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Subjects with bipolar disorder (BD) show heterogeneous cognitive profile and that not necessarily the disease will lead to unfavorable clinical outcomes. We aimed to identify clinical markers of severity among cognitive clusters in individuals with BD through data-driven methods.
We recruited 167 outpatients with BD and 100 unaffected volunteers from Brazil and Spain that underwent a neuropsychological assessment. Cognitive functions assessed were inhibitory control, processing speed, cognitive flexibility, verbal fluency, working memory, short- and long-term verbal memory. We performed hierarchical cluster analysis and discriminant function analysis to determine and confirm cognitive clusters, respectively. Then, we used classification and regression tree (CART) algorithm to determine clinical and sociodemographic variables of the previously defined cognitive clusters.
We identified three neuropsychological subgroups in individuals with BD: intact (35.3%), selectively impaired (34.7%), and severely impaired individuals (29.9%). The most important predictors of cognitive subgroups were years of education, the number of hospitalizations, and age, respectively. The model with CART algorithm showed sensitivity 45.8%, specificity 78.4%, balanced accuracy 62.1%, and the area under the ROC curve was 0.61. Of 10 attributes included in the model, only three variables were able to separate cognitive clusters in BD individuals: years of education, number of hospitalizations, and age.
These results corroborate with recent findings of neuropsychological heterogeneity in BD, and suggest an overlapping between premorbid and morbid aspects that influence distinct cognitive courses of the disease.
Functional impairment is a defining feature of psychotic disorders. A range of factors has been shown to influence functioning, including negative symptoms, cognitive performance and cognitive reserve (CR). However, it is not clear how these variables may affect functioning in first-episode psychosis (FEP) patients. This 2-year follow-up study aimed to explore the possible mediating effects of CR on the relationship between cognitive performance or specific clinical symptoms and functional outcome.
A prospective study of non-affective FEP patients was performed (211 at baseline and 139 at follow-up). CR was entered in a path analysis model as potential mediators between cognitive domains or clinical symptoms and functioning.
At baseline, the relationship between clinical variables or cognitive performance and functioning was not mediated by CR. At follow-up, the effect of attention (p = 0.003) and negative symptoms (p = 0.012) assessed at baseline on functioning was partially mediated by CR (p = 0.032 and 0.016), whereas the relationship between verbal memory (p = 0.057) and functioning was mediated by CR (p = 0.014). Verbal memory and positive and total subscales of PANSS assessed at follow-up were partially mediated by CR and the effect of working memory on functioning was totally mediated by CR.
Our results showed the influence of CR in mediating the relationship between cognitive domains or clinical symptoms and functioning in FEP. In particular, CR partially mediated the relationship between some cognitive domains or clinical symptoms and functioning at follow-up. Therefore, CR could improve our understanding of the long-term functioning of patients with a non-affective FEP.
The COVID-19 pandemic has and will have a huge impact on mental health, especially in countries that have been significantly affected, such as Spain.
Here we aim to provide the perspectives of a group of psychiatrists from Barcelona, one of the epicentres of the pandemic so far, to highlight the potential fatality of a virus that caught us unaware and unprepared, and hopefully this article will be of aid to countries about to face the pandemic.
The unprecedented situations that we have been faced with so far have included reconfiguring hospitals and the redeployment of healthcare professionals, with flexibility and adaptability key to managing the overload in demand. This has led to healthcare professionals being exposed to extremely stressful situations and they have had impossible decisions to make that may have mental health consequences, some of which may be severe and long lasting.
A rebound effect on mental health problems is to be expected in the medium and long term, especially for healthcare professionals and psychiatric patients, necessitating a strengthening of preventive approaches and policies for mental health along with a prompt reopening of mental health services. Ways to provide psychiatric healthcare in the immediate future need to be re-evaluated, and the development of telepsychiatry services is probably to be expected.
Previous literature supports antipsychotics’ (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning.
A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables.
Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011–0.0091) and (b = 0.0026, 95% CI 0.0001–0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033–0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden.
CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.
Psychopathological heterogeneity in manic syndromes may in part reflect underlying latent classes with characteristic outcome patterns. Differential treatment course and outcome after 12 weeks of treatment were examined for three distinct classes of patients with acute mania in bipolar disorder.
Subjects and methods
Three thousand four hundred and twenty-five patients with acute mania were divided into three distinct mania classes: ‘Typical’, ‘Psychotic’ and ‘Dual’ (i.e. comorbid substance use) mania. Persistence of class differences and social outcomes were examined, using multilevel regression analyses and odds ratios.
The three classes showed substantial stability post-baseline in the pattern of associations with class-characteristic variables. Psychotic and Dual mania predicted poorer outcome in terms of psychosis comorbidity and overall bipolar and mania severity, while Dual mania additionally predicted poorer outcome of alcohol and substance abuse. Worse social outcomes were observed for both Dual and Psychotic mania.
The identified distinct classes are stable and associated with differential treatment outcome. Overall, Dual and Psychotic mania show less favourable outcomes compared to Typical mania. These findings additionally give rise to concern on the generalisability of randomized clinical trials RCTs.
There are few controlled studies evaluating the treatment of bipolar mixed states. Evidence suggests that mixed states may be more responsive to some anticonvulsants than to lithium. Olanzapine alone or in combination with divalproate or lithium has been adequately evaluated in randomized clinical trials involving mixed-state patients, whereas risperidone and quetiapine have not. There is also some evidence demonstrating the efficacy of ziprasidone and aripiprazole. The risk of switching to depression is high in mixed states. Conventional antipsychotics, such as haloperidol, may be less efficacious at protecting against a switch to depression than atypical antipsychotics, divalproate or lithium. When choosing drugs for the treatment of mania, and especially for the treatment of mixed states, their efficacy against manic and depressive symptoms, and their safety in terms of the risk of switching to depression should be taken into account.
Clinical guidelines for treatment and research of bipolar disorder greatly benefit from the synthesis of data from individual studies. The British Association for Psychopharmacology bases its guidelines on evidence from opinions (level D) to systematic reviews of primary trial data (level A). The report details conclusions of its 1-day consensus meeting to develop guidelines covering diagnosis, clinical management, pharmacotherapy for acute episodes, relapse prevention and treatment discontinuation. Monotherapy for long-term management is preferred, having reduced side-effects and drug interactions and improved compliance. Combination therapy is often preferred for acute episodes, using antipsychotics for mania or antidepressants for depression. Increased efficacy may be attributed to multiple mechanisms of action and potentially lower doses. In clinical practice, maintenance monotherapy has limited success for chronic episodes and polypharmacy is frequently used, though the best combination remains unclear. A new collaborative approach based on simple clinical trials is required to change current medical practice.
Mixed bipolar states are not infrequent and may be extremely difficult to treat. Lithium, anticonvulsants including valproate and carbamazepine, and antipsychotics such as olanzapine, ziprasidone, and aripiprazole have been reported to be at least partially effective in controlled clinical trials, but many patients do not respond to pharmacological approaches. Electroconvulsive therapy has been tested to be efficacious for the treatment of both manic and depressive episodes, but much less evidence is available with regards to mixed states. The aim of the review was to report the available evidence for the use of electroconvulsive therapy in mixed bipolar states.
A systematic review of the literature on treatment of mixed states, focused on electroconvulsive therapy, was made, beginning in August 1992 and ending in March 2007. The key words were “electroconvulsive therapy” and “mixed bipolar”.
Only three studies met the required quality criteria and were included. This literature suggests that ECT is an effective, safe, and probably underutilized treatment of mixed states. Recent technical developments have made ECT more friendly, tolerable, and safe. Potential alternatives, such as vagus nerve stimulation, deep brain stimulation, or transcranial stimulation, are still far to be proved as effective as ECT.
Patients with bipolar disorder experience a wide range of depressive and manic symptoms. Only 2 drugs are FDA-approved to treat episodes of both mania and depression in patients with bipolar disorder, highlighting the need for treatments with proven efficacy at opposite poles of the bipolar spectrum. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, is approved in the US for the treatment of both bipolar depression and manic and mixed episodes associated with bipolar I disorder. Cariprazine has previously demonstrated broad efficacy in patients with bipolar mania, with significantly greater improvement in favor of cariprazine vs placebo (PBO) across all individual symptom domains (P<.001) measured by the Young Mania Rating Scale (YMRS). Additionally, cariprazine has demonstrated efficacy vs PBO in 3 phase II/III clinical studies in patients with depressive episodes associated with bipolar I disorder (NCT01396447, NCT02670538, NCT02670551). To further assess the broad efficacy of cariprazine in patients with bipolar I disorder, we performed post hoc analyses to evaluate the range of depressive symptoms comprising the individual items of the Montgomery-Åsberg Depression Rating Scale (MADRS) in patients from the bipolar depression studies.
Data from the 3 randomized, double-blind, PBO-controlled trials in patients with bipolar depression were pooled. Least squares (LS) mean change from baseline to week 6 in MADRS individual items was assessed in the pooled cariprazine 1.5 and 3 mg/d groups vs PBO using a mixed-effects model for repeated measures in the intent-to-treat (ITT) population.
There were 1383 patients in the ITT population (placebo=460; cariprazine 1.5-3 mg/d=923). At week 6, LS mean change from baseline was significantly greater for cariprazine 1.5-3 mg/d vs PBO on 9 of 10 individual MADRS items: Apparent Sadness (-2.0 vs -1.6, P<.0001); Reported Sadness (-2.0 vs -1.6, P<.0001); Reduced Sleep (-1.6 vs -1.4, P=.0357); Reduced Appetite (-1.2 vs -1.0, P=.0001); Concentration Difficulties (-1.5 vs -1.2, P=.0002); Lassitude (-1.7 vs -1.4, P=.0003); Inability To Feel (-1.7 vs -1.5, P=.0009); Pessimistic Thoughts (-1.4 vs -1.2, P=.0054) and Suicidal Thoughts (-0.3 vs -0.2, P=.0383); differences between cariprazine and PBO on the Inner Tension item were not significant.
Significant improvement in most MADRS single items suggests broad efficacy in depressive symptoms for cariprazine 1.5-3 mg/d vs PBO in patients with bipolar depression. Coupled with broad efficacy in manic symptoms as demonstrated by significant improvement in all YMRS individual items in patients with bipolar mania or mixed episodes, cariprazine appears be effective across the range of symptoms that affect patients with bipolar disorder.
Neurotrophins such as brain-derived neurotrophic factor (BDNF), inflammation and oxidative damage may contribute to the pathophysiology of bipolar disorder (BD) in terms of illness activity. To date, there is a lack of studies linking the cognitive impairment observed in BD with these neurobiological mechanisms. This study aimed to investigate the role of these neurobiological factors in clinical and cognitive outcomes in a sample of bipolar individuals.
We measured serum BDNF, cytokines and oxidative stress markers in a sample of 133 individuals: 52 euthymic bipolar patients, 32 manic patients and 49 healthy controls. They were all assessed with a comprehensive cognitive battery. Sociodemographic and clinical data were collected. Multiple linear regression models were built to study associations of neurotrophins and inflammatory and oxidative measures with cognitive functioning.
BDNF levels were decreased in euthymic (p = 0.039) and manic (p < 0.001) individuals. Conversely, inflammatory (interleukin 6 (IL-6)) (p = 0.019) and oxidative stress (p = 0.003) measures were increased in bipolar individuals compared to controls. BDNF levels were associated with executive functioning (β = 0.01, p = 0.02) and verbal memory (β = 0.013, p = 0.005), together with other demographic variables. In particular, verbal memory was also associated with obesity (β=-0.04, p = 0.005). Neither inflammatory markers, oxidative stress markers nor other relevant clinical variables showed any association with cognitive outcome.
Of all the peripheral neurobiological factors analysed, BDNF was the only one significantly associated with cognitive dysfunction in bipolar disorder individuals. This study emphasizes the role of BDNF not only across mood phases but also in cognitive functioning.
Schizoaffective disorder, bipolar type (SAD) and bipolar disorder I (BD) present a large clinical overlap. In a 1-year follow-up, we aimed to evaluate days to hospitalization (DTH) and predictors of relapse in a SAD-BD cohort of patients.
A 1–year, prospective, naturalistic cohort study considering DTH as primary outcome and incidence of direct and indirect measures of psychopathological compensation as secondary outcomes. Kaplan-Meyer survival analysis with Log-rank Mantel-Cox test compared BD/SAD subgroups as to DTH. After bivariate analyses, Cox regression was performed to assess covariates possibly associated with DTH in diagnostic subgroups.
Of 836 screened patients, 437 were finally included (SAD = 105; BD = 332). Relapse rates in the SAD sample was n = 26 (24.8%) vs. n = 41 (12.3%) in the BD sample (p = 0.002). Mean ± SD DTH were 312.16 ± 10.6 (SAD) vs. 337.62 ± 4.4 (BD) days (p = 0.002). Patients with relapses showed more frequent suicide acts, violent behaviors, and changes in pharmacological treatments (all p < 0.0005) in comparison to patients without relapse. Patients without relapses had significantly higher mean number of treatments at T0 (p = 0.010). Cox regression model relating the association between diagnosis and DTH revealed that BD had higher rates of suicide attempts (HR = 13.0, 95%CI = 4.0–42.0, p < 0.0005), whereas SAD had higher rates of violent behavior during psychotic episodes (HR = 12.0, 95%CI =.3.3-43.5, p > 0.0005).
SAD patients relapse earlier with higher hospitalization rates and violent behavior during psychotic episodes whereas bipolar patients have more suicide attempts. Psychiatric/psychological follow-up visits may delay hospitalizations by closely monitoring symptoms of self- and hetero-aggression.
Considering the recurrent and chronic nature of bipolar disorder, optimal long-term management requires a preventive strategy that includes pharmacological treatments together with psychological therapies that have shown efficacy in bipolar disorder. Adjunctive psychological interventions, always as an added treatment to the pharmacological therapy, would ensure the effect of medication through the promotion of adherence to therapy regimen (MacDonald et al. 2016), which is often suboptimal in those with bipolar disorder (Levin et al. 2016), and would address other aspects that medication alone cannot reach.
Cognitive functions encompass the mental processes that take place in the brain, in the central nervous system, related to thinking, decision making, planning, paying attention, remembering. In recent years, the increasing prevalence of dementia in the general population has led to a growing interest in stimulating cognitive functions. This greater awareness of the importance of preserving and improving our cognitive functions has been accompanied by a proliferation of brain training programmes, especially with the expansion of new technologies. Even so, neuropsychological rehabilitation and its application in different pathologies have been in use for more than a century. While different assessments and treatment procedures for brain injury began to be developed in the 1970s, neuropsychological evaluations acquired a relevant status in the world of psychiatry in the late twentieth century, with a particular focus on schizophrenia. Currently, the study of cognitive functioning has been extended to other psychiatric illnesses, especially affective disorders such as bipolar disorder and depression.
What we do throughout life contributes to accelerating or to slowing down the ageing process. Although we tend to remember the importance of taking care of ourselves when we feel ill, good health should be considered a long-term investment. A sedentary lifestyle, obesity, tobacco, consumption of alcohol and other substances, and stress, among others, are factors that negatively affect our cells, accelerating the deterioration of tissues in our body. Good health means staying active physically, intellectually and socially, as well as carrying out healthy and regular habits, including a balanced diet and varied physical exercise. Fortunately, control of these factors is in our hands. If we manage to transform healthy behaviours into habits, the effort to maintain them will be less and will be rewarded by the motivation and perceived benefits for health and quality of life.
Every illness represents in some way a threat and increases the sense of vulnerability. The diagnosis of a chronic and recurrent mental disorder influences a person’s self-image and has a strong impact on all members of the family. In the adjustment to the diagnosis, each individual usually undergoes a process in which a variety of beliefs and emotions may arise that will have to be dealt with, in parallel to education about and acceptance of the disorder. It is common for denial to appear first, attributing what has happened to external factors. There is also a tendency for the patient to deny the chronic nature of the disorder, refusing the possibility that another episode may occur. The onset of the disease can often be accompanied by a marked sense of loss, experienced both by the person receiving the diagnosis and by his or her relatives: the loss of the healthy self together with an increase in the feeling of vulnerability, real losses as a consequence of the episodes (work is impaired, social difficulties arise, ruptures occur, family are affected, financial problems ensue, etc.) or perceived loss, sometimes erroneously, of expectations about the person him- or herself or about the future.