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1.  Annals of general psychiatry reviewer acknowledgement 2014 
Contributing reviewers
The editors of Annals of General Psychiatry would like to thank all of our reviewers who have contributed to the journal in volume 13 (2014).
PMCID: PMC4333244
2.  Dromokaition Psychiatric Hospital of Athens: from its establishment in 1887 to the era of deinstitutionalization 
Dromokaition Psychiatric Hospital opened its doors in 1887, following the donation made by Zorzis Dromokaitis from the island of Chios. Private donations and all forms of charities had contributed to a large extent in the establishment of hospitals across Greece, during the late 19th and the early 20th century. Dromokaition was one of them but it was also unique, as it was the first psychiatric hospital in Athens, admitting patients from every part of the country. This paper aimed at highlighting the long service of the institution through the different historical periods the country went through. We present the chronicle of its foundation, the development of its inner structure, and the medical and organizational influences which it received, along the way. The therapeutic methods used during the first decades of its operation reflected the corresponding European standards of the time. As a model institution from its foundation, it followed closely the prevailing European guidelines, throughout its historical path, either as an independent institution or as an integrated one within the National Health Service.
PMCID: PMC4332453
Dromokaition Psychiatric Hospital; Internment; Biological psychiatry; Psychosurgery; Occupational therapy; Deinstitutionalization; Private donation
3.  Adjuvant low-frequency rTMS in treating auditory hallucinations in recent-onset schizophrenia: a randomized controlled study investigating the effect of high-frequency priming stimulation 
Repetitive transcranial magnetic stimulation (rTMS) has been found to be effective in reducing frequency and duration of auditory verbal hallucinations (AVH). Priming stimulation, which involves high-frequency rTMS stimulation followed by low-frequency rTMS, has been shown to markedly enhance the neural response to the low-frequency stimulation train. However, this technique has not been investigated in recent onset schizophrenia patients. The aim of this randomized controlled study was to investigate whether the effects of rTMS on AVH can be enhanced with priming rTMS in recent onset schizophrenia patients.
Forty recent onset schizophrenia patients completed the study. Patients were randomized over two groups: one receiving low-frequency rTMS preceded by priming and another receiving low-frequency rTMS without priming. Both treatments were directed at the left temporo-parietal region. The severity of AVH and other psychotic symptoms were assessed with the auditory hallucination subscale (AHRS) of the Psychotic Symptom Rating Scales (PSYRATS), the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression (CGI).
We found that all the scores of these ratings significantly reduced over time (i.e. baseline through 1, 2, 4 and 6 weeks) in both the treatment groups. We found no difference between the two groups on all measures, except for significantly greater improvement on loudness of AVH in the group with priming stimulation during the follow-ups (F = 2.72; p < .05).
We conclude that low-frequency rTMS alone and high-frequency priming of low-frequency rTMS do not elicit significant differences in treatment of overall psychopathology, particularly AVH when given in recent onset schizophrenia patients. Add on priming however, seems to be particularly better in faster reduction in loudness of AVH.
PMCID: PMC4333242
Schizophrenia; Priming TMS; Transcranial magnetic stimulation; Auditory verbal hallucinations; Randomized controlled trial; Recent onset
4.  Clinical Global Impression-severity score as a reliable measure for routine evaluation of remission in schizophrenia and schizoaffective disorders 
This study aimed to compare the performance of Positive and Negative Syndrome Scale (PANSS) symptom severity criteria established by the Remission in Schizophrenia Working Group (RSWG) with criteria based on Clinical Global Impression (CGI) severity score. The 6-month duration criterion was not taken into consideration.
A convenience sample of 112 chronic psychotic outpatients was examined. Symptomatic remission was evaluated according to RSWG severity criterion and to a severity criterion indicated by the overall score obtained at CGI-Schizophrenia (CGI-SCH) rating scale (≤3) (CGI-S).
Clinical remission rates of 50% and 49.1%, respectively, were given by RSWG and CGI-S, with a significant level of agreement between the two criteria in identifying remitted and non-remitted cases. Mean scores at CGI-SCH and PANSS scales were significantly higher among remitters, independent of the remission criteria adopted. Measures of cognitive functioning were largely independent of clinical remission evaluated according to both RSWG and CGI-S. When applying RSWG and CGI-S criteria, the rates of overall good functioning yielded by Personal and Social Performance scale (PSP) were 32.1% and 32.7%, respectively, while the mean scores at PSP scale differed significantly between remitted and non-remitted patients, independent of criteria adopted. The proportion of patients judged to be in a state of well-being on Social Well-Being Under Neuroleptics-Short Version scale (SWN-K) were, respectively, 66.1% and 74.5% among remitters according to RSWG and CGI-S; the mean scores at the SWN scale were significantly higher only among remitters according to CGI-S criteria.
CGI severity criteria may represent a valid and user-friendly alternative for use in identifying patients in remission, particularly in routine clinical practice.
PMCID: PMC4332923
5.  Prognostic influence of witness/victim experiences and PTSD-specific symptoms on working and educational capacity: a comparison between two groups of individuals post-trauma 
Trauma exposure depends of the type of trauma and can result in the development of posttraumatic stress disorder (PTSD). The type of traumatization (such as Holocaust experiences and other sources of trauma) and specific symptoms of PTSD have influences on the outcome, and specific symptoms of PTSD influence personal and professional outcomes. Another factor is the role of the victim in their traumatization. Some patients are actively traumatized through being victims of torture, while others are passively traumatized by witnessing the traumatization of others.
We compared two groups of victim/witness trauma sufferers (PTSD vs. Holocaust-experience PTSD (HE-PTSD)) with regard to PTSD symptoms, educational and working capacity, and functional outcome parameters.
HE-PTSD survivors with victim/witness trauma experience showed substantially more specific PTSD symptoms and higher symptom-specific intensities but had high social function and education levels. The intensity and type of intrusive memories and sociodemographic factors do not seem to have a prognostic influence on working or educational outcomes.
Identifying the combined victim/witness experience seems to play an important prognostic role in the assessment of PTSD victims. Further studies should consider these findings within other specific traumatization groups.
PMCID: PMC4329647
PTSD symptoms; Educational/working capacity; Prognostic outcome
6.  Smoking reduction in psychiatric inpatients is feasible: results from a 12-month prospective study 
Despite the fact that smoking is a crucial morbidity factor among psychiatric patients, little progress has been made in order to reduce smoking during psychiatric hospitalization.
We studied the smoking behaviour of patients admitted to a non-smoking psychiatric ward, after monitoring them for smoking habits and helping them cope in order to modify their smoking behaviour. For a period of 12 months, we conducted a prospective study of simple smoking avoidance measures in the 2nd Department of Psychiatry of Attikon University Hospital in Athens.
From 330 admitted patients, 170 (51.5%) were smokers; they were monitored for their smoking habits and encouraged by the nursing staff to reduce smoking. The mean number of cigarettes per day (CPD) at admission was 32.2 (sd 22.1) and upon discharge 14.1 (sd 14.8) (t = 11.7, p < 0.001). Most of the smokers, 142 (83.5%), managed to reduce their cigarette consumption per day. Diagnosis did not affect the reduction or increase in CPD. The only factor that predicted reduction in CPD was the female sex.
Our findings indicate that seriously mentally ill psychiatric inpatients despite negative preconceptions and stereotypes respond well to simple measures aiming to reduce their smoking and modify their behaviour.
PMCID: PMC4328044
Psychiatric inpatients; Smoking reduction; Nursing intervention
7.  How do GP practices and patient characteristics influence the prescription of antidepressants? A cross-sectional study 
Under-prescription of antidepressants (ADs) among people meeting the criteria for major depressive episodes and excessive prescription in less symptomatic patients have been reported. The reasons influencing general practitioners’ (GPs) prescription of ADs remain little explored. This study aimed at assessing the influence of GP and patient characteristics on AD prescription.
This cross-sectional study was based on a sample of 816 GPs working within the main health care insurance system in the Seine-Maritime district of France during 2010. Only GPs meeting the criteria for full-time GP practice were included. The ratio of AD prescription to overall prescription volume, a relative measure of AD prescription level, was calculated for each GP, using the defined daily dose (DDD) concept. Associations of this AD prescription ratio with GPs’ age, gender, practice location, number of years of practice, number of days of sickness certificates prescribed, number of home visits and consultations, number and mean age of registered patients, mean patient income, and number of patients with a chronic condition were assessed using univariate and multivariate analysis.
The high prescribers were middle-aged (40–59) urban GPs, with a moderate number of consultations and fewer low-income and chronic patients. GPs’ workload (e.g., volume of prescribed drug reimbursement and number of consultations) had no influence on the AD prescription ratio. GPs with more patients with risk factors for depression prescribed fewer ADs, however, which could suggest the medications were under-prescribed among the at-risk population.
Our study described a profile of the typical higher AD prescriber that did not include heavy workload. In future work, a more detailed assessment of all biopsychosocial components of the consultation and other influences on GP behavior such as prior training would be useful to explain AD prescription in GP’s practice.
Electronic supplementary material
The online version of this article (doi:10.1186/s12991-015-0041-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4308843  PMID: 25632295
Antidepressants; General practice; General practitioners; Cross-sectional study; Pharmaco-epidemiology
8.  Long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response—a prospective open-label study 
While the frequency and importance of antipsychotic switching in patients with schizophrenia, there is insufficient evidence with regard to switching strategy. Quetiapine is one of the drugs of choice for switch because of its unique receptor profile. However, there were no data on the long-term clinical and neurocognitive effect of quetiapine in patients who had responded inadequately to prior antipsychotics. The purpose of this study is to examine the long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response. We hypothesized that quetiapine would show long-term effectiveness in broad symptom dimensions including negative and neurocognitive symptoms while having good tolerability.
Twenty-nine subjects with schizophrenia who did not respond to their current monotherapy of antipsychotic or who could not tolerate the treatment were switched to quetiapine and assessed at baseline and at 3, 6, and 12 months. The outcome measures included the brief assessment of cognition in schizophrenia (BACS), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale (CGI), the Schizophrenia Quality of Life Scale Japanese version (JSQLS), the Athens Insomnia Scale (AIS), and the Drug Attitude Inventory with 30 items (DAI-30). The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), HbA1c, prolactin (PRL), and body weight were also evaluated.
Statistically significant improvements were observed in all subscores of the PANSS, the GAF, and the symptoms and side effects subscale of the JSQLS, the DIEPSS, the AIS, and the PRL level, and nearly significant improvements were observed in the DAI-30. Quetiapine monotherapy was associated with significant improvement in the verbal memory test, even after controlling for the practice effect. Although quetiapine was well tolerated, three subjects dropped out because of the worsening of the psychotic symptoms and two additional subjects dropped out because of somnolence.
In this open-label, single-arm study of 29 patients, quetiapine improved both the clinical symptoms and the neurocognitive impairment in chronic schizophrenia patients who failed to respond to prior antipsychotic treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s12991-014-0039-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4308846  PMID: 25632293
Schizophrenia; Quetiapine; Switching; Antipsychotic; Negative symptom; Cognitive impairment; Treatment resistance
9.  Clinical and economic outcomes of adjunctive therapy with pregabalin or usual care in generalized anxiety disorder patients with partial response to selective serotonin reuptake inhibitors 
This study is done to compare the effect of adjunctive therapy with pregabalin versus usual care (UC) on health-care costs and clinical and patients consequences in generalized anxiety disorder (GAD) subjects with partial response (PR) to a previous selective serotonin reuptake inhibitor (SSRI) course in medical practice in Spain.
Post hoc analysis of patients with PR to SSRI monotherapy enrolled in a prospective 6-month naturalistic study was done. PR was defined as a Clinical Global Impression (CGI) scale score ≥3 and insufficient response with persistence of anxiety symptoms ≥16 in the Hamilton Anxiety Rating Scale (HAM-A). Two groups were analyzed: 1) adjunctive therapy (AT) with pregabalin (150–600 mg/day) to existing therapy and 2) UC (switching to a different SSRI or adding another anxiolytic different than pregabalin). Costs included GAD-related health-care resources utilization. Consequences were a combination of psychiatrist-based measurements [HAM-A, CGI, and Montgomery-Asberg Depression Rating Scale (MADRS)] and patient-reported outcomes [Medical Outcomes Study Sleep (MOS-sleep) scale, disability (World Health Organization Disability Assessment Schedule II (WHO-DAS II) and quality-of-life (Euro Qol-5D (EQ-5D)]. Changes in both health-care costs and scale scores were compared separately at end-of-trial visit by a general linear model with covariates.
Four hundred eighty-six newly prescribed pregabalin and 239 UC GAD patients [mean (SD) HAM-A 26.7 (6.9) and CGI 4.1 (0.5)] were analyzed. Adding pregabalin was associated with significantly higher mean (95% CI) score reductions vs. UC in HAM-A [−14.9 (−15.6; −14.2) vs. −11.2 (−12.2; −10.2), p < 0.001] and MADRS [−11.6 (−12.2; −10.9) vs. −7.8 (−8.7; −6.8), p < 0.001]. Changes in all patient-reported outcomes favored significantly patients receiving pregabalin, including quality-of-life gain; 26.4 (24.7; 28.1) vs. 19.4 (17.1; 21.6) in the EQ-VAS, p < 0.001. Health-care costs were significantly reduced in both cohorts yielding similar 6-month costs; €1,565 (1,426; 1,703) pregabalin and €1,406 (1,200; 1,611) UC, p = 0.777. The effect of sex on costs and consequences were negligible.
In medical practice, GAD patients with PR to SSRI experienced greater consequence improvements with adjunctive therapy with pregabalin versus UC, without increasing health-care cost. The effect of pregabalin was independent of patient gender.
PMCID: PMC4308936  PMID: 25632294
Cost analysis; Generalized anxiety disorder; Pregabalin; SSRI; Partial response; Usual care; Routine medical practice
10.  Alexithymia, anxiety and depression in patients with psoriasis: a case–control study 
Alexithymia, the difficulty in describing or recognizing emotions, has been associated with various psychosomatic pathologies including psoriasis. The aim of this study was to examine the prevalence of alexithymia and its association with anxiety and depression in patients with psoriasis compared with healthy participants, while taking into consideration demographic and clinical variables.
One hundred and eight psoriatic patients and 100 healthy participants from the general population completed the Toronto Alexithymia Scale (TAS-20) and the Hospital Anxiety and Depression Scale (HADS). The severity of patients’ psoriasis was clinically assessed using the Psoriasis Area and Severity Index (PASI).
Psoriatic patients had higher levels of alexithymia compared with healthy participants. While a rather high rate of psoriatic patients presented anxiety and depression as defined by the HADS, the differences that were found in comparison with the control group were not significant. Neither alexithymia nor its dimensions, difficulty in identifying feelings (DIF), difficulty in describing feelings (DDF) and externally oriented thinking (EOT), were associated with gender or psoriasis severity. Age was associated only with EOT, which was independent of depression and anxiety. Higher anxiety and depression were connected with higher alexithymia and DIF, while higher anxiety with higher DDF as well.
The alexithymia prevalence was higher in psoriatic patients than that in healthy participants, while it was positively correlated with anxiety and depression. Difficulty in identifying feelings was connected with both anxiety and depression, whereas difficulty in describing them was only with anxiety. Finally, externally oriented thinking was predicted only from age.
PMCID: PMC4269099  PMID: 25520742
Alexithymia; Anxiety; Depression; Psoriasis; TAS-20
11.  Standardization of the NEO-PI-3 in the Greek general population 
The revised NEO Personality Inventory (NEO-PI-3) includes 240 items corresponding to the Big Five personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience) and subordinate dimensions (facets). It is suitable for use with adolescents and adults (12 years or older). The aim of the current study was to validate the Greek translation of the NEO-PI-3 in the general Greek population.
Material and methods
The study sample included 734 subjects from the general Greek population of whom 59.4% were females and 40.6% males aged 40.80 ± 11.48. The NEO-PI-3 was translated into Greek and back-translated into English, and the accuracy of the translation was confirmed and established. The statistical analysis included descriptive statistics, confirmatory factorial analysis (CFA), the calculation of Cronbach’s alpha, and the calculation of Pearson product–moment correlations. Sociodemographics groups were compared by ANOVA.
Most facets had Cronbach’s alpha above 0.60. Confirmatory factor analysis showed acceptable loading of the facets on their own hypothesized factors and very good estimations of Cronbach’s alphas for the hypothesized factors, so it was partially supportive of the five-factor structure of the NEO-PI-3.The factors extracted with Procrustes rotation analysis can be considered reasonably homologous to the factors of the American normative sample. Correlations between dimensions were as expected and similar to those reported in the literature.
The literature suggests that overall, the psychometric properties of NEO-PI-3 scales have been found to generalize across ages, cultures, and methods of measurement. In accord with this, the results of the current study confirm the reliability of the Greek translation and adaptation of the NEO-PI-3. The inventory has comparable psychometric properties in its Greek version in comparison to the original and other national translations, and it is suitable for clinical as well as research use.
PMCID: PMC4263201  PMID: 25505930
Five-factor personality inventory; NEO-PI-3; Standardization; Psychometrics
12.  Depression and attempted suicide under pregabalin therapy 
Originally developed for the treatment of epilepsy, pregabalin has become a compound with a wide spectrum of indications comprising anxiety disorders and chronic pain and is therefore largely prescribed. Thus, it is important for clinicians to be aware of rare, but serious adverse effects. The following report illustrates the case of a 20-year-old male with a severe depressive syndrome following pregabalin medication which even led to a suicide attempt.
PMCID: PMC4258812  PMID: 25489334
Depression; Anticonvulsants; Suicide; Pregabalin
13.  Pain sensitivity in posttraumatic stress disorder and other anxiety disorders: a preliminary case control study 
Despite substantial research on the comorbidity of anxiety disorders including posttraumatic stress disorder (PTSD) and chronic pain, little is known about the mechanisms underlying these conditions that might be potentially similar. Evoked pain sensitivity is one factor that has been associated with several pain conditions which might also have relevance to anxiety disorders and PTSD. The aim of this preliminary study was to examine evoked pain sensitivity in PTSD compared to other anxiety disorders and in control participants.
The study used a cross-sectional case-control design in which participants completed a battery of questionnaires and structured interview and underwent cold pressor testing.
Of 61 total participants, those in the PTSD (n =16) and other anxiety groups (n =12) endorsed significantly higher levels of psychological symptoms and poorer health functioning than control participants (n =33). The linear trend across baseline, threshold, and tolerance pain ratings from the cold pressor task significantly differed between participants with PTSD and the other anxiety and control groups suggesting lower pain sensitivity to a standardized stimulus of pain in individuals with PTSD.
These findings are similar to some of the prior research and suggest that individuals with PTSD may exhibit lower cold pain sensitivity compared to those with other anxiety disorders. There is a need for future research to determine explanatory mechanisms.
PMCID: PMC4236800  PMID: 25422670
PTSD; Anxiety; Pain sensitivity; Chronic pain; Comorbidity
14.  Histaminergic system in brain disorders: lessons from the translational approach and future perspectives 
Histamine and its receptors were first described as part of immune and gastrointestinal systems, but their presence in the central nervous system and importance in behavior are gaining more attention. The histaminergic system modulates different processes including wakefulness, feeding, and learning and memory consolidation. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the rhodopsin-like family of G protein-coupled receptors, present constitutive activity, and are subjected to inverse agonist action. The involvement of the histaminergic system in brain disorders, such as Alzheimer’s disease, schizophrenia, sleep disorders, drug dependence, and Parkinson’s disease, is largely studied. Data obtained from preclinical studies point antagonists of histamine receptors as promising alternatives to treat brain disorders. Thus, clinical trials are currently ongoing to assess the effects of these drugs on humans. This review summarizes the role of histaminergic system in brain disorders, as well as the effects of different histamine antagonists on animal models and humans.
PMCID: PMC4243384  PMID: 25426159
Antagonist; Autism; Brain disorders; Histamine; Histaminergic system
15.  Psychopathological symptoms of patients with heroin addiction entering opioid agonist or therapeutic community treatment 
The relationship between substance use disorders and psychiatric pathology is still an open question. The main aim of the present study was to verify whether the five psychopathological dimensions identified through the SCL-90 tool in a previous study carried out on patients with heroin addiction entering an outpatient opioid agonist treatment (OAT) were also observable in those entering a residential treatment community (TC). Further aims were to look at differences in the psychopathological profiles of patients entering a TC versus an OAT treatment and at the correlation between gender and the observed psychopathology.
A confirmatory factor analysis was performed on the results of SCL-90 filled by 1,195 patients with heroin dependence entering TC treatment. It replicates the extraction method previously used on 1,055 OAT patients with heroin addiction by using a principal component factor analysis (PCA). The association between the kind of treatment received (TC or OAT), gender, and the psychopathological dimensions was assessed through logistic regression and general linear model (GLM) analysis.
The PCA carried out on the SCL-90 results of patients entering a TC yielded a five-factor solution, confirming the same dimensions observed in patients entering an OAT: ‘worthlessness and being trapped’, ‘somatization’, ‘sensitivity-psychoticism’, ‘panic anxiety’, and ‘violence-suicide’. The logistic regression analysis showed a statistically significant association between ‘somatization’ and ‘violence-suicide’ severity score and OAT. GLM analysis showed that psychopathological factorial scores for ‘worthlessness-being trapped’, ‘somatic symptoms’, and ‘panic anxiety’ dimensions were more severe in OAT vs TC male patients and in TC vs OAT female ones. ‘Violence suicide’ followed the same severity pattern for males, but did not differ in TC vs OAT females, while ‘sensitivity-psychoticism’ did not differ in OAT vs TC patients. The five dimensions did not differ in OAT males vs females.
Our research appears to confirm the existence of a specific aggregation of psychological/psychiatric features within the category of individuals with heroin addiction. It also shows a correlation between the dominant psychopathological subgroup and the assignment to TC versus OAT. Further research is needed to clarify the differences between the five psychopathological subgroups and their determinants.
PMCID: PMC4247563  PMID: 25435897
Psychopathological symptoms; SCL-90; Residential treatment community; Opioid agonist treatment; Gender differences
16.  New DSM-5 maladaptive symptoms in PTSD: gender differences and correlations with mood spectrum symptoms in a sample of high school students following survival of an earthquake 
Gender differences in post-traumatic stress disorder (PTSD) rates were confirmed across different DSM editions as well as the role of bipolar disorder (BD) comorbidity on prevalence and course, but little data is available upon new DSM-5 criteria, including maladaptive behaviors. The aim of this study was to investigate gender differences in DSM-5 PTSD in a sample of young adult earthquake survivors and the impact of lifetime mood spectrum comorbidity.
Five hundred twelve young adult survivors from the L’Aquila 2009 earthquake were evaluated by Trauma and Loss Spectrum-Self Report (TALS-SR) and Mood Spectrum-Self Report (MOODS-SR).
Females showed significantly higher DSM-5 PTSD prevalence rates than men. Similarly, female survivors with DSM-5 PTSD showed significantly higher scores in several of the MOODS-SR and TALS-SR domains with respect to males. Males showed significantly higher scores in the TALS-SR maladaptive coping domain only. A significant positive association between the MOODS-SR manic-hypomanic component and TALS-SR potentially traumatic events and maladaptive coping domains emerged in the whole sample, particularly among men.
This study allows a first glimpse on gender differences in DSM-5 PTSD criteria in a sample of earthquake survivors. Further, possible correlations with subthreshold manic-hypomanic comorbidity are suggested among males, showing a significant trend particularly for lifetime trauma exposure and for the newly introduced maladaptive behaviors.
PMCID: PMC4322820  PMID: 25670961
Trauma; Risk-taking behaviors; maladaptive behaviors; Post-Traumatic Stress Disorder (PTSD); Bipolar Disorder
17.  Comorbid atypical autistic traits as a potential risk factor for suicide attempts among adult depressed patients: a case–control study 
The present study aims to examine if autism spectrum disorder (ASD) is a risk factor for suicide attempts among adult depressed patients and to elucidate the characteristics of suicide attempts in adult depressed patients with ASD.
We conducted a case–control study. Subjects consisted of 336 retrospectively recruited first-time visit patients to our outpatient clinic with a current major depressive episode; 31 of the 336 patients had attempted suicide. The demographic backgrounds (i.e., age, gender, personal/family history of suicidality); specific psychopathology like bipolarity, agitation, and psychotic features; and comorbidity such as physical diseases, alcohol abuse, cluster B personality disorder, and ASD including pervasive developmental disorder not otherwise specified (PDD-NOS) were examined as potential risk factors for suicide attempts. We compared these variables between the suicide attempters and non-attempters. In addition, we compared suicide attempters to non-attempters within the ASD group and non-ASD group. Binary logistic regression analysis was performed using the significant independent variables from the comparisons between the suicide attempters and non-attempters, and the odds ratios (OR) and 95% confidence intervals (CI) were calculated.
Logistic regression analysis demonstrated that agitation during a depressive episode (OR = 7.15, 95% CI = 2.88–17.74), past suicidal behaviors (OR = 4.32, 95% CI =1.70–10.98), and comorbid PDD-NOS (OR = 4.04, 95% CI = 1.20–13.54) were significantly associated with suicide attempts. The most prevalent suicidal method was drug overdose (59.1%) among non-ASD attempters while hanging was the most prevalent (44.4%) in ASD attempters.
Depressed adults with comorbid atypical autistic traits are at higher risk for suicide attempts and may engage in methods that are more lethal.
PMCID: PMC4201698  PMID: 25328535
Autism spectrum disorder; Adult; Atypical; Depressive episode; Suicide attempt; Risk factor; Pervasive developmental disorder-not otherwise specified; Suicide methods
18.  Levetiracetam improves disinhibitory behavior in nonconvulsive status epilepticus 
Nonconvulsive status epilepticus (NCSE) is a severe medical condition and heterogeneous disorder defined by different seizure types and diverse etiologies. NCSE occurs commonly in the elderly and is potentially misdiagnosed as a psychiatric disorder. Current treatment options for NCSE are still unsatisfactory.
Case presentation
We report a case of NCSE in a 55-year-old epileptic male patient with a history of infectious encephalitis, disinhibitory behavior, and a suspected diagnosis of frontotemporal dementia. Add-on levetiracetam (LEV) to carbamazepine treatment improved clinical manifestations and abnormal electroencephalographic discharge.
With disinhibitory behavior in the elderly, the possibility of NCSE should be considered. Moreover, LEV may be an effective and well-tolerated pharmacotherapy for elderly NCSE patients.
PMCID: PMC4205286  PMID: 25339976
Disinhibitory behavior; Levetiracetam; Nonconvulsive status epilepticus; Psychiatric disorder; Infectious encephalitis
19.  Psychiatric manifestations of treatable hereditary metabolic disorders in adults 
Detecting psychiatric disorders of secondary origin is a crucial concern for the psychiatrist. But how can this reliably be done among a large number of conditions, most of which have a very low prevalence? Metabolic screening undertaken in a population of subjects with psychosis demonstrated the presence of treatable metabolic disorders in a significant number of cases. The nature of the symptoms that should alert the clinician is also a fundamental issue and is not limited to psychosis. Hereditary metabolic disorders (HMD) are a rare but important cause of psychiatric disorders in adolescents and adults, the signs of which may remain isolated for years before other more specific organic signs appear. HMDs that present purely with psychiatric symptoms are very difficult to diagnose due to low awareness of these rare diseases among psychiatrists. However, it is important to identify HMDs in order to refer patients to specialist centres for appropriate management, disease-specific treatment and possible prevention of irreversible physical and neurological complications. Genetic counselling can also be provided. This review focuses on three HMD categories: acute, treatable HMDs (urea cycle abnormalities, remethylation disorders, acute intermittent porphyria); chronic, treatable HMDs (Wilson’s disease, Niemann-Pick disease type C, homocystinuria due to cystathionine beta-synthase deficiency, cerebrotendinous xanthomatosis); and chronic HMDs that are difficult to treat (lysosomal storage diseases, X-linked adrenoleukodystrophy, creatine deficiency syndrome). We also propose an algorithm for the diagnosis of HMDs in patients with psychiatric symptoms.
PMCID: PMC4255667  PMID: 25478001
Inherited metabolic diseases; Psychiatric disorders; Neurological signs; Diagnosis; Treatment; Adults
20.  Childhood trauma and adult interpersonal relationship problems in patients with depression and anxiety disorders 
Although a plethora of studies have delineated the relationship between childhood trauma and onset, symptom severity, and course of depression and anxiety disorders, there has been little evidence that childhood trauma may lead to interpersonal problems among adult patients with depression and anxiety disorders. Given the lack of prior research in this area, we aimed to investigate characteristics of interpersonal problems in adult patients who had suffered various types of abuse and neglect in childhood.
A total of 325 outpatients diagnosed with depression and anxiety disorders completed questionnaires on socio-demographic variables, different forms of childhood trauma, and current interpersonal problems. The Childhood Trauma Questionnaire (CTQ) was used to measure five different forms of childhood trauma (emotional abuse, emotional neglect, physical abuse, physical neglect, and sexual abuse) and the short form of the Korean-Inventory of Interpersonal Problems Circumplex Scale (KIIP-SC) was used to assess current interpersonal problems. We dichotomized patients into two groups (abused and non-abused groups) based on CTQ score and investigated the relationship of five different types of childhood trauma and interpersonal problems in adult patients with depression and anxiety disorders using multiple regression analysis.
Different types of childhood abuse and neglect appeared to have a significant influence on distinct symptom dimensions such as depression, state-trait anxiety, and anxiety sensitivity. In the final regression model, emotional abuse, emotional neglect, and sexual abuse during childhood were significantly associated with general interpersonal distress and several specific areas of interpersonal problems in adulthood. No association was found between childhood physical neglect and current general interpersonal distress.
Childhood emotional trauma has more influence on interpersonal problems in adult patients with depression and anxiety disorders than childhood physical trauma. A history of childhood physical abuse is related to dominant interpersonal patterns rather than submissive interpersonal patterns in adulthood. These findings provide preliminary evidence that childhood trauma might substantially contribute to interpersonal problems in adulthood.
PMCID: PMC4304140  PMID: 25648979
Childhood trauma; Interpersonal relationship; Depression; Anxiety
21.  Duplication of the NPHP1 gene in patients with autism spectrum disorder and normal intellectual ability: a case series 
Autism spectrum disorder is a neurodevelopmental disorder characterized by impairments in social interactions, reduced verbal communication abilities, stereotyped repetitive behaviors, and restricted interests. It is a complex condition caused by genetic and environmental factors; the high heritability of this disorder supports the presence of a significant genetic contribution. Many studies have suggested that copy-number variants contribute to the etiology of autism spectrum disorder. Recently, copy-number variants of the nephronophthisis 1 gene have been reported in patients with autism spectrum disorder. To the best of our knowledge, only six autism spectrum disorder cases with duplications of the nephronophthisis 1 gene have been reported. These patients exhibited intellectual dysfunction, including verbal dysfunction in one patient, below-average verbal intellectual ability in one patient, and intellectual disability in four patients.
In this study, we identified nephronophthisis 1 duplications in two unrelated Japanese patients with autism spectrum disorder using a high-resolution single-nucleotide polymorphism array. This report is the first to describe a nephronophthisis 1 duplication in an autism spectrum disorder patient with an average verbal intelligence quotient and an average performance intelligence quotient. However, the second autism spectrum disorder patient with a nephronophthisis 1 duplication had a below-average performance intelligence quotient. Neither patient exhibited physical dysfunction, motor developmental delay, or neurological abnormalities. This study supports the clinical observation of nephronophthisis 1 duplication in autism spectrum disorder cases and might contribute to our understanding of the clinical phenotype that arises from this duplication.
PMCID: PMC4131154  PMID: 25126106
Autism spectrum disorder; Copy-number variants; Duplication; Nephronophthisis 1 gene; Intelligence
22.  Serum proBDNF/BDNF and response to fluvoxamine in drug-naïve first-episode major depressive disorder patients 
We investigated the association between serum proBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and response to fluvoxamine in patients with major depressive disorder (MDD) using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR): physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders.
Fifty-one patients with MDD (M/F, 19:32; age, 38 ± 19 years) and 51 healthy controls (M/F, 22:29; age, 34 ± 17 years) were studied using DSM-IV-TR: physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders. Serum levels of proBDNF and MDNF were measured by sandwich enzyme-linked immunosorbent assay (ELISA).
Serum mature BDNF levels in the MDD patients were significantly lower than those in the healthy controls (t = 3.046, p = 0.0018). On the other hand, no difference was found in serum proBDNF between the MDD patients and the healthy controls (t = −0.979, p = 0.833). A trend of negative correlation was found between baseline serum BDNF and baseline scores of the 17 items of the Hamilton Rating Scale for Depression (HAMD17) (r = −0.183, p = 0.071). No correlation was however found between HAMD17 scores and proBDNF at baseline (r = 0.092, p = 0.421). Furthermore, no correlation was observed between baseline HAMD17 scores and baseline proBDNF/BDNF (r = −0.130, p = 0.190). No changes were observed in serum levels of proBDNF and BDNF during the treatment periods.
These results suggest that there is no association between serum proBDNF/BDNF and fluvoxamine response in MDD patients at least within 4 weeks of the treatment.
PMCID: PMC4118273  PMID: 25089150
BDNF; proBDNF; Major depressive disorder; Serum; Fluvoxamine
23.  Cognitive outcome and gamma noise power unrelated to neuregulin 1 and 3 variation in schizophrenia 
Neuregulins are a family of signalling proteins that orchestrate a broad range of cellular responses. Four genes encoding Neuregulins 1–4 have been identified so far in vertebrates. Among them, Neuregulin 1 and Neuregulin 3 have been reported to contribute to an increased risk for developing schizophrenia. We hypothesized that three specific variants of these genes (rs6994992 and rs3924999 for Neuregulin 1 and rs10748842 for Neuregulin 3) that have been related to this illness may modify information processing capacity in the cortex, which would be reflected in electrophysiological parameters (P3b amplitude or gamma noise power) and/or cognitive performance.
We obtained DNA from 31 patients with schizophrenia and 23 healthy controls and analyzed NRG1 rs6994992, NRG1 rs3924999 and NRG3 rs10748842 promoter polymorphisms by allelic discrimination with real-time polymerase chain reaction (PCR). We compared cognitive outcome, P300 amplitude parameters and an electroencephalographic measure of noise power in the gamma band between the groups dichotomized according to genotype.
Contrary to our hypothesis, we could not detect any significant influence of variation in Neuregulin 1/Neuregulin 3 polymorphisms on cognitive performance or electrophysiological parameters of patients with schizophrenia.
Despite our findings, we cannot discard that other genetic variants and, more likely, interactions between those variants and with genetic variation related to different pathways may still influence cerebral processing in schizophrenia.
PMCID: PMC4065086  PMID: 24976857
Schizophrenia; Brain wave; Auditory evoked potential; NRG1 protein; NRG3 protein
24.  Antidepressant treatment response is modulated by genetic and environmental factors and their interactions 
Although there is a wide variety of antidepressants with different mechanisms of action available, the efficacy of treatment is not satisfactory. Genetic factors are presumed to play a role in differences in medication response; however, available evidence is controversial. Even genome-wide association studies failed to identify genes or regions which would consequently influence treatment response. We conducted a literature review in order to uncover possible mechanisms concealing the direct effects of genetic variants, focusing mainly on reports from large-scale studies including STAR*D or GENDEP. We observed that inclusion of environmental factors, gene-environment and gene-gene interactions in the model improves the probability of identifying genetic modulator effects of antidepressant response. It could be difficult to determine which allele of a polymorphism is the risk factor for poor treatment outcome because depending on the acting environmental factors different alleles could be advantageous to improve treatment response. Moreover, genetic variants tend to show better association with certain intermediate phenotypes linked to depression because these are more objective and detectable than traditional treatment outcomes. Thus, detailed modeling of environmental factors and their interactions with different genetic pathways could significantly improve our understanding of antidepressant efficacy. In addition, the complexity of depression itself demands a more comprehensive analysis of symptom trajectories if we are to extract useful information which could be used in the personalization of antidepressant treatment.
PMCID: PMC4106212  PMID: 25053968
25.  An analysis of early developmental trauma in social anxiety disorder and posttraumatic stress disorder 
The early contributions of childhood trauma (emotional, physical, sexual, and general) have been hypothesized to play a significant role in the development of anxiety disorders, such as posttraumatic stress disorder (PTSD) and social anxiety disorder (SAD). The aim of this study was to assess childhood trauma differences between PTSD and SAD patients and healthy controls, as measured by the Early Trauma Inventory.
We examined individuals (N = 109) with SAD with moderate/severe early developmental trauma (EDT) (n = 32), individuals with SAD with low/no EDT (n = 29), individuals with PTSD with EDT (n = 17), and healthy controls (n = 31). The mean age was 34 years (SD = 11). Subjects were screened with the Mini-International Neuropsychiatric Interview (MINI), Liebowitz Social Anxiety Scale (LSAS), Clinician-Administered PTSD Scale (CAPS), and Childhood Trauma Questionnaire (CTQ). Analysis of variance was performed to assess group differences. Correlations were calculated between childhood traumas.
Although not statistically significant, individuals with PTSD endorsed more physical and sexual childhood trauma compared with individuals with SAD with moderate/severe EDT who endorsed more emotional trauma. For all groups, physical and emotional abuse occurred between ages 6 and 11, while the occurrence of sexual abuse in individuals with PTSD was at 6–11 years and later (13–18 years) in individuals with SAD with moderate/severe EDT. For emotional abuse in all groups, the perpetrator was mostly a primary female caregiver; for sexual abuse, it was mostly a nonfamilial adult male, while for physical abuse, it was mostly a caregiver (male in PTSD and female in SAD with moderate/severe EDT).
The contribution of childhood abuse to the development of PTSD and SAD and the differences between these groups and other anxiety disorders should not be ignored and attention should be given to the frequency and severity of these events. The relationship of the perpetrator(s) and the age of onset of childhood abuse are also important considerations as they provide a useful starting point to assess impact over the life course. This can, in turn, guide clinicians on the optimal timing for the delivery of interventions for the prevention of PTSD and SAD.
PMCID: PMC4052826  PMID: 24920955
Childhood trauma; Social anxiety; PTSD; Early developmental trauma; Anxiety

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