After MRI studies suggested the efficacy of ethyl-EPA in reducing the progressive brain atrophy in Huntington disease (HD), trials were conducted to test its efficacy as a treatment for HD. Trials that continued for 6 months did not find any significant improvement, urging discontinuation of the drug. However, trials that continued for 12 months indicated improvement of motor functions in these patients.

We searched 12 electronic databases to find randomised clinical trials relevant to our inclusion criteria. After screening, only five papers were included. Continuous and binary variables were analysed to compute the pooled mean difference (MD) and risk ratio (RR), respectively. Quality effect model meta-analysis was used as a post hoc analysis for studies at 12 months.

Meta-analysis indicated that ethyl-eicosapentaenoic acid (EPA) has no significant effect on any scale of HD at 6 months. At 12 months, two studies suggested significant improvements of the Total Motor Score and Total Motor Score–4 in both fixed and quality effect models [MD = −2.720, 95% CI (−4.76, –.68), p = 0.009; MD = −2.225, 95% CI (−3.842, −0.607), p = 0.007], respectively. Maximal chorea score showed significant results [MD = −1.013, 95% CI (−1.793, −0.233), p = 0.011] in only fixed-effect model, while no improvement was detected for Stroop colour naming test or symbol digit modality.

Meta-analysis indicated a significant improvement of motor scores only after 12 months. These results should be interpreted cautiously because only two studies had assessed the efficacy of ethyl-EPA after 12 months with one of them having a 6-month open-label phase.

Oxidative stress has been suggested to increase after electroconvulsive therapy (ECT), a treatment which continues to be the most effective for severe depression. Oxidative stress could potentially be mechanistically involved in both the therapeutic effects and side effects of ECT.

We measured sensitive markers of systemic and central nervous system (CNS) oxidative stress on DNA and RNA (urinary 8-oxodG/8-oxoGuo, cerebrospinal fluid 8-oxoGuo, and brain oxoguanine glycosylase mRNA expression) in male rats subjected to electroconvulsive stimulations (ECS), an animal model of ECT. Due to the previous observations that link hypothalamic–pituitary–adrenal (HPA)-axis activity and age to DNA/RNA damage from oxidation, groups of young and middle-aged male animals were included, and markers of HPA-axis activity were measured.

ECS induced weight loss, increased corticosterone (only in middle-aged animals), and decreased cerebral glucocorticoid receptor mRNA expression, while largely leaving the markers of systemic and CNS DNA/RNA damage from oxidation unaltered.

These results suggest that ECS is not associated with any lasting effects on oxidative stress on nucleic acids neither in young nor middle-aged rats.

To review the available literature on obsessive–compulsive symptom (OCS)/obsessive–compulsive disorder (OCD) in patients with schizophrenia.

Electronic searches were carried out to locate studies reporting various aspects of OCS/OCD in patients with schizophrenia.

Available evidence suggests that prevalence of OCS/OCD in patients with schizophrenia is much higher than prevalence in general population and it is seen in all the stages of schizophrenia, starting from at risk mental state to chronic/stabilisation/deficit phases. Symptom profile of OCS/OCD in schizophrenia is similar to that seen in patients with OCD only. Presence of OCS/OCD is associated with higher severity of symptoms of schizophrenia and more negative outcome. At present there is very limited data on the efficacy/effectiveness of various pharmacological measures and psychological interventions, for management of OCS/OCD in patients with schizophrenia. There is some evidence pointing towards beneficial effect of certain antipsychotics, antidepressants and cognitive behaviour therapy. Management of OCS/OCD in patients with schizophrenia involves proper assessment. If the OCS/OCD is related to use of particular antipsychotic use, initial attempt must be made to reduce the dose of antipsychotics, however, if this is not effective, than addition of a selective serotonin reuptake inhibitor (SSRIs) must be considered. If the OCS/OCD is not related to the use of antipsychotic medication, than depending up on the severity of psychotic symptoms, addition of SSRIs must be considered.

This review suggests that OCS/OCD is highly prevalent among patients with schizophrenia and there is limited good quality evidence to make any specific recommendations for management.

Seclusion and mechanical restraint are coercive interventions used at psychiatric hospitals when patients are at imminent risk of harming themselves and/or others. Although these interventions have been used for decades, it remains unclear whether seclusion or mechanical restraint is superior in terms of efficacy and safety. Therefore, we aimed to systematically review studies comparing the intended and unintended effects of seclusion and mechanical restraint.

A systematic search of PubMed and Embase was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Quantitative studies comparing the intended and unintended effects of seclusion and mechanical restraint were included.

The search identified 868 unique records. Fourteen of these (3 reporting on randomized controlled trials and 11 reporting on observational studies) met the predefined inclusion criteria. The study methodology including outcome measures varied significantly across studies. The results of the 11 studies using a subjective outcome measure (patient preference/emotions) were in favour of seclusion, while the 3 studies using an objective outcome measure (duration of coercion/need for transition to other coercive measure) favoured mechanical restraint. There was a high risk of residual confounding by indication and/or bias affecting the reported results.

Based on the available literature, it cannot be determined whether seclusion is superior to mechanical restraint or vice versa. Further studies using stringent methodology are required to answer this question. A cautious conclusion based on this review is that the availability of both methods seems necessary – as both have their pros and cons.

Prior studies suggest that a dysregulation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is involved in the pathophysiology of major depression. We aimed to elucidate changes in cortical GABA content in relation to depression and electroconvulsive therapy (ECT) using magnetic resonance spectroscopy (MRS).

In total, 11 patients with major depression or depressive episode of bipolar disorder (mean pre-ECT Ham-17 of 26) and 11 healthy subjects were recruited. GABA was quantified using short-TE MRS in prefrontal and occipital cortex. Other neurometabolites such as glutathione (GSH), N-acetylaspartate (NAA) and glutamate (Glu) were secondary outcome measures.

No significant differences in GABA/Cr levels were observed between patients at baseline and healthy subjects in prefrontal cortex, t(20)=0.089, p=0.93 or occipital cortex t(21)=0.37, p=0.72. All patients improved on Ham-17 (mean post-ECT Ham-17 of 9). No significant difference was found in GABA, Glu, glutamine, choline or GSH between pre- and post-ECT values. However, we observed a significant decrease in NAA levels following ECT t(22)=3.89, p=0.0038, and a significant correlation between the NAA decline and the number of ECT sessions p=0.035.

Our study does not support prior studies arguing for GABA as a key factor in the treatment effect of ECT on major depression. The reduction in NAA levels following ECT could be due to neuronal loss or a transient dysfunction in prefrontal cortex. As no long-term follow-up scan was performed, it is unknown whether NAA levels will normalise over time.

Depression is a disorder caused by genetics and environmental factors. The aim of this study was to perform a review investigating the interaction between genetic variations located in genes involved in hypothalamus–pituitary–adrenal axis (HPA-axis) and stressful life events (SLEs) in depression.

In this systematic review, we selected articles investigating the interaction between genes involved in the HPA-axis, such as Arginine Vasopressin (AVP), Angiotensin Converting Enzyme (ACE), Corticotrophin Releasing Hormone (CRH), Corticotrophin Releasing Hormone Receptor 1 (CRHR1), Corticotrophin Releasing Hormone Receptor 2 (CRHR2), FK506 binding protein (FKBP5), Nuclear Receptor subfamily 3 group C member 1 (NR3C1), Nuclear Receptor subfamily 3 group C member 2 (NR3C2), and SLE. The literature search was conducted using the Pubmed, Embase, and PsychINFO databases in adherence with the PRISMA guidelines.

The search yielded 48 potentially relevant studies, of which 40 were excluded following screening. Eight studies were included in the final review. A total of 97 single nucleotide polymorphisms (SNPs) were examined in the eight included studies. The most prevalent gene was FKBP5, and the best studied polymorphism was FKBP5:rs1360780. Two of the five studies reported significant gene–environment (G × E) interactions between rs1360780 and SLE. Overall, four studies reported significant G × E interactions between FKBP5, CRH, or CRHR1 and SLE, respectively. No significant G × E interactions were found for the remaining genes.

Our results suggest that genetic variation in three genes in the HPA-axis possibly moderate the effects of SLEs in depression.

The aim of this paper was to provide a systematic review and update on the available longitudinal studies on the impact of prenatal alcohol exposure (PAE) on language, speech and communication development, as well as associated potential environmental confounders during the preschool period.

A literature search was restricted to English, full‐text, peer‐reviewed, longitudinal studies in from 1970 until present: PUBMed, Scopus, Web of Science {C-e Collection, Biological Abstracts, KCI-Kean Journal Database, Russian Science Citation Index, SciELO Citation Index, Zoological Rec-d}, Academic Search Premier (Africa-Wide Information, CINAHL, MEDLINE, PsycINFO. Keywords included: prenatal alcohol exposure (PAE); speech or language or communication outcomes; neurocognitive or neurodevelopment or neurobehavioral or neurobehavioural; infant or baby or toddler or preschooler; longitudinal or follow-up. The inclusion criteria included (i) longitudinal cohorts with at least 2 time-points; (ii) association of light, moderate or heavy PAE on language, speech or communication delay, development or disorder; (iii) environmental confounders; (iv) infants up to preschool age.

Six studies satisfied the threshold for inclusion. Three studies reported that PAE was significantly associated with receptive or expressive delay. These studies demonstrated lower scores on either receptive or expressive communication in the alcohol group in comparison to the non-alcohol group, even after controlling for environmental factors up to 36 months.

Evidence from the longitudinal studies reviewed suggest that PAE influenced delays in receptive and expressive communication up to 36 months. Contextual risk factors played a significant role in language development over time and especially as children approached school age.

Korsakoff’s syndrome (KS) is a chronic neuropsychiatric disorder characterised by severe anterograde amnesia and executive deficits. Theory of Mind (ToM) is the capacity to represent others’ mental states such as their knowledge, thoughts, feelings, beliefs, and intentions in order to explain and predict their behaviour. Surprisingly this topic has received hardly any attention in research on KS, although the severity of behavioural problems in KS suggest possible ToM difficulties. The aim of the present study was therefore to assess whether cognitive and affective ToM are impaired in patients with KS.

We examined 21 KS patients and 21 age- and gender-matched healthy controls on three standardised tests that assess cognitive and affective ToM, including the subtests of the mini-Social Cognition and Emotional Assessment battery and a specialised version of the Sally–Anne Test.

KS patients showed largely impaired cognitive and affective ToM compared to healthy controls, as reflected in large effect sizes on both cognitive and affective ToM tests. Executive deficits explained problems in emotion recognition, but not other ToM aspects.

KS patients have large impairments in both cognitive and affective aspects of social cognition. Their ability to recognise emotions, take the perspective of others, and understand socially awkward situations is vastly compromised. The impairments in ToM functioning are to a large degree functionally discrepant from executive disorders that are commonly present in KS. This study therefore highlights the importance to properly index ToM functioning in neuropsychological assessments for individuals with a possible KS diagnosis.

To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms.

Forty women aged 18–45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is, Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle.

Significant changes in Δ (actual − 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase.

Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.

Although accumulating evidence supports the hypothesis that immune/inflammatory mechanisms are associated with the pathophysiology of bipolar disorder (BD), data about the profile of chemokines (chemotactic cytokines) and chemokine receptors are still scarce. The current study was designed to evaluate the expression of chemokine receptors on lymphocytes of patients with BD in comparison with controls.

Thirty-three patients with type I BD (N = 21 in euthymia; N = 6 in mania/hypomania; N = 6 in depression) and 22 age- and sex-matched controls were subjected to clinical evaluation and peripheral blood draw. The expression of chemokine receptors CCR3, CCR5, CXCR4, and CXCR3 on CD4+ and CD8+ lymphocytes was assessed by flow cytometry.

Patients with BD had decreased percentage of CD4+CXCR3+ (p = 0.024), CD4+CCR3+ (p = 0.042), and CD4+CCR5+ (0.013) lymphocytes in comparison with controls. The percentage of both CD4+ and CD8+ lymphocytes expressing the chemokine receptor CXCR4 was similar in patients with BD and controls. Likewise, the percentages of CD8+CXCR3+, CD8+CCR3+, and CD8+CCR5+ lymphocytes were similar in patients with BD and controls.

Our findings reinforce the hypothesis that immune pathways, especially involving CD4+ lymphocytes, are involved in the physiopathology of BD.

Bipolar disorder (BD) is a debilitating, lifelong neuropsychiatric illness characterised by unsteady mood states which vacillate from (hypo)mania to depression. Despite the availability of pharmaceutical agents which can be effective in ameliorating the acute affective symptoms and prevent episodic relapse, BD is inadequately treated in a subset of patients. The endocannabinoid system (ECS) is known to exert neuromodulatory effects on other neurotransmitter systems critical in governing emotions. Several studies ranging from clinical to molecular, as well as anecdotal evidence, have placed a spotlight on the potential role of the ECS in the pathophysiology of BD. In this perspective, we present advantages and disadvantages of cannabis use in the management of illness course of BD and provide mechanistic insights into how this system might contribute to the pathophysiology of BD.

We highlight the putative role of selective cannabinoid receptor 2 (CB2) agonists in BD and briefly discuss findings which provide a rationale for targeting the ECS to assuage the symptoms of BD. Further, data encourage basic and clinical studies to determine how cannabis and cannabinoids (CBs) can affect mood and to investigate emerging CB-based options as probable treatment approaches.

The probable role of the ECS has been almost neglected in BD; however, from data available which suggest a role of ECS in mood control, it is justified to support conducting comprehensive studies to determine whether ECS manipulation could positively affect BD. Based on the limited available data, we suggest that activation of CB2 may stabilise mood in this disorder.

Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk-taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general.

We have longitudinally examined the behaviour of drunk drivers (n = 203) and controls (n = 211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents.

The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI.

Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities.

There is accumulating evidence that the error-related negativity (ERN), an event-related potential elicited after erroneous actions, is altered in different psychiatric disorders and may help to guide treatment options. Thus, the ERN is a promising candidate as a psychiatric biomarker. Basic methodological requirements for a biomarker are that their measurements are standardised and reliable. The aim of the present study was to establish ERN acquisition in a reliable, time-efficient and patient-friendly way for use in clinical practice.

Healthy subjects performed a speeded Eriksen Flanker Task that increases the number of errors. In a test–retest design (N = 14) with two sessions separated by 28 days we assessed the reliability of the ERN. To ensure external validity, we aimed to replicate previously reported correlation patterns of ERN amplitude with (A) number of errors and (B) negative affect. In order to optimise the clinical use of the task, we determined to which extent the task can be shortened while keeping reliability >0.80.

We found excellent reliability of the ERN (intraclass correlation coefficients = 0.806–0.947) and replicated ERN correlation patterns. The task can be halved to a patient-friendly length of 200 trials (recorded in 8 min) keeping reliability >0.80.

The modified task provides reliable and efficient recording of the ERN, facilitating its use as a psychiatric biomarker.

To evaluate brexpiprazole adjunctive to antidepressant therapies (ADTs) as maintenance treatment in patients with major depressive disorder with inadequate response to ADT, utilising a novel study design.

The study comprised an 8-week prospective treatment period with open-label ADT with double-blind placebo treatment and a 24-week randomised treatment period. Investigators and patients were blinded to treatment periods, randomisation criteria, and timing of randomisation. Patients with early response to open-label ADT were withdrawn at Week 6. Patients fulfilling criteria for inadequate response were randomised to ADT+brexpiprazole 1–3 mg/day, or ADT+placebo. The primary endpoint was full remission: Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤10 and ≥50% decrease from randomisation (i.e. baseline) in MADRS total score for at least 8 consecutive weeks.

The primary efficacy analysis failed to show a statistically significant difference between the proportions of patients on ADT+brexpiprazole (21.4%) and ADT+placebo (24.9%) achieving full remission; odds ratio: 0.83; p=0.2641. The secondary endpoint of change from baseline to Week 6 in MADRS total score showed no difference between ADT+brexpiprazole and ADT+placebo (−0.4; p=0.3259). The most frequent treatment-emergent adverse event (TEAE) in patients receiving ADT+brexpiprazole was weight increased (9.5% vs. 5.0% in ADT+placebo). The incidence of TEAEs leading to withdrawal in the randomised treatment period was 6.3% in the ADT+brexpiprazole group and 3.4% in the ADT+placebo group.

Adjunctive brexpiprazole did not differentiate from ADT+placebo on the primary endpoint of full remission. A number of design elements in this previously untried study design may have contributed to the study result. Brexpiprazole was well tolerated.

Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood–brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice.

Specifically, we implanted wild-type C57BL/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 µl/h at different concentrations (0, 3.5, 7 and 14 mg/ml, i.e. 0, 12.5, 25 and 50 µg/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks.

None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg/ml of clozapine increased PPI but had no effects on locomotor activity.

Our findings indicate that 7 mg/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.

The aim of the current study was to examine whether and to what extent mood disorders, comprising major depression and bipolar disorder, are accompanied by structural changes in the brain as measured using voxel-based morphometry (VBM).

We performed a VBM study using a 3Т MRI system (GE Discovery 750w) in patients with mood disorders (n=50), namely, 39 with major depression and 11 with bipolar disorder compared to 42 age-, sex- and education-matched healthy controls.

Our results show that depression was associated with significant decreases in grey matter (GM) volume of the regions located within the medial frontal and anterior cingulate cortex on the left side and middle frontal gyrus, medial orbital gyrus, inferior frontal gyrus (triangular and orbital parts) and middle temporal gyrus (extending to the superior temporal gyrus) on the right side. When the patient group was separated into bipolar disorder and major depression, the reductions remained significant only for patients with major depressive disorder.

Using VBM the present study was able to replicate decreases in GM volume restricted to frontal and temporal regions in patients with mood disorders, mainly major depression, compared with healthy controls.