Case report: Hyperactive delirium after a single dose of zolpidem administered additionally to psychopharmacotherapy including clozapine.

The non-benzodiazepine hypnotic zolpidem is frequently administered as a short term psychopharmacotherapy for insomnia. Although it is well-established in a broad clinical routine and often well-tolerated, severe delirium and complex sleep behavior were reported in rare cases. Hereby, it remains unclear whether zolpidem's potential for delirium might be enhanced when combined with further psychopharmacotherapeutics. The present case report portrays a young male Caucasian inpatient with schizoaffective disorder, who was admitted due to severe hyperactive delirium after a single dose of zolpidem 10 mg that was administered in addition to already established psychopharmacotherapy including clozapine 200 mg/day, aripiprazole 15 mg/day and cariprazine 4.5 mg/day. In detail, disorientation, agitation, confabulations, bizarre behavior, and anterograde amnesia occurred shortly after ingestion of zolpidem and gained in intensity within a couple of hours. Once zolpidem was discontinued, the abovementioned symptoms subsided completely and did not reoccur. Since a clear temporal association could be drawn between the intake of zolpidem and the onset of hyperactive delirium, the present clinical experience should serve as a cautionary note for combining potent sedative-hypnotics and substances with anticholinergic properties, even in young adults in a good general condition. Moreover, our case argues for the necessity of further research into the pathomechanism of the interaction potential of non-benzodiazepines as zolpidem, especially with substances exerting anticholinergic properties, which are known for their potential to precipitate delirium. Therefore, the metabolic pathways of the concurrently administered substances should be further taken into account.

Case report: Interstitial pneumonitis after initiation of lamotrigine.

The second-generation anticonvulsant lamotrigine is widely used in the psychiatric field as a mood stabilizer or antidepressant augmentation therapy. Although particularly older anticonvulsants are known for their potential to cause hypersensitivity syndromes, newer antiepileptic drugs do hold a certain risk as well. Presenting a case of a 32-year-old male inpatient of African ethnicity suffering from a primary severe depressive episode in the course of a recurrent major depressive disorder, we report the occurrence of a rapid-onset drug-induced pneumonitis. Herewith, the interstitial pneumonitis occurred after the initiation of 25 mg lamotrigine as an augmentation therapy. Except for the clear temporal correlation between the administration of lamotrigine and the onset of pneumonitis, we did not reveal any further potentially causal diagnostic hints. Importantly, no relevant genetic variations of metabolizing enzymes or drug interactions resulting in lamotrigine overdosage as a potential cause of toxicity were identified. Our experience with a potentially life-threatening adverse drug reaction shortly after the initiation of the largely well-tolerated lamotrigine suggests a potential side effect under the second-generation anticonvulsant although similar adverse events are deemed to be very rare.

The impact of the COVID-19 pandemic on the psychosocial rehabilitation of forensic psychiatric patients in Austria.

The coronavirus disease 2019 (COVID-19) pandemic led to increased psychological distress and far-reaching restrictions of freedom. In March 2020, Austrian penal authorities enacted various safety and protection measures to mitigate the propagation of COVID-19. While infection rates in penal institutions were low, restrictive conditions of detention limited the forensic care of offenders. This retrospective longitudinal observational study aimed to evaluate the impact of the pandemic on the psychosocial rehabilitation in forensic psychiatry. Administrative and clinical data obtained from 97 males treated at an inpatient forensic mental health institution were compared before (January 2019 - mid-March 2020) and after (mid-March 2020 - May 2021) the enactment of pandemic-related restrictive measures. The study outcomes related to rehabilitative activities, social contacts, psychopathological stability, and compliance with institutional regulations. During the pandemic, a decrease in individual one-day temporary releases (64 vs. 3, p < .001) and one-day group excursions (103 vs. 10, p < .001) was observed. Likewise, visits by relatives (1440 vs. 429, p < .001) and legal guardians (286 vs. 130, p = .009) decreased. Regarding compliance with institutional regulations, illegal activities decreased from 27 to 8 after enactment of restrictive measures (p = .024). In contrast, long-term temporary releases (122 vs. 188 weeks, p = .131) and admissions to the acute ward (141 vs. 143, p = .712) remained unchanged. Overall, this study demonstrates the substantial impact of COVID-19 on the psychosocial care of forensic psychiatric patients and implies the necessity for guidelines to uphold an appropriate standard of forensic rehabilitation during future pandemics.

The Toxicity Potential of Antidepressants and Antipsychotics in Relation to Other Medication and Alcohol: A Naturalistic and Retrospective Study.

QT interval prolongation and ventricular tachyarrhythmia are potential adverse effects of antidepressant (AD) and antipsychotic- (AP) agents, especially when overdosed. Since AD and AP agents are often prescribed to patients suffering from suicidal intentions, it is essential to estimate these risks in the context of intoxications. This retrospective and naturalistic one-year registry study included 105 patients treated for oral intoxication at the University Department of Emergency Medicine in Vienna, Austria. AD/AP intoxications were present in 26 patients, while in the control group (n = 79) non-AD/AP drugs (n = 54) and exclusively alcohol (n = 25) were the toxic agents. QT intervals, the necessity of intubation, the extent of conscious state, and the subsequent discharge management were compared. The mean age was 34.94 ± 14.6 years, 62 patients (59%) were female. There were no significant between-group differences regarding QT prolongation >470 ms using Bazett's correction (p = 0.178), or >440 ms using Fridericia's correction (p = 0.760). No significant group differences concerning the need for intubation were observed (p = 0.747). The AD/AP and the control group did not significantly differ regarding Glasgow Coma Scale scores (p = 0.439). Patients with AD/AP intoxication were significantly more often transferred to the psychiatric department, while discharge to home was more likely in the control group (p = 0.002). These results suggest that the risk of a potentially life-threatening outcome in cases of intoxication with AD/AP is not substantially higher than in other easily available toxic agents, in line with the advantageous risk/benefit ratio of newer ADs and APs.

Brain morphometry and connectivity differs between adolescent- and adult-onset major depressive disorder.

BACKGROUND: Early-onset (EO) major depressive disorder (MDD) patients experience more depressive episodes and an increased risk of relapse. Thus, on a neurobiological level, adult EO patients might display brain structure and function different from adult-onset (AO) patients. METHODS: A total of 103 patients (66 females) underwent magnetic resonance imaging. Structural measures of gray matter volume (GMV) and functional connectivity networks during resting state were compared between EO (≤19 years) and AO groups. Four residual major depression symptoms, mood, anxiety, insomnia, and somatic symptoms, were correlated with GMV between groups. RESULTS: We found comparatively increased GMV in the EO group, namely the medial prefrontal and insular cortex, as well as the anterior hippocampus. Functional networks in EO patients showed a comparatively weaker synchronization of the left hippocampus with the adjacent amygdala, and a stronger integration with nodes in the contralateral prefrontal cortex and supramarginal gyrus. Volumetric analysis of depression symptoms associated the caudate nuclei with symptoms of insomnia, and persisting mood symptoms with the right amygdala, while finding no significant clusters for somatic and anxiety symptoms. CONCLUSIONS: The study highlights the important role of the hippocampus and the prefrontal cortex in EO patients as part of emotion-regulation networks. Results in EO patients demonstrated subcortical volume changes irrespective of sleep and mood symptom recovery, which substantiates adolescence as a pivotal developmental phase for MDD. Longitudinal studies are needed to differentiate neural recovery trajectories while accounting for age of onset.

Neurobiological predictors for clinical trajectories in fully remitted depressed patients.

BACKGROUND: Serious long term health and economic detriment accompany residual depressive symptoms even in fully remitted depressed patients (rMDD). Neurobiological predictors for rMDD patients' illness trajectory are absent. METHODS: rMDD patients (n = 39, female = 26) underwent magnetic resonance imaging. Baseline analyses of brain structure via voxel-based morphometry and brain function via functional connectivity (FC) at rest were correlated with changes in the Hamilton Depression Rating Scale between baseline and follow-up, and incidence of a recurrent major depressive episode (MDE) within a 2-year period. RESULTS: Gray matter increases in default mode (DN) regions in the posterior cingulate cortex (PCC) and increased resting-state FC within the DN both predicted change of depressive symptoms. Patients with recurrent MDE had larger bilateral nucleus accumbens and left insula volumes. Post hoc exploratory analysis of nucleus accumbens and insula conceptualized as part of the brain's reward circuit demonstrated reduced connectivity in patients with recurrent MDE. CONCLUSIONS: Higher DN connectivity and PCC volume coinciding with a more favorable course of symptoms suggest neural mechanisms of self-recovery beyond the phase of active medical treatment. Alterations in the brain's reward circuit might be a starting point for designing maintenance treatments that prevent recurrent MDEs in rMDD patients.

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D2/3 receptor agonist radioligand study.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.

Prefrontal networks dynamically related to recovery from major depressive disorder: a longitudinal pharmacological fMRI study.

Due to lacking predictors of depression recovery, successful treatment of major depressive disorder (MDD) is frequently only achieved after therapeutic optimization leading to a prolonged suffering of patients. This study aimed to determine neural prognostic predictors identifying non-remitters prior or early after treatment initiation. Moreover, it intended to detect time-sensitive neural mediators indicating depression recovery. This longitudinal, interventional, single-arm, open-label, phase IV, pharmacological functional magnetic resonance imaging (fMRI) study comprised four scans at important stages prior (day 0) and after escitalopram treatment initiation (day 1, 28, and 56). Totally, 22 treatment-free MDD patients (age mean ± SD: 31.5 ± 7.7; females: 50%) suffering from a concurrent major depressive episode without any comorbid DSM-IV axis I diagnosis completed the study protocol. Primary outcome were neural prognostic predictors of depression recovery. Enhanced de-activation of anterior medial prefrontal cortex (amPFC, single neural mediator) indicated depression recovery correlating with MADRS score and working memory improvements. Strong dorsolateral PFC (dlPFC) activation and weak dlPFC-amPFC, dlPFC-posterior cingulate cortex (PCC), dlPFC-parietal lobe (PL) coupling (three prognostic predictors) hinted at depression recovery at day 0 and 1. Preresponse prediction of continuous (dlPFC-PL: R2day1 = 55.9%, 95% CI: 22.6-79%, P < 0.005) and dichotomous (specificity/sensitivity: SP/SNday1 = 0.91/0.82) recovery definitions remained significant after leave-one-out cross-validation. Identified prefrontal neural predictors might propel the future development of fMRI markers for clinical decision making, which could lead to increased response rates and adherence during acute phase treatment periods. Moreover, this study underscores the importance of the amPFC in depression recovery.

Administration of ketamine for unipolar and bipolar depression.

OBJECTIVE: Clinical trials demonstrated that ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages. We reviewed currently available literature investigating efficacy, response rates and safety profile. METHODS: Twelve studies investigating unipolar, seven on bipolar depression were included after search in medline, scopus and web of science. RESULTS: Randomized, placebo-controlled or open-label trials reported antidepressant response rates after 24 h on primary outcome measures at 61%. The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, Beck Depression Inventory (BDI) 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points. Ketamine was always superior to placebo. Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible. Relapse rates ranged between 60% and 92%. To provide best practice-based information to patients, a consent-form for application and modification in local language is included. CONCLUSIONS: Ketamine constitutes a novel, rapid and efficacious treatment option for patients suffering from treatment resistant depression and exhibits rapid and significant anti-suicidal effects. New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings. However, long-term side effects are not known and short duration of antidepressant response need ways to prolong ketamine's efficacy.

Pharmacological treatment strategies in unipolar depression in European tertiary psychiatric treatment centers - A pharmacoepidemiological cross-sectional multicenter study.

This multicenter, cross-sectional study with retrospective assessment of treatment response evaluated the current prescription trends and pharmacological treatment strategies applied in European university/academic psychiatric centers in unipolar depression. Altogether, 1181 adult in- and outpatients with major depressive disorder (MDD) were enrolled in 9 academic sites in 8 European countries. Socio-demographic, clinical, and medication information were retrieved and the present symptom severity was assessed by the Montgomery and Åsberg Depression Rating Scale (MADRS). The symptom improvement during the current MDD episode was covered by retrospective MADRS measurements. Beyond descriptive statistics, analyses of variance (ANOVA) and Spearman correlation analyses were accomplished to determine the influence of symptom severity and treatment response on the prescription patterns. 53.4% of all MDD patients received a selective serotonin reuptake inhibitor (SSRI) and 23.6% a serotonin-norepinephrine reuptake inhibitor (SNRI) as first-line treatment. The majority of participants (59.4%) were treated with polypharmaceutical strategies (median: 2 psychiatric compounds per patient) and for the number of individual drugs we found a significant correlation with the current MADRS total score and the MADRS total score change during the present depressive episode. Benzodiazepines (33.2% of patients), antidepressants (29.0%), antipsychotics (24.2%), and mood stabilizers (10.1%) were the most frequently prescribed adjunctive agents. There were no significant differences between the different psychopharmacological classes used as augmentors in terms of symptom severity and treatment response. In summary, this international cross-sectional study revealed the widespread use of polypharmaceutical treatment strategies in European tertiary psychiatric treatment centers for the management of MDD.

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults.

Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.

Reduced default mode network suppression during a working memory task in remitted major depression.

Insufficient default mode network (DMN) suppression was linked to increased rumination in symptomatic Major Depressive Disorder (MDD). Since rumination is known to predict relapse and a more severe course of MDD, we hypothesized that similar DMN alterations might also exist during full remission of MDD (rMDD), a condition known to be associated with increased relapse rates specifically in patients with adolescent onset. Within a cross-sectional functional magnetic resonance imaging study activation and functional connectivity (FC) were investigated in 120 adults comprising 78 drug-free rMDD patients with adolescent- (n = 42) and adult-onset (n = 36) as well as 42 healthy controls (HC), while performing the n-back task. Compared to HC, rMDD patients showed diminished DMN deactivation with strongest differences in the anterior-medial prefrontal cortex (amPFC), which was further linked to increased rumination response style. On a brain systems level, rMDD patients showed an increased FC between the amPFC and the dorsolateral prefrontal cortex, which constitutes a key region of the antagonistic working-memory network. Both whole-brain analyses revealed significant differences between adolescent-onset rMDD patients and HC, while adult-onset rMDD patients showed no significant effects. Results of this study demonstrate that reduced DMN suppression exists even after full recovery of depressive symptoms, which appears to be specifically pronounced in adolescent-onset MDD patients. Our results encourage the investigation of DMN suppression as a putative predictor of relapse in clinical trials, which might eventually lead to important implications for antidepressant maintenance treatment.

Additive gene-environment effects on hippocampal structure in healthy humans.

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD).

Platelet serotonin transporter function predicts default-mode network activity.

BACKGROUND: The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence. METHODS: A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet Vmax. RESULTS: The present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity. CONCLUSION: This study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.

The genetic blueprint of major depressive disorder: contributions of imaging genetics studies.

OBJECTIVES: To review neuroimaging intermediate phenotypes of MDD and their relation to genetic risk variants. METHODS: A systematic literature search of peer-reviewed English language articels using PubMed ( www.pubmed.org ) was performed. RESULTS: Comprehensive evidence on the influence of serotonergic genes (SLC6A4, HTR1A, MAOA, TPH2) and BDNF on the following neural intermediate phenotypes is displayed: amygdala reactivity, coupling of amygdala-anterior cingulate cortex (ACC) activity, ACC volume, hippocampal volume and serotonin receptor 1A (5-HT1A) binding potential (BP). CONCLUSIONS: Intermediate phenotypes may bridge the gap between genotype and phenotype by reducing the impreciseness of psychiatric phenotypes and yield more insights into the underlying biology.

Imaging genetics of mood disorders.

Mood disorders are highly heritable and have been linked to brain regions of emotion processing. Over the past few years, an enormous amount of imaging genetics studies has demonstrated the impact of risk genes on brain regions and systems of emotion processing in vivo in healthy subjects as well as in mood disorder patients. While sufficient evidence already exists for several monaminergic genes as well as for a few non-monoaminergic genes, such as brain-derived neurotrophic factor (BDNF) in healthy subjects, many others only have been investigated in single studies so far. Apart from these studies, the present review also covers imaging genetics studies applying more complex genetic disease models of mood disorders, such as epistasis and gene-environment interactions, and their impact on brain systems of emotion processing. This review attempts to provide a comprehensive overview of the rapidly growing field of imaging genetics studies in mood disorder research.

Imaging genetics: implications for research on variable antidepressant drug response.

Genetic variation of SLC6A4, HTR1A, MAOA, COMT and BDNF has been associated with depression, variable antidepressant drug responses as well as impacts on brain regions of emotion processing that are modulated by antidepressants. Pharmacogenetic studies are using psychometric outcome measures of drug response and are hampered by small effect sizes that might be overcome by the use of intermediate endophenotypes of drug response, which are suggested by imaging studies. Such an approach will not only tighten the relationship between genes and drug response, but also yield new insights into the neurobiology of depression and individual drug responses. This article provides a comprehensive overview of pharmacogenetic, imaging genetics and drug response studies, utilizing imaging techniques within the context of antidepressive drug therapy.