Karolina Leopold

Risk constellations prior to the development of bipolar disorders: Rationale of a new risk assessment tool

BACKGROUND The precise characterisation of a high risk status for the development of a psychiatric disorder and the question of how well this predicts disease manifestation is of major importance as negative consequences of late diagnosis and treatment have been well demonstrated. In the absence of well defined and disease specific biological markers for bipolar disorder, the recognition of premature stages must rely on combinations of risk factors that have been associated with later disease manifestation. METHODS A review of the literature and our experience from the Early Recognition Centre led us to identify symptom constellations. RESULTS Individual categories defined and grouped included: (I) genetic risk, (II) substance use, misuse or dependence, (III) diagnosis/suspected diagnosis of attention deficit hyperactivity disorder, (IV) pronounced creativity, (V) impairment in psychosocial functioning, (VI) subthreshold affective symptoms, and (VII) early symptomatology including (a) changes in sleep and circadian rhythm, (b) changes in mood, mood swings/affective lability, (c) fearfulness/anxiety, and (d) dissociative symptoms. These risk constellations were operationalised and a new risk assessment instrument, the Early Phase Inventory for Bipolar Disorders (EPIbipolar) was developed. LIMITATIONS Challenges regarding the validity of the data on which the instrument is based, specificity of and correlations between risk categories, and ethical considerations were encountered. CONCLUSIONS Further use of EPIbipolar in research should help to refine prodromal features and narrow these down to a less cumbersome core that can be used to develop a shortened tool for use in clinical care. Prospective longitudinal research is needed to establish the predictive validity of this novel bipolar disorder risk assessment tool.

The characteristics of sleep in patients with manifest bipolar disorder, subjects at high risk of developing the disease and healthy controls

Sleep is highly altered during affective episodes in patients with bipolar disorder. There is accumulating evidence that sleep is also altered in euthymic states. A deficit in sleep regulation may be a vulnerability factor with aetiological relevance in the development of the disease. This study aims to explore the objective, subjective and lifetime sleep characteristics of patients with manifest bipolar disorder and persons with an elevated risk of developing the disease. Twenty-two patients with bipolar I and II disorder, nine persons with an elevated risk of developing the disorder and 28 healthy controls were evaluated with a structured interview to characterize subjective and lifetime sleeping habits. In addition, participants wore an actimeter for six nights. Patients with bipolar disorder had longer sleep latency and duration compared with healthy controls as determined by actigraphy. The subjective and lifetime sleep characteristics of bipolar patients differed significantly from healthy controls. The results of participants with an elevated risk of developing the disorder had subjective and lifetime characteristics that were largely analogous to those of patients with manifest bipolar disorder. In particular, both groups described recurring insomnia and hypersomnia, sensitivity to shifts in circadian rhythm, difficulties awakening and prolonged sleep latency. This study provides further evidence that sleep and circadian timing are profoundly altered in patients with bipolar disorder. It may also tentatively suggest that sleep may be altered prior to the first manic episode in subjects at high risk.

Interaction of hippocampal volume and N-acetylaspartate concentration deficits in schizophrenia: A combined MRI and 1H-MRS study

BACKGROUND Volume deficits assessed with magnetic resonance imaging (MRI) and neurochemical dysfunctions (N-acetylaspartate, NAA) diagnosed using proton MR spectroscopy ((1)H-MRS) are reliable observations in the hippocampus of schizophrenic patients. NAA is an important cerebral amino acid in the synthesis pathways of glutamate, which has been implicated as a pathobiological core of schizophrenic symptomatology, of histological alterations and brain volume deficits in schizophrenia. However, the possible interaction between regional NAA reduction and volume deficits has been targeted only marginally in previous investigations. METHODS In 29 schizophrenic patients and 44 control subjects, a multimodal imaging study with (1)H-MRS and MRI volumetry of the left hippocampus was performed on a 3-Tesla scanner. RESULTS Compared to the control group, the hippocampus of the patients exhibited a significant volume reduction and a significant NAA concentration decrease. In schizophrenic patients, but not in healthy controls, a significant negative correlation between hippocampal NAA concentration and volume (r=-0.455, p=0.017) was observed. None of the imaging parameters was associated with clinical parameters. CONCLUSIONS The results argue for a coexistent neurochemical and structural deficit in the hippocampus of schizophrenic patients. The inverse relationship between the two parameters observed in patients only may reflect an interaction of neurochemistry and brain morphology as a pathobiological mechanism in schizophrenia. This observation is compatible with the important role of NAA in the synthesis of excitatory neurotransmitters and the hypothesized role of glutamate for brain morphology. The independence of the measured imaging parameters from clinical parameters is in line with the neurodevelopmental hypothesis of schizophrenia.

Diagnosis and treatment in the early illness phase of bipolar disorders

The combination of a long undetected illness and significant psychosocial impairment renders early identification and intervention a vital role in bipolar disorders. Early detection forms the basis for adequate education and for treatment from the beginning. Several lines of evidence indicate that the characterization of early phases in the development of bipolar disorders is feasible. Risk factors for the development of bipolar disorders have been established and a manic prodrome has been characterized that is sufficiently long to allow recognition and, potentially, intervention. Centers specifically focussing on early detection and prevention of bipolar disorders need to be established. More research in this field is warranted including both groups of symptomatic subjects and symptom-free persons, with and without a positive family history.

Psychotherapeutic interventions in individuals at risk of developing bipolar disorder: a systematic review

Accumulating data show that patients with bipolar disorder (BD) experience substantial symptomatology months or years before full manifestation. Based on the need for early preventive interventions in BD as well as data suggesting effectiveness of psychotherapeutic interventions for BD, we aimed to review the evidence for psychotherapeutic treatments in help‐seeking individuals considered at risk for BD (At‐Risk‐BD).

Characteristics, symptomatology and naturalistic treatment in individuals at-risk for bipolar disorders: Baseline results in the first 180 help-seeking individuals assessed at the dresden high-risk project

BACKGROUND Considering results from the early recognition and intervention in psychosis, identification and treatment of individuals with at-risk states for the development of bipolar disorders (BD) could improve the course and severity of illness and prevent long-term consequences. Different approaches to define risk factors and groups have recently been published, data on treatment options are still missing. METHODS Help-seeking persons at the early recognition center in Dresden, Germany, were assessed with a standardized diagnostic procedure including following risk factors for BD: familial risk, increasing mood swings, subsyndromal (hypo)manic symptoms, specific sleep and circadian rhythm disturbances, anxiety/fearfulness, affective disorder, decreased psychosocial functioning, increasing periodic substance use, and attention-deficit/hyperactivity disorder. Based on symptomatology and current and/or life-time psychiatric diagnosis, subjects with an at-risk state were offered individual treatment options. RESULTS Out of 180 referred and screened persons, 29 (16%) met criteria for at-risk state for BD. Altogether, 27 (93%) at-risk individuals fulfilled criteria for a current and/or life-time mental illness other than BD; 14 (48%) had received pharmacological and/or psychotherapeutic treatment in the past. Treatments recommended included psychoeducation (100%), psychotherapy alone (62%), pharmacotherapy alone (17%), and psychotherapy+pharmacotherapy (14%). CONCLUSIONS To identify at-risk states for BD, a multifactorial approach including all known risk markers should be used. As most at-risk patients meet criteria for other mental disorders, the short- and long-term impact of different treatment strategies on symptomatic, functional and diagnostic outcomes requires detailed investigation. LIMITATIONS Small sample size of at-risk individuals, lack of sufficient prospective data and control groups.

Trajectories of agouti-related protein and leptin levels during antipsychotic-associated weight gain in patients with schizophrenia.

OBJECTIVE Some but not all second-generation antipsychotics can induce considerable weight gain and metabolic syndrome. Although the exact biochemical mechanisms for these adverse effects are unclear, appetite-regulating neuropeptides of the central nervous system are thought to be implicated in this process. The hypothalamic mediator Agouti-related protein (AGRP) is inhibited by leptin and was shown to increase food intake. The aim of the present study was to investigate the trajectory of AGRP levels during antipsychotic-induced weight gain. METHODS As part of a controlled prospective clinical study, we determined indicators of body fat mass, plasma AGRP, and leptin levels in 16 patients with schizophrenia treated with ziprasidone and 21 patients with schizophrenia treated with olanzapine. Measurements by enzyme-linked immunosorbent assay were obtained before treatment (T0), after 4 weeks (T1), and after 3 months (T2) of treatment. RESULTS Whereas body mass index and leptin levels increased in patients treated with olanzapine compared to patients treated with ziprasidone, plasma AGRP levels did not differ among the treatment groups and did not change over time. Associations between AGRP and fat mass as well as appetite were disrupted in the olanzapine-treated patients but not in the ziprasidone group. CONCLUSION Future studies are needed to test whether the lack of a decrease in AGRP levels during weight gain in patients treated with olanzapine could perpetuate adverse metabolic long-term effects.

Temperament and prodromal symptoms prior to first manic/hypomanic episodes: Results from a pilot study

BACKGROUND Prodromal symptoms prior to first episode mania/hypomania have been reported. However, the relationship between temperament and manic/hypomanic prodromal symptoms has not been investigated. We hypothesized that subjects scoring higher on cyclothymic and irritable temperament scales show more manic/hypomanic prodromal symptoms. METHOD Euthymic patients diagnosed with bipolar-I or -II disorder within 8 years underwent retrospective assessments with the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire (TEMPS-A) and the Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R). RESULTS Among 39 subjects (36.1 ± 9.9 years, females = 59%, bipolar-I = 62%) 100% and 92.3% reported subthreshold mania (mean = 7.4 ± 2.9) or subthreshold depressive symptoms (mean = 2.4 ± 1.5), and 87.2% and 43.6% reported general psychopathology (mean = 3.2 ± 2.0) or subthreshold psychotic symptoms (mean = 0.7 ± 1.0) prior to their first hypo-/manic episode. Subjects with higher cyclothymic and irritable temperament scores showed more subthreshold symptoms prior to the first manic/hypomanic episode, mainly subthreshold hypo-/manic symptoms (cyclothymic temperament r = 0.430; p = 0.006; irritable temperament r = 0.330; p = 0.040), general psychopathology symptoms (cyclothymic temperament r = 0.316; p = 0.05; irritable temperament r = 0.349; p = 0.029) and subthreshold psychotic symptoms (cyclothymic temperament r = 0.413; p = 0.009). In regression analyses, cyclothymic temperament explained 16.1% and 12.5% of the variance of the BPSS-R total score (p = 0.045) and psychosis subscore (p = 0.029). LIMITATIONS Retrospective study, no control group, small sample size. CONCLUSION We present data, which indicate a relationship between cyclothymic and irritable temperament and prodromal symptoms prior to the first manic/hypomanic episode. These findings support the notion that assessing cyclothymic temperament to identify people at-risk of developing bipolar-I and -II disorder may help to increase the predictive validity of applied at-risk criteria.

Longitudinal changes in the antecedent and early manifest course of bipolar disorder—A narrative review of prospective studies

Objective: Prospective study designs ideally allow patients to be followed from the first manifestations of the illness or even from an at-risk stage. It can thus provide data on the predictive value of changes in clinical symptomatology, cognition or further biological markers to broaden our understanding of the etiopathology and symptomatic trajectory of bipolar disorders. The scope of this narrative review is to summarize evidence from prospectively collected data on psychopathological and other clinical and biological changes in the early developmental course of bipolar disorders. Methods: The narrative review was based on a literature search conducted in February 2016 within the PubMed library for prospective study data of persons in antecedent and early manifest stages of manifest bipolar disorder published within the last 15 years. Results: A total of 19 prospective studies were included. Regarding psychopathological features; personality, temperament and character traits as well as changes in sleep and circadian rhythm, the evidence suggests that risk factors for the development of bipolar disorder can already be described and should be studied further to understand their interaction, mediation with other factors and timing in the developmental process of bipolar disorder. Apart from the positive family history, childhood anxiety, sleep problems, subthreshold (hypo)manic symptoms and certain character traits/emotionality should be identified and monitored already in clinical practice as their presence likely increases risk of bipolar disorder. Up to date no substantiated evidence was found from prospective studies addressing cognitive features, life events, immunological parameters and morphological central nervous system changes as potential risk factors for bipolar disorder. Conclusion: For an improved understanding of episodic disorders, longitudinal data collection is essential. Since the etiology of bipolar disorders is complex, a number of potential risk factors have been proposed. Prospective studies addressing this spectrum and resilience factors are critical and will be best conducted within multi-site research networks or initiatives.

Type 2 diabetes and pre-diabetic abnormalities in patients with bipolar disorders.

BACKGROUND Abnormalities in the glucose metabolism cause nervous and organic damage and are a cardiovascular risk factor. They could be a main cause for the increased morbidity and mortality rates found in patients with bipolar disorders. The exact prevalence of diabetes and pre-diabetic abnormalities, however, is not clear. METHODS 85 euthymic outpatients with bipolar disorders from two university hospitals in Germany underwent an oral glucose tolerance test, laboratory screening and clinical measurements. Socio-demographic data, medication, severity of illness, global functioning and life quality were assessed. RESULTS Diabetes mellitus was found in 7% of the patients, pre-diabetic abnormalities in 27%. The group of patients with abnormalities in the glucose metabolism had significantly lower quality of life and global functioning. Higher BMI, leptin, triglycerides and CRP levels significantly increased the likelihood for pre-diabetes/diabetes. LIMITATIONS The low sample size did only allow limited assessment of impact of medication on the results. No healthy controls were assessed. CONCLUSIONS One-third of the patients with bipolar disorders showed abnormalities in the glucose metabolism and this was associated with impaired global functioning and lower quality of life. Early detection and intervention strategies fitting the needs of patient with bipolar disorder are needed to improve both physical and mental health.