Prolonged grief disorder in an inpatient psychiatric sample: psychometric properties of a new clinical interview and preliminary prevalence.

BACKGROUND: Prolonged Grief Disorder (PGD) was newly included in the ICD-11 and DSM-5-TR. It is not yet part of the standard assessments in many healthcare systems, including psychiatric wards. Because disordered grief is associated with suicidality, sleep problems and substance use disorders, an investigation into PGD in psychiatric inpatients is warranted. METHOD: We interviewed N = 101 psychiatric inpatients who were admitted to the open psychiatric wards and the day hospital of a German psychiatric hospital and who had lost a person close to them. Assessments comprised clinical interviews and self-report instruments covering PGD and other mental disorders. We specifically developed the International Interview for Prolonged Grief Disorder according to ICD-11 (I-PGD-11) for the study and examined its psychometric properties. RESULTS: The prevalence rate of PGD among bereaved patients according to ICD-11 was 16.83% and according to DSM-5-TR 10.89%. The I-PGD-11 showed good psychometric properties (Mc Donald's ω = 0.89, ICC = 0.985). Being female, having lost a child or spouse, and unnatural or surprising circumstances of the death were associated with higher PGD scores. TRIAL REGISTRATION: Approval was obtained by the ethics committee of the of the Goethe University Frankfurt (2021-62, 2023-17) and the Chamber of Hessian Physicians (2021-2730-evBO). The study was preregistered ( https://doi.org/10.17605/OSF.IO/K98MF ). LIMITATIONS: We only assessed inpatients of one psychiatric clinic in Germany, limiting the generalizability of our findings. CONCLUSION: The present study underlines the importance of exploring loss and grief in psychiatric inpatients and including PGD in the assessments. Given that a significant minority of psychiatric inpatients has prolonged grief symptoms, more research into inpatient treatment programs is needed.

Levomethadone Therapeutic Drug Monitoring to Aid Opioid Withdrawal Therapy: A Short Communication.

BACKGROUND: Therapeutic drug monitoring (TDM) is recommended for opioid maintenance therapy with levomethadone. However, TDM has not yet been applied to monitor opioid withdrawal therapy clinically, although tools to improve it are required. METHODS: In this observational cohort study, repeated TDM with levomethadone was performed according to a prospective opioid withdrawal study protocol. Objective and subjective opioid withdrawal symptoms were measured using validated rating scales and correlated to levomethadone plasma concentrations. Plasma levels were measured using high-pressure liquid chromatography with column switching and spectroscopic detection of methadone and its major metabolite. RESULTS: This study included 31 opioid-dependent patients who participated in standardized opioid withdrawal therapy. The serum levels of levomethadone were found to be highly variable and below the recommended therapeutic reference range of 250 ng/mL for maintenance therapy. These serum levels were positively correlated with dosage (r = 0.632; P < 0.001) and inversely correlated with subjective (r = -0.29; P = 0.011) and objective (r = -0.28; P = 0.014) withdrawal symptoms. CONCLUSIONS: The evidence provided sheds light on how to improve levomethadone withdrawal therapy in patients with opioid dependence. It seems likely that higher initial doses at the beginning and lower dose reductions would have been advantageous. TDM can enhance the safety of opioid withdrawal therapies, minimize withdrawal symptoms, and reduce dropout rates.

The Influence of Pharmacogenetics on the Clinical Relevance of Pharmacokinetic Drug-Drug Interactions: Drug-Gene, Drug-Gene-Gene and Drug-Drug-Gene Interactions.

Drug interactions are a well-known cause of adverse drug events, and drug interaction databases can help the clinician to recognize and avoid such interactions and their adverse events. However, not every interaction leads to an adverse drug event. This is because the clinical relevance of drug-drug interactions also depends on the genetic profile of the patient. If inhibitors or inducers of drug metabolising enzymes (e.g., CYP and UGT) are added to the drug therapy, phenoconcversion can occur. This leads to a genetic phenotype that mismatches the observable phenotype. Drug-drug-gene and drug-gene-gene interactions influence the toxicity and/or ineffectivness of the drug therapy. To date, there have been limited published studies on the impact of genetic variations on drug-drug interactions. This review discusses the current evidence of drug-drug-gene interactions, as well as drug-gene-gene interactions. Phenoconversion is explained, the and methods to calculate the phenotypes are described. Clinical recommendations are given regarding the integratation of the PGx results in the assessment of the relevance of drug interactions in the future.

Current use of anticholinergic medications in a large naturalistic sample of psychiatric patients.

Due to the high number of psychotropic drugs with anticholinergic potential, patients taking psychotropic drugs are at high risk for anticholinergic adverse drug reactions (ADRs). The aim of this study was to analyze the prevalence and type of pharmacodynamic anticholinergic drug-drug interactions in psychiatric patients. The retrospective longitudinal analysis used data from a large pharmacovigilance study conducted in ten German psychiatric hospitals. Anticholinergic burden of drugs was defined as "strong" or "moderate" based on current literature. Number and type of anticholinergic drugs were assessed. In total, 27,396 patient cases (45.6% female) with a mean age of 47.3 ± 18.3 years were included. 17.4% (n = 4760) of patients were ≥ 64 years. 35.4% of the patients received between one and four anticholinergic drugs simultaneously. A combination of drugs with anticholinergic potential was detected in 1738 cases (6.3%). Most prescribed drugs were promethazine (n = 2996), olanzapine (n = 2561), biperiden (n = 1074), and doxepin (n = 963). Patients receiving anticholinergic combinations were younger (45.7 vs. 47.4 years, p < 0.01) and had a longer inpatient stay (median 18 vs. 26.5 days, p < 0.001). The prevalence of anticholinergic drug use in psychiatry is high. Further efforts need to focus on reducing the rate of anticholinergics and inappropriate medication especially in the elderly. Anticholinergic ADRs can be prevented by avoiding high-risk drug combinations. Replacing tricyclic antidepressants and first-generation antihistamines with drugs with lower anticholinergic potential and avoiding biperiden could reduce 59.3% of anticholinergic drug application.

Pharmacodynamic Drug-Drug interactions of QT-prolonging drugs in hospitalized psychiatric patients.

At least 170 approved drugs are linked to QT prolongation, which can lead to serious adverse drug reactions (ADRs), such as Torsade de Pointes (TdP). The aim of this study was to analyze the prevalence and type of pharmacodynamic drug-drug interactions (DDIs) between QT-prolonging drugs in psychiatry. The present retrospective analysis used data from a large pharmacovigilance study, conducted in 10 psychiatric hospitals in Germany. Patients medication lists were screened for QT-prolonging drugs, classified according to the Arizona Center for Education and Research on Therapeutics (AZCERT). In total, 27,396 patient cases (46% female) with a mean (± standard deviation) age of 47 ± 18 years were included in the study. Altogether, 83% of the cases received at least one and up to eight QT-prolonging drugs at the same time. Combination of drugs with a known or possible risk for TdP (according to the AZCERT) was detected in 13,670 cases (50%). Most frequently prescribed psychotropic high-risk drugs (n = 48,995) were the antipsychotics pipamperone (n = 6202), quetiapine (n = 5718), prothipendyl (n = 4298), and risperidone (n = 4265). The replacement of high-risk drugs such as tricyclic antidepressants, levomepromazine, melperone, and promethazine with more tolerable drugs could avoid 11% of QT-prolonging drugs and increase the tolerability of psychopharmacological treatment. More than 80% of psychiatric patients receive at least one QT-prolonging drug during their hospital stay, and almost 50% of these drugs are combined in clinical practice. For the prevention of cardiac ADRs, the physician should evaluate the risk for QT prolongation for each drug and patient-specific risk factors before prescribing these drugs or drug combinations.

[Quality of treatment outcomes in alcohol- and substance-related disorders: an evaluation of inpatients from ten psychiatric hospitals]. / Ergebnisqualität bei alkohol- und substanzbezogenen Störungen: eine Auswertung stationär behandelter Patienten aus 10 psychiatrischen Kliniken.

AIM OF THE STUDY: Alcohol and substance-related disorders (ICD 10 F1x.x) are among the most frequent diagnoses made in hospitalized patients requiring somatic and psychiatric care. In order to assess the success of treatment, it is important to establish and implement outcome indicators in practice. METHOD: In 2016, global treatment indicators for admission and at discharge were collected at 10 Vitos clinics in Hesse (CGI and GAF). More than 10,000 patients with ICD10 F1x diagnoses were included in the evaluation. RESULTS: The evaluations show significant improvements of the clinical status as well as differences in treatment duration, remissions and gender differences. CONCLUSION: The study suggests that global indicators of outcome quality are useful in the assessment of treatment success of alcohol and substance-related disorders. Limitations of the study design, instruments and sample are critically reviewed.

Frequencies of Genetic Polymorphisms of Clinically Relevant Gene-Drug Pairs in a German Psychiatric Inpatient Population.

INTRODUCTION: Genetic variation is known to affect enzymatic activities allowing differentiating various metabolizer types (e. g., slow or rapid metabolizers), in particular CYP2C19 and CYP2D6. METHODS: PGx-testing was conducted in adult major depressive disorder inpatients admitted to the Vitos Klinik Eichberg between 11/2016 and 7/2017 (n=108, 57% female). We conducted a two-sided Z-Test (p=0.05) to analyze and compare frequencies of CYP2D6, CYP2C19, CYP3A4, CYP3A5 and CYP2C9 metabolizer groups with other European and psychiatric inpatient cohorts. The HLA-A and -B genes were also analyzed. RESULTS: Non-normal metabolizer status of CYP2D6 were present in 47%. More specifically, 35 % were intermediate, 7% poor and 4% ultra-rapid metabolizers. 68% were CYP2C19 non-normal metabolizers. 8% were ultra-rapid and 31% rapid metabolizers. Notably, only 13% were NM for CYP2C19 and NM for CYP2D6 (activity score of 1 or more). For CYP2C9 we found 16% to be intermediate metabolizers, 1.0% poor metabolizer. CYP3A4 and CYP3A5 genetic polymorphisms were present in 25% and 19% respectively. HLA-B TAG- SNPs for *15:01 was positive in 25 patients, showing the need for different Tag-SNPs in Caucasians. HLA-B *57:01 TAG-SNP was positive in 8% of the patients, HLA-A TAG-SNP for *31:01 in Caucasians was positive in 9%. Z-Test showed statistical significance for our results. DISCUSSION: Our results suggest that our psychiatric inpatients were enriched with genotypes consistent with non-normal drug metabolism compared to reference populations. We therefore conclude that pharmacogenetic testing should be implemented in clinical practice to guide drug therapy.

Potentially inappropriate medication in older psychiatric patients.

PURPOSE: Many psychotropic drugs are listed as potentially inappropriate medication (PIM) in the older population. Potentially inappropriate means that prescription of those drugs in older adults may cause significant harm. The objective of this study was to analyze the prevalence and sort of PIM prescribing in a naturalistic, real-world psychiatric setting. METHODS: The retrospective analysis gathered data from a large pharmacovigilance study, conducted at 10 psychiatric hospitals. Data from inpatients aged ≥ 65 years were included for the analysis. The number and sort of PIM, as defined by the German PRISCUS list, were controlled by analyzing the patients' medication profile. RESULTS: In total, 4760 patient cases (59.2% female) with a mean (mean ± standard deviation (SD)) age of 77.33 ± 7.77 years were included into the study. Altogether, 1615 cases (33.9%) received at least 1 PRISCUS-PIM per day (regular and as-needed medication included). The most frequently prescribed PRISCUS-PIM (n = 2144) were zopiclone > 3.75 mg/day (n = 310), lorazepam > 2 mg/day (n = 269), haloperidol > 2 mg/day (n = 252), and diazepam (n = 182). Cases with PRISCUS-PIM were younger (75.7 vs. 78.2 years, p < 0.001) and had a longer (26 vs. 22 days, p < 0.001) hospital length of stay. Replacing benzodiazepines and z-substances, haloperidol > 2 mg, tricyclic antidepressants, first generation antihistaminergic drugs, and clonidine by non-PIM could reduce 69.9% of PRISCUS-PIM-prescribing. CONCLUSIONS: The prevalence of PRISCUS-PIM is high in the hospitalized psychiatric setting. Rational deprescribing of inappropriate anticholinergics, benzodiazepines, and antipsychotics in the older population is a key component to reduce the risk of adverse drug reactions. More tolerable medications should be prescribed.

Prevalence and sort of pharmacokinetic drug-drug interactions in hospitalized psychiatric patients.

Psychiatric patients are high-risk patients for the development of pharmacokinetic drug-drug interactions (DDIs), leading to highly variable (victim) drug serum concentrations. Avoiding and targeting high-risk drug combinations could reduce preventable adverse drug reactions (ADRs). Pharmacokinetic cytochrome P450 (CYP)-mediated DDIs are often predictable and, therefore, preventable. The retrospective, longitudinal analysis used informations from a large pharmacovigilance study (Optimization of pharmacological treatment in hospitalized psychiatric patients study, study number 01VSF16009, 01/2017), conducted in 10 psychiatric hospitals in Germany. Medication data were examined for the co-prescription of clinically relevant CYP inhibitors or inducers and substrates of these enzymes (victim drugs). In total, data from 27,396 patient cases (45.6% female) with a mean (mean ± standard deviation (SD)) age of 47.3 ± 18.3 years were available for analysis. CYP inhibitors or inducers were at least once prescribed in 14.4% (n = 3946) of the cases. The most frequently prescribed CYP inhibitors were melperone (n = 2504, 28.1%) and duloxetine (n = 1324, 14.9%). Overall, 51.0% of the cases taking melperone were combined with a victim drug (n = 1288). Carbamazepine was the most frequently prescribed CYP inducer (n = 733, 88.8%). Combinations with victim drugs were detected for 58% (n = 427) of cases on medication with carbamazepine. Finally, a DDI was detected in 43.6% of the cases in which a CYP inhibitor or inducer was prescribed. The frequency of CYP-mediated DDI is considerably high in the psychiatric setting. Physicians should be aware of the CYP inhibitory and inducing potential of psychotropic and internistic drugs (especially, melperone).

Effects of age on depressive symptomatology and response to antidepressant treatment in patients with major depressive disorder aged 18 to 65 years.

BACKGROUND: There is evidence that symptomatology in patients with major depressive disorder (MDD) changes with age. However, studies comparing depressive symptomatology between different age groups during antidepressant therapy are rare. We compared demographic and clinical characteristics in depressed patients of different age groups at baseline and during treatment. METHODS: 889 MDD inpatients were divided into four age groups (18-29, 30-39, 40-49, 50-65 yrs.). Demographic and clinical characteristics including depressive symptomatology (assessed by the Inventory of Depressive Symptoms) were assessed at baseline and weekly during treatment. RESULTS: At baseline, young patients (18-29 years) significantly more often reported cognitive symptoms like irritability, suicidality, negative self-concept and interpersonal sensitivity and more often suffered from drug abuse and comorbid personality disorders. Late middle aged patients (50-65 years) significantly more often suffered from neuro-vegetative symptoms such as reduced general interest, sexual interest and sleep disturbances and more often showed a recurrent MDD and comorbid physical disorders. During therapy, symptoms such as interpersonal sensitivity in young patients and low interest in sex in late middle aged patients persisted until the end of treatment while all other symptoms declined until day 56. LIMITATIONS: The herein presented age differences in depressive symptomatology only hold true for the study medication and are not generalizable to other antidepressants agents. CONCLUSION: There are substantial differences in the clinical presentation of depression between age groups. Whereas many of these differences disappear during treatment, some differences persisted until the end of treatment. These findings my help to more specifically tailor the treatment of depressed patients.

Pharmacogenetic Testing in Depressed Patients and Interdisciplinary Exchange between a Pharmacist and Psychiatrists Results in Reduced Hospitalization Times.

INTRODUCTION: Pharmacogenetics (PGx) is a well-researched tool to improve pharmacotherapy. So far, it has not been implemented into daily practice in Germany. In psychopharmacology, substantial benefit can be expected by using PGx due to the excessive CYP metabolism of the psychotropic drugs as well as already discovered target polymorphisms (e. g., serotonin receptor). METHODS: An evaluation of a naturalistic pharmacist-led pilot implementation of PGx testing in a psychiatric hospital in patients undergoing inpatient treatment for major depressive disorder was conducted. Length of stay, number of antidepressant switches, and rehospitalization rates were analyzed. A PGx-tested intervention cohort of n=49 was retrospectively compared to a control cohort of n=94 patients. RESULTS: The intervention cohort showed significantly shorter stays than the control, after correction of the length of hospital stay and the time to genotyping results (mean intervention: 36.3 d (SD: ±19.3 d); control: 46.6 d (±19.1 d); p=0.003). Antidepressant- naïve patients had the largest benefit from the PGx testing (intervention: 24.7 d (±13.5 d); control: 50.2 d (±22.5 d); p < 0.001. The number of antidepressant switches during the entire stay did not differ between the groups: 0.41 (0.64) vs. 0.21 (0.46); p=0.063 [95% CI -0.01-0.40]). DISCUSSION: Depressed patients, especially treatment-naïve, seem to benefit from PGx testing prior to treatment. Although the results of this retrospective evaluation are promising, more systematic prospective studies are needed to assess the effect of PGx testing on the treatment of major depressive disorder.

Predictors of the effectiveness of an early medication change strategy in patients with major depressive disorder.

BACKGROUND: Patients with Major Depressive Disorder (MDD) who are non-improvers after two weeks of antidepressant treatment have a high risk of treatment failure. Recently, we did not find differences in outcomes in non-improvers randomized to an early medication change (EMC) strategy compared to treatment as usual (TAU). This secondary analysis investigated possible predictors of higher remission rates in the EMC strategy. METHODS: Of 192 non-improvers (i.e. decrease of ≤20% on the HAMD-17 depression scale) after a two-week treatment with escitalopram, n = 97 were randomized to EMC (immediate switch to high doses of venlafaxine XR) and n = 95 to TAU (continued escitalopram until day 28 with non-responders switched to venlafaxine XR). We first analyzed patient characteristics, psychopathological features and subtypes of MDD by logistic regression analyses as possible predictors of remission rates. In a second investigation, we analyzed the predictors, which showed a significant association in the first analysis before Bonferroni-Holm correction by chi-squared tests separated for treatment groups. All analyses were corrected by Bonferroni-Holm method. RESULTS: The first analyses yielded no statistically significant results after correction for multiple testing. In the second analyses, however, patients with prior medication at study entry showed higher remission rates in EMC than in TAU (24.2% versus 8.6%, p = 0.017; Bonferroni-Holm corrected significance level: p = 0.025.). Furthermore, patients with a recurrent course of MDD benefited less from treatment as usual (p = 0.009; Bonferroni-Holm corrected significance level: p = 0.025). Age, sex, age of onset, psychiatric or somatic comorbidities, and other subtypes of MDD did not predict remission rates. CONCLUSIONS: Although in our first analysis we found statistically non-significant results, the second analysis showed significant differences in remission rates between patients with or without previous medication and in patients with recurrent MDD or the first depressive episode. It would therefore be valuable to examine in larger and prospective studies whether remission rates can be increased by quick escalation of treatment in certain subgroups of patients. Promising subgroups to be tested are patients who were previously medicated, and who show a recurrent course of MDD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00974155 . Registered at the 10th of September 2009. Retrospectively registered.

Validation of pharmacist-physician collaboration in psychiatry: 'the Eichberger-model'.

Background Collaboration between physicians and pharmacists can increase medication safety. In the "Eichberger model" a clinical pharmacist is employed and working full time in a psychiatric hospital. Objective The aim of this study was to determine the expected type of expertise from a clinical pharmacist in psychiatry and the acceptance of the pharmacist's recommendations. Method All email requests to the clinical pharmacist from January 1st to April 30th 2015 were screened retrospectively and type of requester and content of request were extracted. Maintenance rate of drug therapy was analyzed by reviewing patient charts 2 weeks after medication prescription. Results A total of 147 requests were included. 85 (57.8%) requests were from attending physicians and 62 (42.2%) from residents. 82.1% of all physicians were contacting the clinical pharmacist during the study period. Most common reasons for requests were: appropriate drug selection (31.3%), drug interactions (25.2%), possible adverse drug events (17%) and switching drugs (12.2%). The acceptance rate by the physicians was 100%, with an implementation and maintenance rate of both 98.6%. Conclusion We found a high acceptance level of the pharmacist's recommendations. The pharmacist's skills were requested by the majority of physicians and included a in a large variety of specific questions. A pharmacist can play an important role to optimize patient care in collaboration with the physician in psychiatry.

Early improvement of executive test performance during antidepressant treatment predicts treatment outcome in patients with Major Depressive Disorder.

Executive dysfunctions frequently occur in patients with Major Depressive Disorder and have been shown to improve during effective antidepressant treatment. However, the time course of improvement and its relationship to treatment outcome is unknown. The aim of the study was to assess the test performance and clinical outcome by repetitive assessments of executive test procedures during antidepressant treatment. Executive test performance was assessed in 209 -patients with Major Depressive Disorder (mean age 39.3 ± 11.4 years) and 84 healthy controls five times in biweekly intervals from baseline to week 8. Patients were treated by a defined treatment algorithm within the early medication change study (EMC trial; ClinicalTrials.gov NCT00974155), controls did not receive any intervention. Cognitive domains were processing speed, cognitive flexibility, phonemic and semantic verbal fluency. Intelligence was assessed at baseline. Depression severity was tested once a week by the Hamilton Depression Rating Scale (HAMD17). 130 patients (62%) showed executive dysfunctions in at least one of four tests at baseline. Linear mixed regression models revealed that the course of depression severity was associated to the course of cognitive flexibility (p = 0.004) and semantic verbal fluency (p = 0.020). Cognitive flexibility and semantic verbal fluency may be candidates easily to apply for therapy response prediction in clinical routine, which should be tested in further prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00974155 EudraCT: 2008-008280-96.

A combined marker of early non-improvement and the occurrence of melancholic features improve the treatment prediction in patients with Major Depressive Disorders.

BACKGROUND: Early Improvement of depressive symptoms within two weeks of antidepressant treatment is a highly sensitive but less specific predictor of later treatment outcome. The aim of this study was to identify clinical features at treatment initiation which are associated with early improvement and non-improvement as well as to identify variables predicting non-remission in patients showing an early improvement. METHODS: 889 patients with a major depressive episode according to DSM-IV who had participated in an antidepressant treatment trial served as study sample. Clinical predictors (demographic variables, psychopathology, comorbid disorders) were analysed in 698 (79%) early improver (Hamilton Depression Rating Scale reduction > 20% after 14 days of treatment) compared to 191 (21%) non-improver. Furthermore, clinical predictors for later remission and non-remission were analysed in the 698 patients showing an early improvement. RESULTS: Patients with more severe depression and suicidality were more likely to become non-improver, and also non-remitter after 8 weeks of treatment in case of early improvement. Early improver with melancholic, anxious or atypical depression as well as with comorbid social phobia or avoidant personality disorder had an increased risk for non-remission at study end. The combined marker of early non-improvement and the occurrence of melancholic features increased the specificity of treatment prediction from 30% to 90%. LIMITATIONS: Comorbid disorders were only assessed at baseline. CONCLUSIONS: Patients with early non-improvement and melancholic features at treatment initiation have a particularly high risk of later non-remission. This group of patients should be considered more attention in treatment decisions.

Guideline adherence of antidepressant treatment in outpatients with major depressive disorder: a naturalistic study.

Little is known about guideline adherence of naturalistic antidepressant drug therapy in outpatients with major depressive disorder (MDD). The aim of the study was to analyze guideline adherence, especially regarding treatment length, treatment evaluation and medication change strategies. We investigated 889 patients with MDD who had been admitted for inpatient treatment and were enrolled in the early medication change trial (ClinicalTrials.gov NCT00974155). We investigated all patients at screening visit regarding previous outpatient drug treatment in the index episode, which was assessed by structured interviews. Demographic variables were obtained from patients and patients' records. 51.0% of the patients had received previous drug treatment in the index episode, 56.6% were females, and their mean age was 40.0 years. In the 153 patients who were pharmacologically treated at least 8 weeks, medication was not changed in 129 (84.3%) patients. Patients who had a medication change in their index episode (n = 24, 15.7%) waited 71.1 weeks (±110.4) for their treatment optimization. Only 5 of those 153 patients (3.3%) had a dose increase, whereas 132 patients (86.3%) had no dose adaption at all. Antidepressant blood levels were measured in 46 patients (30.1%). We conclude that a large proportion of patients with MDD is not treated in adherence to treatment guidelines recommending treatment evaluation (e.g. therapeutic drug monitoring) and treatment change after 4 to 8 weeks in non-responders. Earlier treatment optimization may prevent long-term suffering of patients and may avoid inpatient treatment.

Dosing Recommendations of Aripiprazole Depot with Strong Cytochrome P450 3A4 Inhibitors: A Relapse Risk.

A 50-year-old male patient with comorbid human immunodeficiency virus developed a relapse of bipolar disorder after a switch from oral aripiprazole 10 mg/day to intramuscular aripiprazole depot 200 mg every 28 days plus oral aripiprazole 5 mg/day. The patient was concomitantly taking lopinavir, saquinavir, ritonavir, silybum marianum extract, and omeprazole. Only 1 week after the switch, the patient developed mood swings, irritability, depressive mood, and lack of drive. The oral aripiprazole was increased again to stabilize the patient. The measured trough drug concentration of aripiprazole was low and may be correlated to the relapse. When oral aripiprazole was increased back to 10 mg again, the depressive symptoms subsided. The dose of the next depot injection was increased to 300 mg and that of oral aripiprazole decreased back to 5 mg/day. Because trough drug concentrations were still low after 28 days, the depot dose was increased to 400 mg every 28 days, which is double that recommended in the prescriber's information. Two months after the initial switch from oral to intramuscular aripiprazole, the patient's mood stabilized on aripiprazole depot 400 mg every 28 days. More clinical data, especially regarding the pharmacokinetic drug interactions of aripiprazole depot are needed to improve dosing recommendations, and prevent relapses or adverse drug events. Genetic polymorphisms may play an important role in the clinical relevance of drug interactions concerning aripiprazole depot.

A patient with acute mania after discontinuation of lithium. / Akut manischer Patient nach Absetzen von Lithium.

The abrupt discontinuation of lithium in patients with bipolar disease puts the patient at a high risk for a relapse. Lithium is a drug with a narrow therapeutic index. Intoxications might occur during the treatment. The individual risk-benefit-ratio should be discussed with the patient before starting lithium. Atypical antipsychotics are an alternative to lithium in the treatment of bipolar disease. Several guidelines recommend the use of atypical antipsychotics in a long acting (depot) formulation in bipolar patients (off label use). The long acting (depot) formulations offer the benefit that during a hypomanic or a beginning manic episode, the drug can not easily be discontinued. During the phase of early signs of a beginning manic episode the patients tend not to see the need to take any medication (lack of insight into illness) which leads to non-adherence that puts the patient at a high risk for a manic episode. If lithium is prescribed, special counselling is needed, especially about fluid intake and potential drug interactions (NSAIDS, ACE-inhibitors, diuretics).