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The experience of Infertility is extremely stressful for all people. The goals of this chapter are to provide the mental health practitioner with an understanding of the relationship between infertility in men and women and psychiatric illnesses. Patients with a history of major depression are at an increased risk of recurrence of major depression during infertility evaluation and treatment, and women who have had recurrent miscarriages are especially high risk for depression. Some patients will need to continue their antidepressants during the infertility process and pregnancy, and in this chapter we will discuss the risks and benefits associated with antidepressants in this population. Research on the interaction of the infertility medications and bipolar disorder destabilization is lacking, but it is important for the mental health practitioner to recognize that the dramatic hormonal changes associated with ovarian stimulation may lead to increased lability, especially if the medications have the side effect of insomnia. While some mood stabilizers such as lamotrigine are considered relatively safe to take in pregnancy, others, such as valproic acid are associated with congenital abnormalities and should be discontinued. Personality disorder patients may also react to the stress of infertility treatment with primitive defenses that are difficult for the infertility treatment team to manage, such as acting out and splitting. In this chapter, we will discuss the intersection of personality disorders and psychiatry and we will also provide guidance about when to recommend that patients defer or stop infertility treatment due to psychiatric illnesses.
Neuroprogressive models of the trajectory of cognitive dysfunction in patients with bipolar disorder (BD) have been proposed. However, few studies have explored the relationships among clinical characteristics of BD, cognitive dysfunction, and aging.
We conducted a cross-sectional analysis in euthymic participants with the MATRICS Cognitive Consensus Battery, the Trail Making Test B, the Stroop Test, and the Wechsler Test of Adult Reading. Age- and gender-equated control participants without a mental disorder [‘Healthy Controls’ – HC)] were assessed similarly. We compared cognitive performance both globally and in seven domains in four groups: younger BD (age ⩽49 years; n = 70), older BD (age ⩾50 years; n = 48), younger HC (n = 153), and older HC (n = 44). We also compared the BD and HC groups using age as a continuous measure. We controlled for relevant covariates and applied a Bonferroni correction.
Our results support both an early impairment (‘early hit’) model and an accelerated aging model: impairment in attention/vigilance, processing speed, and executive function/working memory were congruent with the accelerated aging hypothesis whereas impairment in verbal memory was congruent with an early impairment model. BD and HC participants exhibited similar age-related decline in reasoning/problem solving and visuospatial memory. There were no age- or diagnosis-related differences in social cognition.
Our findings support that different cognitive domains are affected differently by BD and aging. Longitudinal studies are needed to explore trajectories of cognitive performance in BD across the lifespan.
Bipolar disorder is a source of marked disability, morbidity and premature death. There is a paucity of research on personalised psychosocial interventions for bipolar disorder, especially in low-resource settings. A pilot randomised controlled trial (RCT) of a culturally adapted psychoeducation intervention for bipolar disorder (CaPE) in Pakistan reported higher patient satisfaction, enhanced medication adherence, knowledge and attitudes regarding bipolar disorder, and improvement in mood symptom scores and health-related quality of life measures compared with treatment as usual (TAU).
The current protocol describes a larger multicentre RCT to confirm the clinical and cost-effectiveness of CaPE in Pakistan. Trial registration: NCT05223959.
A multicentre individual, parallel-arm RCT of CaPE in 300 Pakistani adults with bipolar disorder. Participants over the age of 18, with a diagnosis of bipolar I or II disorder who are currently euthymic, will be recruited from seven sites: Karachi, Lahore, Multan, Rawalpindi, Peshawar, Hyderabad and Quetta. Time to recurrence will be the primary outcome assessed using the Longitudinal Interval Follow-up Evaluation (LIFE). Secondary measures will include mood symptoms, quality of life and functioning, adherence to psychotropic medications, and knowledge and attitudes regarding bipolar disorder.
This trial will assess the effectiveness of the CaPE intervention compared with TAU in reducing the time to recurrence for people with bipolar disorder currently in remission in Pakistan and determine the effect on clinical outcomes, quality of life and functioning.
A successful trial might lead to rapid implementation of CaPE in clinical practice, not only in Pakistan, but also in other low-resource settings, including those in high-income countries, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority group patients with bipolar disorder.
Paediatric bipolar disorder – bipolar disorder occurring in prepubertal children – is a diagnosis subject to considerable controversy. Whilst historically considered to be very rare, proponents since the 1990s have argued that mania can present differently in children and, as such, is much more common than previously thought. Such proposals raise questions about the validity of proposed phenotypes and potential risks of iatrogenic harm.
I critically examine the construct of paediatric bipolar disorder using Robins and Guze’s (1970) influential criteria for validity of a psychiatric diagnosis. I review, in turn, evidence relating to its clinical description, delimitation from other conditions, follow-up studies, family studies, laboratory studies, and treatment response.
Across domains, existing research highlights significant challenges establishing the diagnosis. This includes significant heterogeneity in operationalising criteria for children; variable or poor inter-rater reliability; difficulty distinguishing paediatric bipolar disorder from other conditions; large differences in rates of diagnosis between the United States of America and other countries; limited evidence of continuity with adult forms; and a lack of evidence for proposed paediatric phenotypes in children at genetic high-risk of the condition. Laboratory and treatment studies are limited, but also do not provide support for the construct.
Evidence for the more widespread existence of paediatric bipolar disorder and its various proposed phenotypes remains weak. The ongoing popularity of the diagnosis, most evident in America, may reflect social pressures and broader limitations in psychiatric nosology. The uncertainty around the diagnosis highlights the need for careful longitudinal assessment of children potentially affected.
The balance between neurotoxic and neuroprotective effects of kynurenine pathway (KP) components has been recently proposed as a key element in the pathophysiology of bipolar disorder (BD) and related mood episodes. This comprehensive overview explored the link of KP with symptom severity and other clinical features of BD.
We searched Medline, Embase, and PsycInfo electronic databases for studies assessing the association of peripheral and/or central concentrations of KP metabolites with putative clinical features, including symptom severity and other clinical domains in BD.
We included the findings of 13 observational studies investigating the possible variations of KP metabolites according to symptom severity, psychotic features, suicidal behaviors, and sleep disturbances in BD. Studies testing the relationship between KP metabolites and depression severity generated mixed and inconsistent findings. No statistically significant correlations with manic symptoms were found. Moreover, heterogeneous variations of the KP across different clinical domains were shown. Few available studies found (a) higher levels of cerebrospinal fluid kynurenic acid and lower of plasma quinolinic acid in BD with psychotic features, (b) lower central and peripheral picolinic acid levels in BD with suicide attempts, and (c) no significant correlations between KP metabolites and BD-related sleep disturbances.
An imbalance of KP metabolism toward the neurotoxic branches is likely to occur in people with BD, though evidence on variations according to specific clinical features of BD is less clear. Additional research is needed to clarify the role of KP in the etiopathogenesis of BD and related clinical features.
Chapter 14 outlines the range of mood difficulties and disorders in children and young people, including low mood and depression, bipolar affective disorder and emotion regulation difficulties. We also discuss the emerging personality difficulties and disorders. We consider treatment approaches and support for children and young people with mood difficulties and disorders.
Abnormal auditory processing of deviant stimuli, as reflected by mismatch negativity (MMN), is often reported in schizophrenia (SCZ). At present, it is still under debate whether this dysfunctional response is specific to the full-blown SCZ diagnosis or rather a marker of psychosis in general. The present study tested MMN in patients with SCZ, bipolar disorder (BD), first episode of psychosis (FEP), and in people at clinical high risk for psychosis (CHR).
Source-based MEG activity evoked during a passive auditory oddball task was recorded from 135 patients grouped according to diagnosis (SCZ, BD, FEP, and CHR) and 135 healthy controls also divided into four subgroups, age- and gender-matched with diagnostic subgroups. The magnetic MMN (mMMN) was analyzed as event-related field (ERF), Theta power, and Theta inter-trial phase coherence (ITPC).
The clinical group as a whole showed reduced mMMN ERF amplitude, Theta power, and Theta ITPC, without any statistically significant interaction between diagnosis and mMMN reductions. The mMMN subgroup contrasts showed lower ERF amplitude in all the diagnostic subgroups. In the analysis of Theta frequency, SCZ showed significant power and ITPC reductions, while only indications of diminished ITPC were observed in CHR, but no significant decreases characterized BD and FEP.
Significant mMMN alterations in people experiencing psychosis, also for diagnoses other than SCZ, suggest that this neurophysiological response may be a feature shared across psychotic disorders. Additionally, reduced Theta ITPC may be associated with risk for psychosis.
Inflammation plays a crucial role in the pathogenesis of major depressive disorder (MDD) and bipolar disorder (BD). This study aimed to examine whether the dysregulation of complement components contributes to brain structural defects in patients with mood disorders.
A total of 52 BD patients, 35 MDD patients, and 53 controls were recruited. The human complement immunology assay was used to measure the levels of complement factors. Whole brain-based analysis was performed to investigate differences in gray matter volume (GMV) and cortical thickness (CT) among the BD, MDD, and control groups, and relationships were explored between neuroanatomical differences and levels of complement components.
GMV in the medial orbital frontal cortex (mOFC) and middle cingulum was lower in both patient groups than in controls, while the CT of the left precentral gyrus and left superior frontal gyrus were affected differently in the two disorders. Concentrations of C1q, C4, factor B, factor H, and properdin were higher in both patient groups than in controls, while concentrations of C3, C4 and factor H were significantly higher in BD than in MDD. Concentrations of C1q, factor H, and properdin showed a significant negative correlation with GMV in the mOFC at the voxel-wise level.
BD and MDD are associated with shared and different alterations in levels of complement factors and structural impairment in the brain. Structural defects in mOFC may be associated with elevated levels of certain complement factors, providing insight into the shared neuro-inflammatory pathogenesis of mood disorders.
Tardive dyskinesia (TD) is a heterogeneous, hyperkinetic movement disorder induced by dopamine-receptor blocking agents that presents a unique challenge in the treatment of psychosis. Although acceptance of TD as a serious consequence of antipsychotic treatment was resisted initially, subsequent research by many investigators in psychopharmacology contributed to a rich store of knowledge on many aspects of the disorder. While basic neuroscience investigations continue to deepen our understanding of underlying motor circuitry, past trials of potential treatments of TD focusing on a range of theoretical targets were often inconclusive. Development of newer antipsychotics promised to reduce the risk of TD compared to older drugs, but their improved tolerability unexpectedly enabled an expanding market that paradoxically both increased the absolute number of patients at risk and diminished attention to TD which was relegated to legacy status. Fortunately, development and approval of novel vesicular monoamine transporter inhibitors offered evidence-based symptomatic treatment of TD for the first time and rekindled interest in the disorder. Despite recent progress, many questions remain for future research including the mechanisms underlying TD, genetic predisposition, phenomenological diversity, whether new cases are reversible, how to implement best practices to prevent and treat TD, and whether the development of novel antipsychotics free of the risk of TD is attainable. We owe our patients the aspirational goal of striving for zero prevalence of persistent symptoms of TD in anyone treated for psychosis.
Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic-inflammatory disease associated with poor outcomes and decreased quality of life. NAFLD is overrepresented in patients with psychiatric disorders like depression, bipolar disorder, and schizophrenia; however, a comprehensive review on NAFLD and psychiatric disorders remains to be delineated. This review endeavors to investigate the association of NAFLD with psychiatric disorders, including shared pathogenesis and future clinical derivatives. Extant literature suggests that patients with psychiatric disorders (in particular, mood disorders) are more susceptible to the development of NAFLD due to multiple reasons, including but not limited to hypothalamic–pituitary–adrenal axis dysregulation, metabolic syndrome, and chronic perceived stress. Moreover, the clinical manifestations of mood disorders (e.g., anhedonia, psychomotor retardation, lifestyle modification, etc.), and potentially long-term treatment with weight-gaining agents, differentially affect these patients, making them more prone to NAFLD. Considering the increased morbidity associated with both mood disorders and NAFLD, our review recommends regular screenings for NAFLD in select patients with mood disorders exhibiting signs of increased risk (i.e., obesity, metabolic syndrome, diabetes, or family history of NAFLD) for better diagnosis and holistic care of both potentially interrelated conditions.
There is ongoing debate on the nosological position of bipolar disorder (BD) and borderline personality disorder (BPD). Identifying the unique and shared risks, developmental pathways, and symptoms in emerging BD and BPD could help the field refine aetiological hypotheses and improve the prediction of the onset of these disorders. This study aimed to: (a) systematically synthesise the available evidence from systematic reviews (SRs) and meta-analyses (MAs) concerning environmental, psychosocial, biological, and clinical factors leading to the emergence of BD and BPD; (b) identify the main differences and common features between the two disorders to characterise their complex interplay and, (c) highlight remaining evidence gaps.
Data sources were; PubMed, PsychINFO, Embase, Cochrane, CINAHL, Medline, ISI Web of Science. Overlap of included SRs/MAs was assessed using the corrected covered area process. The methodological quality of each included SR and MA was assessed using the AMSTAR.
22 SRs and MAs involving 249 prospective studies met eligibility criteria. Results demonstrated that family history of psychopathology, affective instability, attention deficit hyperactivity disorder, anxiety disorders, depression, sleep disturbances, substance abuse, psychotic symptoms, suicidality, childhood adversity and temperament were common predisposing factors across both disorders. There are also distinct factors specific to emerging BD or BPD.
Prospective studies are required to increase our understanding of the development of BD and BPD onset and their complex interplay by concurrently examining multiple measures in BD and BPD at-risk populations.
Numerous studies of resting-state functional imaging and voxel-based morphometry (VBM) have revealed differences in specific brain regions of patients with bipolar disorder (BD), but the results have been inconsistent.
A whole-brain voxel-wise meta-analysis was conducted on resting-state functional imaging and VBM studies that compared differences between patients with BD and healthy controls using Seed-based d Mapping with Permutation of Subject Images software.
A systematic literature search identified 51 functional imaging studies (1842 BD and 2190 controls) and 83 VBM studies (2790 BD and 3690 controls). Overall, patients with BD displayed increased resting-state functional activity in the left middle frontal gyrus, right inferior frontal gyrus (IFG) extending to the right insula, right superior frontal gyrus and bilateral striatum, as well as decreased resting-state functional activity in the left middle temporal gyrus extending to the left superior temporal gyrus and post-central gyrus, left cerebellum, and bilateral precuneus. The meta-analysis of VBM showed that patients with BD displayed decreased VBM in the right IFG extending to the right insula, temporal pole and superior temporal gyrus, left superior temporal gyrus extending to the left insula, temporal pole, and IFG, anterior cingulate cortex, left superior frontal gyrus (medial prefrontal cortex), left thalamus, and right fusiform gyrus.
The multimodal meta-analyses suggested that BD showed similar patterns of aberrant brain activity and structure in the insula extending to the temporal cortex, fronto-striatal-thalamic, and default-mode network regions, which provide useful insights for understanding the underlying pathophysiology of BD.
People with severe mental illness (SMI) have more physical health conditions than the general population, resulting in higher rates of hospitalisations and mortality. In this study, we aimed to determine the rate of emergency and planned physical health hospitalisations in those with SMI, compared to matched comparators, and to investigate how these rates differ by SMI diagnosis.
We used Clinical Practice Research DataLink Gold and Aurum databases to identify 20,668 patients in England diagnosed with SMI between January 2000 and March 2016, with linked hospital records in Hospital Episode Statistics. Patients were matched with up to four patients without SMI. Primary outcomes were emergency and planned physical health admissions. Avoidable (ambulatory care sensitive) admissions and emergency admissions for accidents, injuries and substance misuse were secondary outcomes. We performed negative binomial regression, adjusted for clinical and demographic variables, stratified by SMI diagnosis.
Emergency physical health (aIRR:2.33; 95% CI 2.22–2.46) and avoidable (aIRR:2.88; 95% CI 2.60–3.19) admissions were higher in patients with SMI than comparators. Emergency admission rates did not differ by SMI diagnosis. Planned physical health admissions were lower in schizophrenia (aIRR:0.80; 95% CI 0.72–0.90) and higher in bipolar disorder (aIRR:1.33; 95% CI 1.24–1.43). Accident, injury and substance misuse emergency admissions were particularly high in the year after SMI diagnosis (aIRR: 6.18; 95% CI 5.46–6.98).
We found twice the incidence of emergency physical health admissions in patients with SMI compared to those without SMI. Avoidable admissions were particularly elevated, suggesting interventions in community settings could reduce hospitalisations. Importantly, we found underutilisation of planned inpatient care in patients with schizophrenia. Interventions are required to ensure appropriate healthcare use, and optimal diagnosis and treatment of physical health conditions in people with SMI, to reduce the mortality gap due to physical illness.
Use of Monoamine Oxidase Inhibitors (MAOIs) has experimented an important reduction in recent years, being replaced by other antidepressant drugs (ADs) associated with a better safety profile. Its use has been restricted to instructed professionals treating resistant and atypical depression. Thus, treatment-emergent affective switch (TEAS) induced by MAOIs is a rare event nowadays.
To describe a manic episode associated to a one-year-long treatment with phenelzine, a MAOI agent.
We present the case of a 47-year-old man hospitalized in our acute psychiatric unit after presenting compatible clinical symptoms with a manic episode. He showed severe irritability, decreased need for sleep, pressured speech, increased energy and goal-directed activities. The patient had started phenelzine a year ago for the treatment of major depressive episode resistant to previous pharmacological essayed treatments. No previous history of TEAS was reported, although he had already taken other ADs and mood-stabilizer treatments in the past.
Several studies reported the effectiveness of MAOIs for the treatment of monopolar depressive episodes resistant to other ADs, especially when atypical symptoms were observed. Data on the use of MAOIs for the treatment of drug-resistant bipolar depressive episodes is scarce. Few studies have described a good response without showing and increased risk of TEAS.
As MAOIs have fallen out of favour with modern psychiatry, there is scarce evidence on the prevalence of TEAS in patients undergoing treatment with these drugs. Further research is needed in order to accurately define these complex relationships.
Treatment-Resistant Depression continues to represent a great challenge for clinicians.
We investigated patients with history of resistance, assessing prognostic factors, response to treatments, and remission over time.
We recruited 202 unipolar and bipolar depressed inpatients. According to anamnestic backgrounds, patients were assigned to: A) Non-resistant
: responders, with no characteristics of resistance in the current episode. B) Resistant: resistant to two antidepressant trials of adequate doses and duration. C) Pseudo-resistant
: non-responders, not classifiable as Resistant because of inadequate trials. During hospitalization, patients were treated by clinical judgment, following a rehabilitation program.
Episodes of illness
On the day of admission, non-responders were 44.5% of the sample, but 39.3% of them did not meet the Resistant criteria, defining the Pseudo-resistant
differed from others by younger age, fewer illness episodes, higher rate of personality disorders, and different therapies during hospitalization [Fig.1,2,3]. Pseudo-resistant
remission rate, significantly greater than Resistant one, was comparable to Non-resistant
[Tab.1]. *Kruskal-Wallis Test **Chi-Squared Test
This study outlines a new group of depressed patients that, apparently drug-resistant, displays the same outcome as responders when treated with first-line drugs during hospitalization, certainly taking benefit from the psychoeducational program. Quick recognition of these patients could be crucial to giving optimal care.
Schizophrenia (SZ) and bipolar disorder (BD) are severe mental illnesses with large overlapping heritability. Both disorders are associated with altered neurophysiological responses, as measured with magnetoencephalography (MEG) or electroencephalography (EEG), particularly reduced mismatch negativity (MMN) and 40 Hz auditory steady-state responses (ASSR). These deficits could potentially both serve as early markers of illness and provide insight into the underlying pathophysiology as endophenotypes. First-degree relatives to patients with SZ and BD also show some neurophysiological deficits, however whether these deficits can be detected in adolescent offspring of patients is undetermined.
We aim to investigate whether adolescents at familial high risk of schizophrenia and bipolar disorder show aberrant MMN and ASSR compared to population-based controls.
We will investigate MMN and 40 Hz ASSR in 15 year old adolescents (n ≈ 175) born to parents diagnosed with either SZ (FHR-SZ), BD (FHR-BD), or neither SZ or BD (population-based controls, PBC) using MEG. We will first perform sensor-level analyses and subsequently apply dynamic causal modeling (DCM) to investigate effective connectivity and make inferences about the underlying neurobiological mechanisms. We will investigate whether current psychopathology, cognitive status, and genetic risk for SZ and BD predict neurophysiological responses in the adolescents. Investigations are part of The Danish High Risk and Resilience Study - VIA (VIA15), a population-based longitudinal cohort study integrating social, psychological and biological risk factors and outcomes for SZ and BD.
Final results are expected in 2024
The VIA15 study will allow for unprecedented insight into the neurobiological development of schizophrenia and bipolar disorder.
Circadian rhythm (CR) dysfunction is a prominent feature in bipolar disorder (BD) and sleep disturbances are characteristic, although not essential to the diagnosis.
To review the literature regarding the CR dysfunction and its impact on the onset and clinical course of BD.
We conducted a MEDLINE search using bipolar disorder, circadian rhythm and sleep as keywords, selecting studies written in English.
CR dysfunction is a trait marker of BD. It’s known that during depressive episodes insomnia is present, with difficulty falling asleep/ maintaining sleep and early awakening. Regarding mania, decreased need for sleep is a critical marker. During the euthymic period significant alterations in sleep pattern have been described. It’s also known that changes in the sleep pattern occur prior to those in mood patterns, indicating that sleep dysregulation may trigger the onset of mood episodes or relapses. Therefore, CR disruption may be associated with the pathophysiology of BD and some factors have already been identified: irregularity of the sleep-wake rhythm, eveningness chronotype, abnormality of melatonin secretion, vulnerability of clock genes and the irregularity of social zeitgeber.
Disturbances of sleep are pervasive, and an essential feature of BD, worse during mood episodes, but still present during euthymic periods. It remains to determine whether circadian rhythm dysfunction is a trait marker or mood state dependent. Further studies are warranted to clarify this association.
Bipolar Disorder (BD) is a life-course illness with evidence of a progressive nature. Although different staging models have been proposed from a theoretical perspective,longitudinal studies are scarce.
The aim of the present study was to apply four staging models in a sample of BD patients and to observe their progression in 10 years of retrospective evaluation.
In a naturalistic sample of 100 BD patients, a retrospective assessment of clinical stages across 10 years of observation at six time points (T0: 2010; T1: 2013; T2: 2015; T3: 2018; T4: 2019; T5:2020) was performed according to the BD staging models (Berk et al., 2007; Kapczinski et al., 2009; Kupka et al., 2012 and Duffy et al., 2014). Socio-demographic and clinical variables were collected and the staging progression across time was analyzed.
A significant progressive staging worsening emerged over 10 years of BD observation for each examined model (p<0.001). Moreover, for all considered staging approaches, stage values were lower over the time points for BD II, lower number of lifetime episodes and hospitalizations (p<0.05). Finally, the stage increase was associated with a lower age at first elevated episode (p<0.05).
Present preliminary results confirm the relevance of illness onset and early intervention in BD, given their role in patients classified into worse clinical staging. There is an emerging need of a standardized universal staging model in order to better characterize BD patients, their treatment and their clinical course.