OBJECTIVES This review summarizes the literature on psychiatric and medical comorbidities in bipolar disorder. The coexistence of other Axis I disorders with bipolar disorder complicates psychiatric diagnosis and treatment. Conversely, symptom overlap in DSM-IV diagnoses hinders definition and recognition of true comorbidity. Psychiatric comorbidity is often associated with earlier onset of bipolar symptoms, more severe course, poorer treatment compliance, and worse outcomes related to suicide and other complications. Medical comorbidity may be exacerbated or caused by pharmacotherapy of bipolar symptoms. METHODS Articles were obtained by searching MEDLINE from 1970 to present with the following search words: bipolar disorder AND, comorbidity, anxiety disorders, eating disorder, alcohol abuse, substance abuse, ADHD, personality disorders, borderline personality disorder, medical disorders, hypothyroidism, obesity, diabetes mellitus, multiple sclerosis, lithium, valproate, lamotrigine, carbamazepine, atypical antipsychotics. Articles were prioritized for inclusion based on the following considerations: sample size, use of standardized diagnostic criteria and validated methods of assessment, sequencing of disorders, quality of presentation. RESULTS Although the literature establishes a strong association between bipolar disorder and substance abuse, the direction of causality is uncertain. An association is also seen with anxiety disorders, attention-deficit/hyperactivity disorder, and eating disorders, as well as cyclothymia and other axis II personality disorders. Medical disorders accompany bipolar disorder at rates greater than predicted by chance. However, it is often unclear whether a medical disorder is truly comorbid, a consequence of treatment, or a combination of both. CONCLUSION To ensure prompt, appropriate intervention while avoiding iatrogenic complications, the clinician must evaluate and monitor patients with bipolar disorder for the presence and the development of comorbid psychiatric and medical conditions. Conversely, physicians should have a high index of suspicion for underlying bipolar disorder when evaluating individuals with other psychiatric diagnoses (not just unipolar depression) that often coexist with bipolar disorder, such as alcohol and substance abuse or anxiety disorders. Anticonvulsants and other mood stabilizers may be especially helpful in treating bipolar disorder with significant comorbidity.

Psychiatric and medical comorbidities of bipolar disorder.

How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans

Cushing’s syndrome is caused by a chronic excess of glucocorticoids. A number of psychiatric and psychological disturbances may be associated with the condition, regardless of its aetiology. Major depression is the most common co-morbid disorder. Other psychopathological aspects of Cushing’s syndrome in adults include mania, anxiety disorders and cognitive dysfunction. The presence of depression connotes a severe clinical presentation and, in patients with hypothalamic-pituitary forms of Cushing’s syndrome, is prognostically useful. Inhibitors of corticosteroid production (e.g. ketoconazole, metyrapone, aminoglutethimide), rather than antidepressant drugs, are generally successful in relieving depressive symptoms, as well as other disabling symptoms. These drugs can be used to control symptoms prior to surgical treatment of Cushing’s syndrome. Long-standing hypercortisolism may cause some degree of irreversible pathological damage and induce highly individualised affective responses based on each patient’s psychological assets and liabilities. As a result, upon normalisation of cortisol levels, treatment may still be required, and should encompass both psychotherapeutic strategies (particularly cognitive-behavioural therapies that have been found to be effective in affective disorders) and psychotropic drug treatment [antidepressants such as tricyclic agents and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors]. In patients with severe anxiety, benzodiazepines (e.g. clonazepam in small doses) may also be helpful.

Psychiatric disorders associated with Cushing's syndrome. Epidemiology, pathophysiology and treatment.

Stress and neurodevelopmental processes in the emergence of psychosis

Chronic exposure to hypercortisolism has significant impact on patient’s health and health-related quality of life (HRQoL), as demonstrated with generic questionnaires. We have developed a diseasegenerated questionnaire to evaluate HRQoL in patients with Cushing’s syndrome (CS; CushingQoL). Objective: Validate the CushingQoL questionnaire in patients with CS in clinical practice conditions. Design: Observational, international, cross-sectional study. Methods: A total of 125 patients were recruited by 14 investigators from Spain, France, Germany, The Netherlands, and Italy over a 2-month period. Clinical and hormonal data were collected and correlated with results of the generic short form 36 (SF-36) questionnaire, a question on self-perceived general health status and the CushingQoL score. Results: A total of 107 patients were pituitary-dependent and 18 adrenal-dependent CS; 104 (83%) were females,meanage45years(range20‐73years);39(31%)werecurrentlyhypercortisolemic;and47(38%) adrenalinsufficient.Inclinicalpractice,CushingQoLwasfeasible(117;94%ofpatientsfullyrespondedtothe questionnaire in a mean time of 4 min), reliable (Crohnbach’s aZ0.87), and valid (factorial analysis demonstrated unidimensionality and Rasch analysis lead to a final version with 12 items). A significant (P!0.001) correlation was observed between CushingQoL score and patients self-perceived general health status and dimensions of SF-36 (Pearson’s correlation coefficient R0.597). Patients with current hypercortisolism scored worse (lower) than those without (44G22 vs 56G21, PZ0.004). Linear regression analysis identified female gender and hypercortisolism as significant predictors for worse QoL. Conclusion: CushingQoL is useful to evaluate HRQoL in patients with CS and correlates with clinical parameters.

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Evaluation of health-related quality of life in patients with Cushing's syndrome with a new questionnaire

OBJECTIVE Cushing's syndrome is associated with psychiatric and psychological disturbances. The aim of this study was to ascertain the extent of mental illness in patients before and after treatment for Cushing's syndrome. DESIGN AND PATIENTS Patients with Cushing's syndrome were identified for a prospective study. Control patients were selected with pituitary adenomas secreting GH or PRL. The aim was to reassess patients after Cushing's syndrome had been treated. MEASUREMENTS Psychiatric symptoms were measured and classified using the Present State Examination (PSE), and analysed on the Catego Programme. The Hamilton Rating Scale (HRS) was used to measure depression. The Crown-Crisp Experiential Index was used to measure common psychoneurotic symptoms (anxiety, phobia, obsession, somatic, depression and hysteria scales). The Eysenck Personality Inventory was used to assess extroversion and neuroticism. Cortisol, ACTH, and other hormones were measured by conventional methods. Parametric and non-parametric tests were used where appropriate. RESULTS Catego analysis of psychiatric ratings showed only 8 patients of 43 with active Cushing's syndrome (19%) were normal. Psychiatric diagnoses were obtained as follows: neurotic depression in 20 (46%), possible neurotic depression in 1 (2%), reactive depression in 6 (14%), and non-specific neurotic symptoms in 8 (19%). Additional Catego ratings of suspected other psychoses were made for 3 patients who were also depressed. None of these 43 patients with active Cushing's syndrome had ratings of schizophrenia or mania, obsessional neurosis or pathological anxiety. In the control group 13 (87%) were normal, 1 patient with acromegaly had an anxiety state and one patient with a prolactinoma had neurotic depression. It was possible to reassess the Present State Examination after treatment in 25 patients, when cortisol levels had been substantially reduced (to normal in 88%), the percentage rated as psychiatrically normal increased from 19 to 68 (chi 2 = 11.7, 1 d.f., P < 0.01). Hamilton Rating Scale scores for depression showed significant improvements after treatment for Cushing's syndrome (mean decrease from 9.2 to 2.4, n = 36, P < 0.001). Crown-Crisp experiential index data showed significant improvements in anxiety, somatic symptoms, and depression (n = 25, P < 0.05). Eysenck Personality Inventory assessments showed a significant improvement in neuroticism score (n = 26 P = 0.016), but no significant change in extroversion (P = 0.5) or lie score (P = 0.6). CONCLUSIONS Most patients with Cushing's syndrome had significant psychiatric pathology, usually depressive illness. As cortisol levels were returned to normal there were significant improvements in scores for depression and anxiety. Management of patients with Cushing's syndrome should include careful assessment of psychological and psychiatric illness.

Brian Faragher

Papers

A prospective study of psychiatric and psychological aspects of Cushing's syndrome.