[BIPOLAR DISORDER AS A MULTI-SYSTEM ILLNESS].

INTRODUCTION: Bipolar disorder is a chronic condition, characterized by high distress in patients and high suicide rates (30%). Most patients suffer from medical and other psychiatric comorbidities, which worsen the psychiatric symptoms and decrease the likelihood of remission. More than 70% of bipolar patients have cardio-metabolic symptoms, with higher rates compared to other psychiatric disorders. Cardiovascular disease is the major cause of high mortality rates in these patients, with 1.5-2 fold increased risk of mortality, compared to the general population without psychiatric symptoms. The rates of cardiovascular risk factors and their resulting increased mortality rates are similar to those found in schizophrenia. In addition to cardio-metabolic conditions, 50% of patients with bipolar disorder suffer from other medical symptoms, which are also associated with worse outcomes. Therefore, the current perspective is that bipolar disorder is not only a psychiatric disorder, but rather a multi-system illness, affecting the entire body. The optimal treatment for these patients should include diagnosis, monitoring and treatment of both psychiatric and physical symptoms, which would improve their prognosis.

Neuromodulation of Attentional Control in Major Depression: A Pilot DeepTMS Study.

While Major Depressive Disorder (MDD) is primarily characterized by mood disturbances, impaired attentional control is increasingly identified as a critical feature of depression. Deep transcranial magnetic stimulation (deepTMS), a noninvasive neuromodulatory technique, can modulate neural activity and induce neuroplasticity changes in brain regions recruited by attentional processes. This study examined whether acute and long-term high-frequency repetitive deepTMS to the dorsolateral prefrontal cortex (DLPFC) can attenuate attentional deficits associated with MDD. Twenty-one MDD patients and 26 matched control subjects (CS) were administered the Beck Depression Inventory and the Sustained Attention to Response Task (SART) at baseline. MDD patients were readministered the SART and depressive assessments following a single session (n = 21) and after 4 weeks (n = 13) of high-frequency (20 Hz) repetitive deepTMS applied to the DLPFC. To control for the practice effect, CS (n = 26) were readministered the SART a further two times. The MDD group exhibited deficits in sustained attention and cognitive inhibition. Both acute and long-term high-frequency repetitive frontal deepTMS ameliorated sustained attention deficits in the MDD group. Improvement after acute deepTMS was related to attentional recovery after long-term deepTMS. Longer-term improvement in sustained attention was not related to antidepressant effects of deepTMS treatment.

Selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion and action in pancreatic ß cells.

Selective serotonin reuptake inhibitors (SSRIs) are antidepressants used for the treatment of mood and anxiety disorders. Here, we demonstrate that incubation (2 h) of murine islets or Min6 ß cell line with the SSRIs paroxetine, fluoxetine, or sertraline inhibited insulin-induced Tyr phosphorylation of insulin receptor substrate (IRS)-2 protein and the activation of its downstream targets Akt and the ribosomal protein S6 kinase-1 (S6K1). Inhibition was dose-dependent with half-maximal effects at ∼15-20 µM. It correlated with a rapid dephosphorylation and activation of the IRS kinase GSK3ß. Introduction of GSK3ß siRNAs eliminated the inhibitory effects of the SSRIs. Inhibition of IRS-2 action by 30 µM SSRI was associated with a marked inhibition of glucose-stimulated insulin secretion from murine and human pancreatic islets. Secretion induced by basic secretagogues (KCl and Arg) was not affected by these drugs. Prolonged treatment (16 h) of Min6 cells with sertraline resulted in the induction of inducible nitric oxide synthase; activation of endoplasmic reticulum stress, and the initiation of the unfolded protein response, manifested by enhanced transcription of ATF4 and C/EBP homologous protein. This triggered an apoptotic process, manifested by enhanced caspase 3/7 activity, which resulted in ß cell death. These findings implicate SSRIs as inhibitors of IRS protein function and insulin action through the activation of GSK3ß. They further suggest that SSRIs inhibit insulin secretion; induce the unfolded protein response; activate an apoptotic process, and trigger ß cell death. Given that SSRIs promote insulin resistance while inhibiting insulin secretion, these drugs might accelerate the transition from an insulin-resistant state to overt diabetes.

Methylphenidate enhances cognitive performance in adults with poor baseline capacities regardless of attention-deficit/hyperactivity disorder diagnosis.

We compare the view that the effect of methylphenidate (MPH) is selective to individuals with attention-deficit/hyperactivity disorder (ADHD) with an alternative approach suggesting that its effect is more prominent for individuals with weak baseline capacities in relevant cognitive tasks. To evaluate theses 2 approaches, we administered sustained attention, working memory, and decision-making tasks to 20 ADHD adults and 19 control subjects, using a within-subject placebo-controlled design. The results demonstrated no main effects of MPH in the decision-making tasks. In the sustained attention and working-memory tasks, MPH enhanced performance of both ADHD and non-ADHD adults to a similar extent compared with placebo. Hence, the effect of MPH was not selective to ADHD adults. In addition, those benefitting most from MPH in all 3 task domains tended to be individuals with poor task performance. However, in most tasks, individuals whose performance was impaired by MPH were not necessarily better (or worse) performers. The findings suggest that the administration of MPH to adults with ADHD should consider not only clinical diagnosis but also their functional (performance-based) profile.

Can computerized cognitive tests assist in the clinical diagnosis of attention-deficit hyperactivity disorder?

A group of 34 children and adolescents suspected of having attention-deficit hyperactivity disorder were referred for a computerized evaluation that included sustained attention, working memory, planning, and set-shifting. Although only sustained attention had reasonable specificity, all tests had questionable contribution to the diagnostic evaluation.

Long-term follow-up of adolescents with resistant depression treated with repetitive transcranial magnetic stimulation.

OBJECTIVE: There is a paucity of information about repetitive transcranial magnetic stimulation (rTMS) as a treatment for adolescent depression, and there are no data about its long-term effectiveness and safety in this age group. The aim of this study was to evaluate symptoms of depression and cognitive functioning in young people who had been treated 3 years previously with rTMS for resistant depression. METHODS: Eight of 9 subjects who had participated in an open-label rTMS study were reassessed using the Child and Adolescent Depression Rating Scale-Revised and the Beck Depression Inventory II. Six of the subjects were also cognitively reassessed using the Cambridge Neuropsychological Test Automated Battery. The follow-up assessments were compared with the earlier pretreatment, inter-treatment and posttreatment assessments. RESULTS: At 3-year follow-up, there was no evidence of deterioration in symptoms of depression or cognitive functioning compared to the last assessment after rTMS. CONCLUSION: Preliminary evidence suggests that rTMS treatment of resistant depression in adolescents is not associated with long-term cognitive deterioration and that posttherapy clinical improvement can be maintained. It seems that some subjects may derive long-term benefit from the rTMS course.

The effects of TENS, interferential stimulation, and combined interferential stimulation and pulsed ultrasound on patients with disc herniation-induced radicular pain.

BACKGROUND: Electrotherapy is part of a physician's toolbox for treating various musculoskeletal conditions, including radicular pain, but the preferred modality is yet unclear. OBJECTIVE: To compare the short-term efficacy of three electrotherapeutic modalities in relieving lumbar disc herniation (LDH)-induced radicular pain. METHODS: Fourteen patients with LDH-induced radicular pain attended a single session of electrotherapy, which included four 10-min consecutive treatments: transcutaneous electrical nerve stimulation (TENS), interferential (IF) stimulation, a combined treatment with pulsed ultrasound and IF current (CTPI), and a sham control. Treatments were randomized and the straight leg raise (SLR) degree was measured immediately before and after each treatment. RESULTS: Each of the three active modalities significantly improved the SLR score. The most prominent improvement was observed in the CTPI condition, followed by IF and, finally, TENS. The sham stimulation did not affect the SLR scores. CONCLUSIONS: A single session with either TENS, IF current or CTPI is sufficient to improve the range of motion and degree of radicular pain associated with LDH. CTPI appears to be the most effective modality of the three, possibly due to greater penetration efficiency of the induced current. The effects of a long-term treatment schedule are yet to be identified.

Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: a feasibility study.

Treatment for negative symptoms and cognitive deficits, core elements of schizophrenia, remains inadequate. Stimulation of the prefrontal cortex via transcranial magnetic stimulation (TMS) yields only moderate results, possibly due to limited stimulation depth. Deep-TMS enables deeper and wider stimulation than before. This preliminary study is the first to examine deep-TMS as a possible add-on treatment for negative symptoms and cognitive deficits of schizophrenia. The effect of 20 daily deep-TMS sessions (20 Hz, 120% motor threshold) over the prefrontal cortex of 15 patients indicated improvement in cognition and negative symptoms that was maintained at 2-wk post-treatment follow-up.

Methylphenidate reduces orienting bias in healthy individuals.

BACKGROUND: Healthy individuals show subtle orienting bias, a phenomenon known as pseudoneglect, reflected in a tendency to direct greater attention toward one hemispace. Accumulating evidence indicates that this bias is an individual trait, and attention is preferentially directed contralaterally to the hemisphere with higher dopamine signaling. Administration of methylphenidate (MPH), a dopamine transporter inhibitor, was shown to normalize aberrant spatial attention bias in psychiatric and neurological patients, suggesting that the reduced orienting bias following administration of MPH reflects an asymmetric effect of the drug, increasing extracellular dopamine in the hemisphere with lower dopamine signaling. AIM: We predicted that, similarly to its effect on patients with brain pathology, MPH will reduce the orienting bias in healthy subjects. METHODS: To test this hypothesis, we examined the behavioral effects of a single dose (20 mg) of MPH on orienting bias in 36 healthy subjects (18 females) in a randomized, double-blind placebo-controlled, within-subject design, using the greyscales task, which has been shown to detect subtle attentional biases in both patients and healthy individuals. RESULTS/OUTCOMES: Results demonstrate that healthy individuals vary in both direction and magnitude of spatial orienting bias and show reduced magnitude of orienting bias following MPH administration, regardless of the initial direction of asymmetry. CONCLUSIONS/INTERPRETATIONS: Our findings reveal, for the first time in healthy subjects, that MPH decreases spatial orienting bias in an asymmetric manner. Given the well-documented association between orienting bias and asymmetric dopamine signaling, these findings also suggest that MPH might exert a possible asymmetric neural effect in the healthy brain.

rTMS for adolescents: Safety and efficacy considerations.

In light of both the FDA's clearance of repetitive transcranial magnetic stimulation (rTMS) for adult major depressive disorder and concerns about safety and efficacy of existing antidepressant therapies for adolescent depression, there is increasing interest in rTMS as a novel treatment for adolescent depression. We reviewed English-language studies using rTMS in persons under the age of 18, yielding 6 published reports. Because rTMS is typically delivered at or above 1 Hz for psychiatric indications, our search was confined to these frequencies. Also included are studies involving rTMS above 1 Hz for non-psychiatric indications. Articles were retrieved from the MEDLINE database. There were 19 reported subjects under age 18 who have been administered rTMS at a frequency above 1 Hz: 10 for major depression, 5 for spastic cerebral palsy and 4 for epilepsia partialis continua. We found that most subjects responded favorably to rTMS and no adverse events have been reported. However data are insufficient for drawing firm conclusions about safety and efficacy. Further studies of rTMS as a treatment for adolescent depression are warranted.

Double dissociation between cognitive and affective empathy in borderline personality disorder.

We sought to characterize the cognitive and affective empathic abilities of patients with borderline personality disorder (BPD). While controls showed higher cognitive as compared with affective empathy scores, the BPD group demonstrated the opposite pattern. These results suggest that a dysfunctional pattern of empathic capacity may account for behavioral difficulties in BPD.

Reducing Stigma Toward Psychiatry Among Medical Students: A Multicenter Controlled Trial.

OBJECTIVE: To examine the effect of a novel antistigma intervention curriculum (ASIC) in reducing stigma toward psychiatry among medical students. METHODS: Medical students from 8 hospitals in central Israel were divided into intervention (n = 57) and control (n = 163) arms. The students completed the 30-item Attitudes Toward Psychiatry (ATP-30) and the Attitudes Toward Mental Illness (AMI) scales at psychiatry rotation onset and conclusion. The ASIC was designed to target prejudices and stigma through direct informal encounters with people with serious mental illness (SMI) during periods of remission and recovery. Supervised small-group discussions followed those encounters to facilitate processing of thoughts and emotions that ensued and to discuss salient topics in psychiatry. The study was conducted between November 2017 and July 2018. RESULTS: Significant between-group differences were found at endpoint for attitudes toward psychiatry and psychiatric patients (P < .001). Although changing attitudes toward psychiatry as a career choice was not part of the ASIC, a significant between-group difference emerged by endpoint (P < .001). CONCLUSIONS: Implementation of an ASIC that includes contact with individuals with lived SMI experience followed by supervised small-group discussions is effective in reducing stigma in medical students' perceptions of people with mental illness and psychiatry. Further evaluation is warranted with regard to the long-term destigmatizing effects of an ASIC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03907696.

Neuropsychological evidence of impaired cognitive empathy in euthymic bipolar disorder.

The empathic abilities have never been examined in bipolar disorder patients, despite frequent observations of impaired social behavior. To examine the neuropsychological processes that underlie the affective and cognitive empathic ability in bipolar disorder, the authors compared affective and cognitive empathic abilities, as well as theory of mind and executive functions, of euthymic bipolar disorder patients and healthy comparison subjects. Significant deficits in cognitive empathy and theory of mind were observed, while affective empathy was elevated in bipolar disorder. Patients showed impaired cognitive flexibility (shifting and reversal learning) but intact planning behavior. Impaired cognitive empathy was related with performance in neurocognitive tasks of cognitive flexibility, suggesting that prefrontal cortical dysfunction may account for impaired cognitive empathy in bipolar disorder.

Efficiency of Tissue Penetration by Currents Induced by 3 Electrotherapeutic Techniques: A Comparative Study Using a Novel Deep-Tissue Measuring Technique.

BACKGROUND: Electrotherapy provides a wide range of treatment alternatives for musculoskeletal pathologies. However, for the electrical stimulation to exert a significant therapeutic effect, the induced current must often penetrate deep inside the target tissue. OBJECTIVE: The objective was to systematically compare the penetration efficiency of 3 electrotherapeutic stimulation modalities: transcutaneous electrical nerve stimulation (TENS), interferential (IF) stimulation, and combined therapy with pulsed ultrasound and IF current (CTPI). DESIGN: This was a comparative, experimental laboratory study. METHODS: The penetration efficiency was evaluated as a voltage difference between 2 of an 8-contact spinal cord stimulation array. Each of 20 participants with a preimplanted spinal cord stimulation array was stimulated with TENS (3 different electrode configurations), IF current (3 configurations), and CTPI (1 configuration). RESULTS: Significant differences in penetration efficiency were found between the various stimulation conditions and electrode configurations. CTPI showed the highest penetration efficiency, followed by IF, and finally TENS. Penetration efficiency was inversely and significantly correlated with skinfold thickness in all conditions, but this correlation was lowest for the CTPI stimulation. LIMITATIONS: Our study design did not include a condition of combined therapy with pulsed ultrasound and TENS, and it did not directly control for current or voltage density under the stimulating electrodes. In addition, further research is required to determine whether a higher stimulation intensity of the target tissue is advantageous clinically. CONCLUSIONS: Pending further testing, CTPI stimulation could prove more effective than IF and TENS in reaching deeper tissues, especially considering the variability in adipose tissue thickness in the population, for example, in cases of patients with obesity.

Initial Evaluation of Pain Intensity Among Depressed Patients as a Possible Mediator Between Depression and Pain Complaints.

Pain complaints are frequently described by depressed patients, and are mostly attributed to abnormal pain perception and modulation. The present study aimed to assess whether a unique pain processing profile differentiates depressed patients from healthy controls. Participants were 25 patients suffering from a moderate-severe unipolar depressive episode and 25 age and sex-matched healthy controls. Thermal stimuli were used to assess sensory threshold and pain threshold. Pain-60 temperature (temperature that induces pain ratings of 60 out of 100) was the first noxious stimuli to be administered during the experimental session. Central pain inhibition was assessed via conditioned pain modulation (CPM) and the degree of central nervous system excitability was assessed via mechanical temporal summation. Depressed patients reported higher levels of pain compared with healthy controls, and a significantly higher perceived pain during the last month. Additionally, they displayed significantly lower pain-60 temperature values compared with healthy controls (p = 0.01). Otherwise, no significant group differences were found in measures of pain perception and modulation. Our results suggest that the initial evaluation of pain intensity among depressed patients, as validated by pain-60 temperature values, is increased compared with healthy controls, and might be the mediator between depression and pain complaints. Possibly, depressed patients' negative bias in the processing of pain is similar to their processing pattern of facial expression or future events. Further studies are necessary in order to establish the mechanisms underlying the excessive pain complaints reported by patients with unipolar depression.

Cognition in young schizophrenia outpatients: comparison of first-episode with multiepisode patients.

Cognitive impairments are recognized as a central feature of schizophrenia (SZ), largely independent of other symptoms, and a major cause of poor functioning. Studies indicate cognitive deterioration in the first years after the onset of SZ. These studies, however, have been criticized for using a small sample size, for having limited monitoring of confounding variables, and for the inclusion of cohorts of different ages. The current study compared the cognitive profile of first-episode schizophrenia patients, multi-episode schizophrenia patients and healthy controls (n = 44, n = 39, and n = 44; respectively). The study focused on the early stages of the disorder, recruiting only young patients. All subjects underwent an extensively validated computerized cognitive assessment (Cambridge Neuropsychological Test Automated Battery). The results revealed widespread cognitive impairments in SZ patients, compared with healthy control subjects. The multiepisode SZ patients were significantly more impaired than the first-episode ones, with deficits mainly related to psychomotor speed, pattern memory, and executive functioning. The functioning in other cognitive domains (ie, attention and spatial memory) was deficient even at an early stage of the disorder. These findings can help clarify the course of cognitive decline in young-aged SZ patients and aid in the development of phase-appropriate interventions.

Ultimatum bargaining behavior of people affected by schizophrenia.

Forty-nine people suffering from schizophrenia performed an interactive bargaining task involving small monetary rewards, known in classical game theory as the Ultimatum Game. In this task, the subject, in the role of the Proposer, has to offer his or her (anonymous) counterpart, the Responder, a share of a given sum of money. If the Responder accepts the offer, then the sum is split accordingly between the two. Otherwise, if he or she decides to reject the offer, both receive nothing. The patients' strategic behavior in both roles was compared with that of healthy and clinical controls. It was hypothesized that cognitive deficits characterizing schizophrenia, together with difficulties in social judgment, would impair the patients' bargaining ability. We found that in general schizophrenic patients did not fully exploit their strategic power as Proposers. In contrast, as Responders, schizophrenic patients acted not significantly different from controls. Further investigation is needed to establish the links between cognitive and symptomatic mediators and strategic decision-making ability.

Integration of emotional and cognitive aspects of theory of mind in schizophrenia and its relation to prefrontal neurocognitive performance.

INTRODUCTION: There is substantial evidence that patients with schizophrenia present with impaired Theory of Mind (ToM). Whereas previous studies have focused on general ToM abilities, the present study is aimed at testing the underlying behavioural and neurocognitive mechanisms of the impaired integration of affective and cognitive aspects of ToM (the integration of emotional information with mentalising) in patients with schizophrenia. METHODS: Twenty-six patients with schizophrenia and 35 healthy controls were tested on two ToM tasks involving the integration of affective and cognitive ToM abilities: "Faux Pas" and "reading the mind in the eyes" tasks. To assess the neurocognitive bases of impaired ToM, the ID/ED test (intradimensional/extradimensional shifting test from the CANTAB) was administered. RESULTS: Patients performed poorly on both the cognitive-affective integration ToM tasks and the ID/ED task as compared to controls. Furthermore, patients' ToM scores were selectively correlated with the reversal trials, which are believed to be associated with orbitofrontal functioning. In addition, more than 50% of the variance in recognising and understanding Faux Pas could be explained by patients' symptomatology. Performance on orbitofrontal related tasks was correlated with subjects' Faux Pas scores in the patients group, but not in the healthy control group. CONCLUSIONS: Schizophrenic patients appear to have considerable impairment in affective and cognitive ToM integration, which may be related to orbitofrontal dysfunction. These results are in line with previous findings regarding empathy and the importance of the orbitofrontal area in the integration of cognition and affect.

Reasons for referral for electroconvulsive therapy: a comparison between adolescents and adults.

OBJECTIVE: In order to improve our understanding of the use of electroconvulsive therapy (ECT) in adolescent patients, we aimed to evaluate the reasons for referral for ECT in different age groups. METHOD: We compared the reasons for adolescent and adult referrals by a retrospective file review of 13 consecutive adolescents and 56 consecutive adults treated in our ECT unit during a 5-year period. RESULTS: There was a significant association between age group and reason for referral. Non-response to pharmacotherapy was a significantly more common reason among adults. Adolescents were mainly referred due to catatonia and suicidal behaviour. CONCLUSION: Our results support the need to study reasons for referral to ECT, beyond non-response to pharmacotherapy, especially in adolescent patients.