two years of follow-up. We selected MDD patients (N = 17) from the NEtherlands Study of Depression and Anxiety (NESDA), who received ≥ two antidepressants, indicative for insufficient response, during the two year follow-up, a group of MDD patients who received only one antidepressant (N = 32) and a healthy control group (N = 19) matched on clinical characteristics and demographics. An independent component analysis (ICA) of baseline resting-state scans was conducted after which functional connectivity within the components was compared between groups. We observed lower connectivity of the right insula within the salience network in the group with ≥ two antidepressants compared to the group with one antidepressant. No difference in connectivity was found between the patient groups and healthy control group. Given the suggested role of the right insula in switching between task-positive mode (activation during attention-demanding tasks) and task-negative mode (activation during the absence of any task), we explored whether right insula activation differed during switching between these two modes. We observed that in the ≥2 antidepressant group, the right insula was less active compared to the group with one antidepressant, when switching from task-positive to task-negative mode than the other way around. These findings imply that lower right insula connectivity within the salience network may serve as an indicator for prospective insufficient response to antidepressants. This result, supplemented by the diminished insula activation when switching between task and rest related networks, could indicate an underlying mechanism that, if not sufficiently targeted by current antidepressants, could lead to insufficient response. When replicated, these findings may contribute to the identification of biomarkers for early detection of insufficient response.

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

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[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.

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.

Cortisol, dehydroepiandrosterone sulfate, fatty acids, and their relation in recurrent depression.

BACKGROUND: Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity, fatty acid metabolism, and their relation have been associated with (recurrent) major depressive disorder (MDD), although conflicting findings exist. AIMS: To determine whether alterations in HPA-axis activity and fatty acids in recurrent MDD remain during remission (i.e. reflect a potential trait factor). Furthermore, to test the association between HPA-axis activity and fatty acids in patients versus controls. METHODS: We cross-sectionally compared 73 remitted unmedicated recurrent MDD patients with 46 matched never-depressed controls. Measurements included salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) (awakening, evening, and after sad mood induction) and erythrocyte fatty acid parameters: (I) three main fatty acids [omega-3 docosahexaenoic acid (DHA), and the omega-3 eicosapentaenoic acid/omega-6 arachidonic acid (EPA/AA)-ratio], and (II) structural fatty acid indices [chain length, unsaturation and peroxidation]. RESULTS: Patients showed higher cortisol awakening responses (p = 0.006) and lower evening cortisol/DHEAS ratios (p = 0.044) compared to matched controls. Fatty acids did not differ between patients and controls, but HPA-axis indicators were significantly associated with fatty acid parameters in both groups (0.001 ≤ p ≤ 0.043). Patients and controls significantly differed in the relations between awakening DHEAS or cortisol/DHEAS ratios and fatty acid parameters, including unsaturation and peroxidation indices (0.001≤ p ≤ 0.034). Significance remained after correction for confounders. CONCLUSIONS: Our results further support alterations in HPA-axis activity, i.e. a lower baseline, but higher responsiveness of awakening cortisol, in remitted medication-free recurrent MDD patients. Furthermore, the relationship between HPA-axis and fatty acids showed significant differences in recurrent MDD patients versus controls. Prospective research is needed to determine the predictive value of this relationship for MDD recurrence.

[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.

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.

[Systematic review of the side effects of benzodiazepines]. / Aandacht voor bijwerkingen van benzodiazepinen is belangrijk: een systematisch overzicht.

- Benzodiazepines are used frequently, despite the risk of severe side effects.- The Generic module 'Side effects; prevention, monitoring and treatment of side effects of drugs for psychiatric disorders' will be published soon. This contains recommendations for reduction in the risk for falls and fractures, cognitive problems and dependency related to the use of benzodiazepines or Z-drugs (zopiclone, zolpidem).- Prescribing physicians and pharmacists are compulsorily required to provide extensive information to patients on the anticipated effects and side effects of benzodiazepines, and on the limited prescription period.- A lot of information has become available from systematic literature reviews by the Benzodiazepines working group. Different benzodiazepines present similar risks of falls and fractures; higher doses present a higher risk, and Z-drugs are no safer.- In comparison with placebo, benzodiazepines and Z-drugs soon cause cognitive problems, even at low doses and in drugs with a short half-life. There is almost no development of tolerance for these cognitive problems.- Tailored patient education letters for ceasing benzodiazepine use are more effective than the standard letters. Different dose-tapering schemes have comparable success rates (on average 50%). Augmentation with cognitive behavioural therapy is effective for dose reduction.- It is therefore important to carefully consider the use of benzodiazepines before using them.

Agreement between clinical and MINI diagnoses in outpatients with mood and anxiety disorders.

BACKGROUND: Standardized Diagnostic Interviews (SDIs) such as the Mini International Neuropsychiatric Interview (MINI) are widely used to systematically screen for psychiatric disorders in research. To support generalizability of results to clinical practice, we assessed agreement between the MINI and clinical diagnoses. METHODS: Agreement was assessed in a large, real life dataset (n = 7016) using concordance statistics such as sensitivity, specificity, efficiency and area under the curve (AUC). RESULTS: 41.5% of clinical diagnoses were mood disorders, 26.5% were anxiety disorders. Overall, we found moderate agreement between MINI and clinical diagnoses (median efficiency: 0.92, median AUC: 0.79). For mood disorders, the AUC for all participants showed a range between 0.55 and 0.81 (median: 0.73), and for anxiety disorders the AUC ranged from 0.78 to 0.88 (median: 0.83). The AUC showed better agreement for mood disorders in the single diagnosis group than in the total group (median 0.77 vs. 0.71). For anxiety disorders, the AUC for the single diagnosis group was comparable to the AUC of the total group (median: 0.81 vs. 0.83 respectively). Numbers of false positives were high for both mood and anxiety diagnoses, but less so in the single diagnosis group. LIMITATIONS: Time lag between MINI and clinical diagnosis, the availability of only the primary clinical diagnosis, and relatively high severity of the current sample are limitations of the current study. CONCLUSIONS: Agreement between MINI and clinical diagnoses was moderate at best, which partly reflects the difference between the different measures used in the current study.

Biological profiling of prospective antidepressant response in major depressive disorder: Associations with (neuro)inflammation, fatty acid metabolism, and amygdala-reactivity.

BACKGROUND: A better understanding of factors underlying antidepressant non-response may improve the prediction of which patients will respond to what treatment. Major depressive disorder (MDD) is associated with alterations in fatty acid metabolism, (neuro)inflammation and amygdala-reactivity. However, their mutual relations, and the extent to which they are associated with prospective antidepressant-response, remain unknown. PURPOSE: To test (I) alterations in (neuro)inflammation and its associations with fatty acid metabolism and amygdala-reactivity in MDD-patients compared to controls, and (II) whether these alterations are associated with prospective paroxetine response. METHODS: We compared 70 unmedicated MDD-patients with 51 matched healthy controls at baseline, regarding erythrocyte membrane omega-6 arachidonic acid (AA), inflammation [serum (high-sensitivity) C-reactive protein (CRP)], and in a subgroup amygdala-reactivity to emotional faces using functional magnetic resonance imaging (fMRI) (N=42). Subsequently, we treated patients with 12 weeks paroxetine, and repeated baseline measures after 6 and 12 weeks to compare non-responders, early-responders (response at 6 weeks), and late-responders (response at 12 weeks). RESULTS: Compared to controls, MDD-patients showed higher CRP (p=0.016) and AA (p=0.019) after adjustment for confounders at baseline. AA and CRP were mutually correlated (p=0.043). In addition, patients showed a more negative relation between AA and left amygdala-reactivity (p=0.014). Moreover, AA and CRP were associated with antidepressant-response: early responders showed lower AA (p=0.018) and higher CRP-concentrations (p=0.008) than non-responders throughout the study. CONCLUSION: Higher observed CRP and AA, their mutual association, and relation with amygdala-reactivity, are corroborative with a role for (neuro)inflammation in MDD. In addition, observed associations of these factors with prospective antidepressant-response suggest a potential role as biomarkers. Future studies in independent samples are needed to replicate and test the clinical applicability of these biological predictors for treatment response to result in a precision/personalized medicine approach for treatment.