Sex-specific self-reported mood changes by patients with bipolar disorder

INTRODUCTION: While the prevalence of bipolar disorder I is similar between men and women, the clinical course may differ. This study investigated if there are differences in the clinical presentation of bipolar disorder between the sexes. METHODS: Mood patterns were documented using ChronoRecord software for self-reporting. Patients entered mood, medications, sleep, life events and menstrual data daily acquired over the period of three months. 8662 Days of data were received from 80 patients: 3483 days from 35 men and 5179 days from 45 women. RESULTS: The distribution of the time spent in mood categories differed between men and women (P<0.001). Men were depressed 17.0% of the time, euthymic 74.0% of the time and manic 5.6% of the time. Women were depressed 28.3% of the time, euthymic 64.2% of the time and manic 7.5% of the time. Over 80% of all reported symptoms for both sexes were mild. Women exhibited large mood fluctuations (greater than 10 in either direction on a 100-unit scale) more frequently than men. Most of the reproductive aged women (55%) reported significant mood changes across the menstrual cycle. CONCLUSIONS: The clinical course of bipolar disorder differed between the sexes. Women reported depression and large fluctuations in mood more frequently than men. Women also experienced mood changes across the menstrual cycle.     

Creativity in familial bipolar disorder

Studies have demonstrated relationships between creativity and bipolar disorder (BD) in individuals, and suggested familial transmission of both creativity and BD. However, to date, there have been no studies specifically examining creativity in offspring of bipolar parents and clarifying mechanisms of intergenerational transmission of creativity. We compared creativity in bipolar parents and their offspring with BD and bipolar offspring with attention-deficit/hyperactivity disorder (ADHD) with healthy control adults and their children. 40 adults with BD, 20 bipolar offspring with BD, 20 bipolar offspring with ADHD, and 18 healthy control parents and their healthy control children completed the Barron–Welsh Art Scale (BWAS), an objective measure of creativity. Adults with BD compared to controls scored significantly (120%) higher on the BWAS Dislike subscale, and non-significantly (32%) higher on the BWAS Total scale. Mean BWAS Dislike subscale scores were also significantly higher in offspring with BD (107% higher) and offspring with ADHD (91% higher) than in healthy control children. Compared to healthy control children, offspring with BD had 67% higher and offspring with ADHD had 40% higher BWAS Total scores, but these differences failed to reach statistical significance when adjusted for age. In the bipolar offspring with BD, BWAS Total scores were negatively correlated with duration of illness. The results of this study support an association between BD and creativity and contribute to a better understanding of possible mechanisms of transmission of creativity in families with genetic susceptibility for BD. This is the first study to show that children with and at high risk for BD have higher creativity than healthy control children. The finding in children and in adults was related to an enhanced ability to experience and express dislike of simple and symmetric images. This could reflect increased access to negative affect, which could yield both benefits with respect to providing affective energy for creative achievement, but also yield liabilities with respect to quality of interpersonal relationships or susceptibility to depression.     

Current irritability robustly related to current and prior anxiety in bipolar disorder

BackgroundAlthough current irritability and current/prior anxiety have been associated in unipolar depression, these relationships are less well understood in bipolar disorder (BD). We investigated relationships between current irritability and current/prior anxiety as well as other current emotions and BD illness characteristics.MethodsOutpatients referred to the Stanford Bipolar Disorders Clinic during 2000–2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prevalence and clinical correlates of current irritability and current/prior anxiety and other illness characteristics were examined.ResultsAmong 497 BD outpatients (239 Type I, 258 Type II; 58.1% female; mean ± SD age 35.6 ± 13.1 years), 301 (60.6%) had baseline current irritability. Patients with versus without current irritability had significantly higher rates of current anxiety (77.1% versus 42.9%, p < 0.0001) and history of anxiety disorder (73.1% versus 52.6%, p < 0.0001). Current irritability was more robustly related to current anxiety than to current anhedonia, sadness, or euphoria (all p < 0.001), and current irritability-current anxiety associations persisted across current predominant mood states. Current irritability was more robustly related to past anxiety than to all other assessed illness characteristics, including 1° family history of mood disorder, history of alcohol/substance use disorder, bipolar subtype, and current syndromal/subsyndromal depression (all p < 0.05).LimitationsLimited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample.ConclusionsIn BD, current irritability was robustly related to current/prior anxiety. Further studies are warranted to assess longitudinal clinical implications of relationships between irritability and anxiety in BD.     

Parental diagnoses in youth with narrow phenotype bipolar disorder or severe mood dysregulation

OBJECTIVE: Controversy exists regarding whether nonepisodic irritability and hyperarousal (severe mood dysregulation) is a phenotype of pediatric bipolar disorder. The authors compared axis I diagnoses in parents of children with narrow phenotype bipolar disorder and parents of youth with severe mood dysregulation. METHOD: Parents of youth with narrow phenotype bipolar disorder (proband N=33, parent N=42) and youth with severe mood dysregulation (proband N=30, parent N=37) were interviewed by clinicians who were blind to the child's diagnostic status using the Diagnostic Interview for Genetic Studies. RESULTS: Compared to parents of youth with severe mood dysregulation, parents of youth with narrow phenotype bipolar disorder were significantly more likely to be diagnosed with bipolar disorder. There were no other diagnostic differences between the two groups. CONCLUSIONS: These data suggest that narrow phenotype bipolar disorder may be distinct from severe mood dysregulation in terms of familial aggregation. Additionally, the familiality of narrow phenotype bipolar disorder and adult DSM-IV bipolar disorder is high.     

Different psychophysiological and behavioral responses elicited by frustration in pediatric bipolar disorder and severe mood dysregulation

OBJECTIVE: Researchers disagree as to whether irritability is a diagnostic indicator for pediatric mania in bipolar disorder. The authors compared the behavioral and psychophysiological correlates of irritability among children with severe mood dysregulation (i.e., nonepisodic irritability and hyperarousal without episodes of euphoric mood) and narrow-phenotype bipolar disorder (i.e., a history of at least one manic or hypomanic episode with euphoric mood) as well as those with no diagnosis (i.e., healthy comparison children). METHOD: Subjects with severe mood dysregulation (N=21) or narrow-phenotype bipolar disorder (N=35) and comparison subjects (N=26) completed the affective Posner task, an attentional task that manipulated emotional demands and induced frustration. Mood response, behavior (reaction time and accuracy), and brain activity (event-related potentials) were measured. RESULTS: The severe mood dysregulation and narrow-phenotype bipolar disorder groups both reported significantly more arousal than comparison subjects during frustration, but behavioral and psychophysiological performance differed between the patient groups. In the frustration condition, children with narrow-phenotype bipolar disorder had lower P3 amplitude than children with severe mood dysregulation or comparison subjects, reflecting impairments in executive attention. Regardless of emotional context, children with severe mood dysregulation had lower N1 event-related potential amplitude than comparison subjects or children with narrow-phenotype bipolar disorder, reflecting impairments in the initial stages of attention. Post hoc analyses demonstrated that the N1 deficit in children with severe mood dysregulation is associated with oppositional defiant disorder symptom severity. CONCLUSIONS: Results indicate that while irritability is an important feature of severe mood dysregulation and narrow-phenotype bipolar disorder, the pathophysiology of irritability may differ among the groups and is influenced by oppositional defiant disorder severity.     

双相障碍患者代谢综合征风险研究

目的 调查双相障碍患者长期治疗中代谢综合征的风险发生率及分析可能的相关因素.方法 采用横断面研究.以单用心境稳定剂或联用抗精神病药连续6月以上的门诊双相障碍患者为调查对象.采用统一问卷及实验室检测.代谢综合征诊断标准采用2004年中华医学会糖尿病分会代谢综合征标准.结果 共入组128例,双相障碍患者中代谢综合征的发生率为36.7%(47例).药物类别及用药时间与代谢综合征的发病风险有关(回归系数B值分别为-0.614,-0.797;P值分别为0.028,0.001).结论 与普通人群相比,双相障碍患者有较高的代谢综合征发病风险.用药时间越长代谢综合征的发生风险越高.联用抗精神病药能增加代谢综合征的发生率.临床上应注意监测代谢指标及对代谢异常进行干预.     

Correlation between emotion dysregulation and mood symptoms of bipolar disorder: A systematic review and meta-analysis

Background

Emotion dysregulation (ED) is a transdiagnostic construct characterized by difficulties regulating intense emotions. People with bipolar disorder (BD) are more likely to show ED and use maladaptive emotion regulation strategies than adaptive ones. However, little is known about whether ED in BD is a trait or it is rather an epiphenomenon of mood symptoms.

Methods

We conducted a systematic review and meta-analysis of the evidence across major literature databases reporting correlations between measures of emotion regulation (overall ED and different emotion regulation strategies) and measures of depressive and (hypo)manic symptoms in BD from inception until April 12th, 2022.

Results

Fourteen studies involving 1371 individuals with BD were included in the qualitative synthesis, of which 11 reported quantitative information and were included in the meta-analysis. ED and maladaptive strategies were significantly higher during periods with more severe mood symptoms, especially depressive ones, while adaptive strategies were lower.

Conclusion

ED significantly correlates with BD symptomatology, and it mainly occurs during mood alterations. ED may be a target for specific psychotherapeutic and pharmacological treatments, according to precision psychiatry. However, further studies are needed, including patients with mood episodes and longitudinal design, to provide more robust evidence and explore the causal direction of the associations.     

Corticolimbic metabolic dysregulation in euthymic older adults with bipolar disorder

The corticolimbic dysregulation hypothesis of bipolar disorder suggests that depressive symptoms are related to dysregulation of components of an anterior paralimbic network (anterior cingulate, anterior temporal cortex, dorsolateral prefrontal cortex, parahippocampal gyrus, and amygdala) with excessive anterior limbic activity accompanied by diminished prefrontal activity. In younger patients, such abnormalities tend to resolve with remission of depression, but it remains to be established whether the same is true for older patients. This was a cross-sectional, between-subjects design conducted with 16 euthymic, medicated patients with bipolar disorder (10 type I, six type II) and 11 age-matched healthy controls. All participants were over age 50. Our main outcome measures were relative rates of cerebral metabolism derived from a resting ¹⁸flourodeoxyglucose positron emission tomography scan in specified regions of interest in the corticolimbic network. Resting metabolic rates in bipolar patients were significantly greater than in controls in bilateral amygdalae, bilateral parahippocampal gyri, and right anterior temporal cortex (BA 20, 38); they were significantly lower in bipolar patients than in controls in the bilateral dorsolateral prefrontal cortices (BA 9, 10, 46). The evidence of corticolimbic dysregulation observed is consistent with the hypothesis that bipolar disorder entails progressive, pernicious neurobiological disruptions that may eventually persist during euthymia. Persistent corticolimbic dysregulation may be related to residual affective, behavioral, and cognitive symptoms in older patients with bipolar disorder, even when not experiencing syndromal mood disturbance.     

Evaluating the emotion regulation of positive mood states among people with bipolar disorder using hierarchical clustering

BACKGROUNDPeople with bipolar disorder (BD) frequently struggle with the recurrence of affective symptoms. However, the interplay between coping mechanism and positive mood state remains under-researched.AIMTo explore the associations among behavioral approach system (BAS) sensitivity level, coping, and positive mood states among people with BD.METHODSUsing a cross-sectional study design, 90 participants with BD were presented with four BAS-activating life event scenarios and assessed with regard to their BAS trait sensitivity, coping flexibility, and mood states. A hierarchical clustering method was used to identify different groups with different styles of coping. Multiple hierarchical regression analyses were conducted to examine the mediating and moderating roles of different components of coping on mood states.RESULTSA three-cluster solution was found to best fit the present data set. The findings showed that a low mass of coping combined with low BAS sensitivity level protects people with BD from detrimentally accentuating mood states when they encounter BAS-activating life events. Moreover, coping flexibility is demonstrated to mediate and moderate the relationships between BAS sensitivity level and mood states. Specifically, subduing the perceived controllability and reducing the use of behavioral-activation/emotion-amplifying coping strategies could help buffer the effect of positive affect.CONCLUSIONThe judicious use of coping in emotion regulation for people with BD when encountering BAS-activating life events was indicated. Practical applications and theoretical implications are highlighted.     

心境障碍问卷在抑郁障碍中筛查双相障碍的初步应用

目的 应用心境障碍问卷(MDQ)对诊断为抑郁障碍的精神专科住院患者进行双相障碍的筛查,评估MDQ的应用价值.方法 应用MDQ对48例抑郁障碍住院患者进行评定,以美国精神障碍诊断与统计手册第4版轴Ⅰ障碍定式检查-病人研究版( SCID- Ⅰ/P)为标准对患者进行重新诊断,并与MDQ筛查结果进行比较.结果 48例患者中,以MDQ得分≥7分判断为双相障碍者13例(27.1％);SCID- Ⅰ/P诊断为双相障碍者17例(35.4％),其中MDQ得分≥7分者11例.操作特征曲线分析显示,MDQ筛查双相障碍的敏感性为0.647,特异性为0.935.结论 住院诊断为抑郁障碍的患者中未被识别的双相障碍比例较高,采用MDQ有助于从抑郁障碍中筛查出双相障碍.     

Neural correlates of masked and unmasked face emotion processing in youth with severe mood dysregulation

Reproducibility of results is important in improving the robustness of conclusions drawn from research, particularly in functional magnetic resonance imaging (fMRI). In this study, we aim to replicate a previous study on the neural correlates of face emotion processing above and below awareness level using an independent sample of youth with severe mood dysregulation (SMD) and healthy volunteers (HV). We collected fMRI data in 17 SMD and 20 HV, using an affective priming paradigm with masked (17 ms) and unmasked (187 ms) faces (angry, happy, neutral, blank oval). When processing masked and unmasked angry faces, SMD patients exhibited increased activation in the parahippocampal gyrus (PHG) and superior temporal gyrus relative to HV. When processing masked and unmasked happy faces, SMD patients showed decreased activation in the insula, PHG and thalamus compared with HV. During masked face processing in general across emotions, youth with SMD showed greater ventromedial prefrontal cortex (vmPFC) activation relative to HV. Perturbed activation in emotion processing areas (e.g. insula, PHG, superior temporal gyrus and thalamus) manifests as hyper-sensitivity toward negative emotions and hypo-sensitivity toward positive emotions may be important in the etiology and maintenance of irritability, aggression and depressive symptoms in SMD. vmPFC dysfunction may mediate over-reactivity to face emotions associated with irritability.     

Morphology of the subgenual prefrontal cortex in pediatric bipolar disorder

Objectives

The subgenual prefrontal cortex (SGPFC) is an important brain region involved in emotional regulation and reward mechanisms. Volumetric abnormalities in this region have been identified in adults with bipolar disorder but thus far not in pediatric cases. We examined the volume of this brain region in subjects with pediatric bipolar disorder (PBD) and compared them to healthy controls.

Methods

Fifty one children and adolescents (mean age ± SD; 13.2 ± 2.9 y) with DSM-IV PBD and 41 (mean age ± SD; 13.7 ± 2.7 y) healthy comparison subjects (HC) underwent 1.5 T structural magnetic resonance imaging (MRI) brain scans. We traced the SGPFC manually and compared SGPFC gray matter volumes using analysis of covariance with age, gender, and intracranial volume as covariates. We also examined the relationship of family history of affective disorders and medication status to SGPFC volumes.

Results

SGPFC volumes were not significantly different in PBD and HC subjects. However, exploratory analysis showed PBD subjects who had one or more first degree relatives with mood disorders (n = 33) had significantly smaller left hemisphere SGPFC compared to HC (p = 0.03 Sidak corrected). Current usage of a mood stabilizer was significantly associated with larger right SGPFC volume in PBD (F = 4.82, df = 1/41, p = 0.03).

Conclusion

Subjects with PBD and a close family history of mood disorders may have smaller left SGPFC volumes than HC. Mood stabilizing medication may also impact SGPFC size and could have masked more subtle abnormalities overall.     

Monotherapy treatment of bipolar disorder with levetiracetam

Bipolar patients with early-onset, comorbid substance abuse, rapid cycling, and mixed episodes are difficult to treat and frequently require rational polypharmacy. When polypharmacy is unsuccessful, the clinician must consider the off-label use of newer psychotropics. Levetiracetam is a novel anticonvulsant with antikindling, inhibitory, and neuroprotective properties that is effective in an animal model of mania. This case report describes a patient with treatment-resistant rapid cycling bipolar disorder who failed 15 psychotropics, individually or in various combinations (maximum of 6), but ultimately responded to levetiracetam monotherapy and remained without bipolar features during 1 year of maintenance treatment, excluding 1 week during which the patient was medicine noncompliant. Further, methylphenidate used to treat comorbid attention deficit disorder did not precipitate manic features. Levetiracetam should be further studied for its potential use in the treatment of bipolar disorders.     

Neuropsychological performance in pediatric bipolar disorder.

BACKGROUND: Growing awareness of childhood bipolar disorder necessitates further cognitive neuroscience research to determine unique developmental differences between pediatric and adult onset bipolar disorder. We sought to examine whether neuropsychological function in children with bipolar disorder resembles that in adults with the illness and to extend our knowledge about cognitive function in pediatric bipolar disorder. METHODS: We administered a computerized neuropsychological test battery known as the Cambridge Neuropsychological Test Automated Battery to a sample of 21 children and adolescents with bipolar disorder and compared them with 21 age- and gender-matched controls. RESULTS: In comparison to controls, children with bipolar disorder were impaired on measures of attentional set-shifting and visuospatial memory. Post hoc analyses in pediatric bipolar disorder subjects did not show significant associations between neuropsychological performance and manic symptomatology or attention-deficit/hyperactivity disorder comorbidity. CONCLUSIONS: Cambridge Neuropsychological Test Automated Battery data presented here in pediatric bipolar disorder fit well within the broader framework of known neurocognitive deficits in adult bipolar disorder. Our pediatric bipolar disorder subjects demonstrated selective deficiencies in attentional set-shifting and visuospatial memory. Our work suggests altered ventrolateral prefrontal cortex function, especially when linked to other lesion and neuroimaging studies.     

Metabolic syndrome in subjects with bipolar disorder and major depressive disorder in a current depressive episode: Population-based study: Metabolic syndrome in current depressive episode

ObjectiveTo assess the differences in the prevalence of the metabolic syndrome (MetS) and their components in young adults with bipolar disorder (BD) and major depressive disorder (MDD) in a current depressive episode.MethodsThis was a cross-sectional study with young adults aged 24–30 years old. Depressive episode (bipolar or unipolar) was assessed using the Mini International Neuropsychiatric Interview – Plus version (MINI Plus). The MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III).ResultsThe sample included 972 subjects with a mean age of 25.81 (±2.17) years. Both BD and MDD patients showed higher prevalence of MetS compared to the population sample (BD = 46.9%, MDD = 35.1%, population = 22.1%, p < 0.001). Higher levels of glucose, total cholesterol and LDL cholesterol, Body Mass Index, low levels of HDL cholesterol, and a higher prevalence of abdominal obesity were observed in both BD and MDD individuals with current depressive episode compared to the general population. Moreover, there was a significant difference on BMI values in the case of BD and MDD subjects (p = 0.016).ConclusionMetabolic components were significantly associated with the presence of depressive symptoms, independently of the diagnosis.     

Memantine: New prospective in bipolar disorder treatment

We review preclinical and clinical evidences strongly suggesting that memantine, an old drug currently approved for Alzheimer's dementia, is an effective treatment for acute mania and for the prevention of manic/hypomanic and depressive recurrences of manicdepressive illness. Lithium remains the first line for the treatment and prophylaxis of bipolar disorders, but currently available treatment alternatives for lithium resistant patients are of limited and/or questionable efficacy. Thus, research and development of more effective mood stabilizer drugs is a leading challenge for modern psychopharmacology. We have demonstrated that 21 d administration of imipramine causes a behavioural syndrome similar to a cycle of bipolar disorder, i.e., a mania followed by a depression, in rats. Indeed, such treatment causes a behavioural supersensitivity to dopamine D2 receptor agonists associated with an increase sexual activity and aggressivity(mania). The dopamine receptor sensitization is followed, after imipramine discontinuation, by an opposite phenomenon(dopamine receptor desensitization) and an increased immobility time(depression) in the forced swimming test of depression. Memantine blocks the development of the supersensitivity and the ensuing desensitization associated with the depressive like behavior. On the basis of these observations we have suggested the use of memantine in the treatment of mania and in the prophylaxis of bipolar disorders. To test this hypothesis we performed several naturalistic studies that showed an acute antimanic effect and a long-lasting and progressive mood-stabilizing action(at least 3 years), without clinically relevant side effects. To confirm the observations of our naturalistic trials we are now performing a randomized controlled clinical trial. Finally we described the studies reporting the efficacy of memantine in maniclike symptoms occurring in psychiatric disorders other than bipolar. Limitations: A randomized controlled clinical trial is needed to confirm our naturalistic observations.Conclusion: We believe that this review presents enough pharmacological and clinical information to consider the administration of memantine in the treatment of bipolar disorders that no respond to standard mood stabilizers.     

Screening for bipolar disorder in a county jail at the time of criminal arrest

OBJECTIVE: This study assessed the operating characteristics of the mood disorder questionnaire (MDQ) among offenders arrested and detained at a county jail. METHOD: The MDQ, a brief self-report instrument designed to screen for all subtypes of bipolar disorder (BP I, II and NOS) was voluntarily administered to adult detainees at the Ottawa County Jail in Port Clinton, Ohio. A confirmatory diagnostic evaluation was also performed using the mini-international neuropsychiatric interview (MINI). The MDQ was scored using a standard algorithm requiring endorsement of 7/13 mood items as well as two items that assess whether manic or hypomanic symptoms co-occur and cause moderate to severe functional impairment. In addition to the standard algorithm for scoring the MDQ, modifications were also tested in an attempt to improve overall sensitivity. RESULTS: Among 526 jail detainees who completed the MDQ, 37 (7%) screened positive for bipolar disorder. Of 164 detainees who agreed to a research diagnostic evaluation, 32 (19.5%) screened positive on the MDQ, while 55 (33.5%) met criteria for bipolar disorder according to the MINI. When administered to the sample of 164 adult jail detainees, the sensitivity of the MDQ was 0.47 and the specificity was 0.94. The MDQ was significantly better at detecting BP I (0.59) than BP II/NOS (0.19; p=0.008). Modification of scoring the MDQ improved the sensitivity for detection of BP II from 0.23 to 0.54 with minimal decrease in specificity (0.84). The optimum sensitivity and specificity of the MDQ was achieved by decreasing the item threshold to 3/13 and eliminating the symptom co-occurrence and functional impairment items. CONCLUSION: The MDQ was found to have limited utility as a screening tool for bipolar disorder in a correctional setting, particularly for the BP II subtype.     

双相情感性精神障碍预防性治疗的对照研究

目的：评价丙戊酸镁预防性治疗双相情感障碍的儿及副作用。：９６例频发双相情感精神障碍的病人随机分为两组,分别使用丙戊酸镁（４７例）和碳酸锂（４９例）进行预防性随访时间为３９个月,使用躁狂量表（ＢＲＭＳ）、汉密尔顿抑郁量表（ＨＡＭＩ）,和副反应（ＴＥＳＳ）评定疗效和副作用。结果：丙戊酸镁缄及碳酸锂组预防性治疗有效率分别为８５．０％和８２．１％,副作用发生率分别为８１。．０％和５７．１％,经Ｒｉｄｉｔ分     

Using affect-modulated startle to study phenotypes of pediatric bipolar disorder

OBJECTIVES: Affective neuroscience research that investigates core symptoms of pediatric bipolar disorder (PBD) may be effective in differentiating PBD phenotypes. The current study used affect-modulated startle to examine potential differences in reactivity to emotional stimuli (reward and punishment) in narrow and broad phenotype PBD and controls. METHODS: Thirty children meeting DSM-IV bipolar disorder criteria (i.e. narrow phenotype PBD with defined manic episodes with elevated/expansive mood), 19 children meeting criteria for severe mood dysregulation (i.e. broad phenotype with chronic irritability, hyper-reactivity, and hyperarousal), and 19 controls completed a lottery startle paradigm involving reward (money) and punishment (loud noise). Startle probes were presented during anticipation of the emotional stimulus, immediately following the presentation of the stimulus, or during return to baseline following the stimulus. RESULTS: By self-report, patients and controls found the putative punishment to be preferable to the neutral condition. In the reward condition, patient samples reported greater arousal than did controls, but no between-group differences were found on the magnitude of startle response during the reward, punishment, or neutral conditions. CONCLUSIONS: The failure to find differences in affect-modulated startle between control children and those with narrow or broad PBD phenotypes speaks to the methodological challenges associated with studying reward mechanisms in PBD. Alternative paradigms that focus on different aspects of reward mechanisms are discussed.