Objectives The notion that sufferers of bipolar disorder achieve complete syndromal and functional recovery between illness episodes has been brought into question by evidence that a large proportion of patients fail to regain premorbid levels of functioning after the resolution of major affective symptoms. A growing body of evidence suggests that bipolar patients exhibit neuropsychological impairment that persists even during the euthymic state, which may be a contributory factor to poor psychosocial outcome. However, the aetiology of such impairment and its relation to progression of illness are not well understood. This review aims to consider evidence from studies investigating both the relationship between cognitive impairment and clinical outcome and studies of neurocognitive function in unaffected first-degree relatives (FDRs) of bipolar sufferers to address issues of the temporal evolution of cognitive impairment in bipolar disorder. Methods Systematic literature review. Results The weight of evidence suggests that greater neuropsychological dysfunction in bipolar disorder is associated with a worse prior course of illness, particularly the number of manic episodes, hospitalizations and length of illness. The most consistent finding was a negative relationship between the number of manic episodes and verbal declarative memory performance. Impairment in unaffected FDRs was reported in verbal declarative memory and some facets of executive function. Conclusions Cognitive impairment may be a trait vulnerability factor for bipolar disorder that is present before illness onset and worsens as the illness progresses. Further investigation into the causal relationship between cognitive impairment and illness course is essential.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1399-5618.2006.00277.x

Evolution of cognitive impairment in bipolar disorder: a systematic review of cross‐sectional evidence

Objective: A major aim of this longitudinal high-risk study is to identify reliable early indicators of emerging bipolar disorder (BD) among offspring from well-characterized parents.

Methods:  High-risk offspring were recruited from families in which one parent had BD diagnosed on the basis of the Schedule for Affective Disorders and Schizophrenia – Lifetime version (SADS-L) interviews and DSM-IV diagnostic criteria and the other parent was well. Bipolar parents were further subdivided on the basis of response or non-response to long-term lithium. A comparison group of offspring was recruited from well parents diagnosed on the basis of either SADS-L interviews or the family history method. All consenting offspring from high-risk and control families were assessed longitudinally with the Schedule for Affective Disorders and Schizophrenia for School-aged Children – Present and Lifetime version (KSADS-PL) interviews and DSM-IV diagnoses were made on a blind consensus review. The offspring were reassessed on average annually, as well as at any time symptoms developed.

Results:  Antecedent conditions to BD in both high-risk groups included sleep and anxiety disorders, while attention-deficit hyperactivity disorder and pre-psychotic conditions were antecedents among the offspring of lithium non-responders only. Among those offspring developing BD, the index mood episode was almost always depressive.

Conclusions:  Despite a specific genetic risk, BD began with non-specific psychopathology and/or depressive disorders in a majority of offspring. Therefore, diagnosis based only on cross-sectional assessment of symptoms appears to be insufficient for the accurate early detection of emerging BD. Other parameters such as family history and associated antecedents should be taken into account.

The early manifestations of bipolar disorder: a longitudinal prospective study of the offspring of bipolar parents.

Neurocognitive endophenotypes (endophenocognitypes) from studies of relatives of bipolar disorder subjects: a systematic review.

Background: More and more epidemiological, genetic and neuroimaging studies show similarities between bipolar disorder (BD) and schizophrenia (SZ). Cognitive functions are known to be highly impaired in SZ and are increasingly studied in BD. When both populations are compared, the conclusions appear to be contradictory. The purpose of this review is to help define the profile of cognitive deficits in BD and in SZ. Methods: A systematic review of the literature of neuropsychological studies comparing BD and SZ was made, beginning in January 1990 and ending in January 2005. Thirty-eight studies met the required quality criteria and were included in this review. Results: Bipolar patients exhibit extensive cognitive abnormalities with a pattern of deficits that is not unique to this disease. However, when compared to schizophrenic patients, bipolar patients demonstrate a lesser degree of deficits, particularly concerning premorbid and current intelligence quotient and perhaps attention, verbal memory and executive functions. When looking into effect sizes, there seem to be different profiles even in studies finding no significant differences. Conclusions: The neuropsychological differences reported between both groups could be due to the presence of psychotic features, to environmental factors (stressful events, duration of the disease and number of hospitalisations) and could also be related to differences during the neurodevelopmental phase. Further studies should confirm whether these results are truly related to different neurobiological backgrounds.

Specificity of cognitive deficits in bipolar disorder versus schizophrenia. A systematic review.

Genetics and intermediate phenotypes of the schizophrenia--bipolar disorder boundary.

Background: Cognitive dysfunction is evident in some euthymic patients with established bipolar disorder (BD), including deficits in visual backward masking (VBM) tasks which map to a specific neural pathway. A high-risk paradigm would clarify the temporal relation of cognitive dysfunction to clinical course.



Method:  We compared euthymic offspring (age range: 18–32 years) of lithium-responsive bipolar parents with and without a previous lifetime history of psychiatric illness to healthy comparison subjects with a negative family history, on a VBM task that requires target location.



Results:  High-risk offspring with no lifetime psychiatric history performed the VBM task at levels of healthy controls. High-risk offspring with a previous history of a mood disorder, in complete remission, made significantly more errors at short target-mask intervals than control or never ill offspring. These higher error rates were not a consequence of faster response times.



Conclusions:  There is preliminary evidence of specific cognitive dysfunction early in the course of illness in affected offspring of parents with lithium responsive BD. VBM is ideal for future longitudinal studies addressing whether cognitive dysfunction in BD is a trait marker or a consequence of illness manifestation.

A pilot study of visual backward masking performance among affected versus unaffected offspring of parents with bipolar disorder

Recently, we have found an association between bipolar disorder patients who are excellent responders to lithium prophylaxis and a polymorphic marker located in the first intron of the phospholipase C-γ1 gene (PLC-γ1) [Turecki et al., 1998: Mol Psychiatry 3:534-538]. As this variant is not known to be functional, we searched for other markers within the coding region, using single-strand conformational polymorphism (SSCP) analysis. We have identified three polymorphic sites localized in three different exons of the PLC-γ1 gene (exons 9, 26, 31). Variation studies of these potentially functional sites in a group of 133 bipolar patients with an excellent response to lithium prophylaxis and a comparison group of 99 healthy controls showed no difference in genotype distributions for exon 9 (chi-square = 1.41, df = 2, P = 0.49), exon 26 (chi-square = 2.26, df = 2, P = 0.13), or exon 31 (chi-square = 1.41, df=2, P = 0.49). Similar results were observed for allele distributions. These results suggest that our previous findings were not the result of linkage disequilibrium with these variants.

Identification of three polymorphisms in the translated region of PLC-γ1 and their investigation in lithium responsive bipolar disorder

In addition to the widely known and used MCMI specific to adults, Millon has also developed additional instruments, which are increasingly being used. These include inventories for adolescents (the Millon Adolescent Clinical Inventory [MACI] ), medical patients (Millon Behavioral Health Inventory [MBHI]), and nonpsychiatric patients (the Personality Adjective Check List [PACL]). The fmal chapter describes the newest ofthe Millon Inventories, the Millon Index ofPersonality Styles (MIPS), which attempts to measure "personal styles" of adults free of psychiatric problems.

https://journals.sagepub.com/doi/pdf/10.1177/070674379904400311

Martin Alda

Papers

A pilot study of visual backward masking performance among affected versus unaffected offspring of parents with bipolar disorder

Identification of three polymorphisms in the translated region of PLC-γ1 and their investigation in lithium responsive bipolar disorder

Book Review: Biological Psychiatry: Antidepressants: New Pharmacological Strategies