Age at onset in bipolar affective disorders: a review

Bipolar affective disorder (BPAD) is a multifactorial disorder with various clinical presentations. Etiologic heterogeneity may partly underlie the phenotypic heterogeneity. Efforts to dissect BPAD have been based on the course of the disorders (BP I versus BP II or rapid cycling), comorbidity pattern (panic attacks, suicide attempts, addiction or hyperactivity), differences between the sexes, and clinical pattern (cycloid and puerperal psychosis). The present article provides a comprehensive review of the existing data, showing that age at onset (AAO) identifies homogeneous sub-groups of patients with BPAD. Recent work has demonstrated the existence of three--early, intermediate and late--onset bipolar sub-groups based on AAO, following Kendell's criteria for validity (The American Journal of Psychiatry 2003; 160: 999). We will also show how these distinctions may be of use in the search for genetic vulnerability factors and other pathogenic influences. Following Kendell's criteria, we show that AAO of bipolar disorders has been tested with most of the available strategies for establishing the validity of clinical syndromes. We also present data from genetic epidemiologic studies in bipolar disorder, showing that AAO sub-groups may reduce the underlying genetic heterogeneity. No accurate AAO thresholds to define valid sub-groups have been identified precisely. Until recently, studies defined early- and late-onset as corresponding to early or mid-adulthood, not taking into account juvenile-onset bipolar disorder. A recently proposed theoretical model with three AAO sub-groups (onset age 17, 27 and 46) is discussed.     

Predicting the long-term outcome of affective disorders

Factors influencing the long-term outcome of affective disorders were investigated in 106 patients with an average length of course of 28 years. Univariate statistical analyses, stepwise multiple discriminance analyses and path analysis were applied. A direct unfavourable influence on the frequency of persisting alteration (evaluated according to the Global Assessment Scale) was found to have the low self-confident premorbid personality and a higher number of episodes during course, whereas only the variable “male” had such an influence on the social consequences of the illness. The variable “manic episode” (bipolarity) and “age at onset” had only an indirect influence, in that bipolar patients had more episodes, and younger patients more frequently had a bipolar course and therefore had more episodes. The unfavourable long-term outcome was due in those cases to the higher number of episodes.     

Psychotic symptoms and age of onset in affective disorders.

Prevalence of hallucinations and delusions was studied in 1,763 patients with unipolar major depression, bipolar affective disorder, and schizoaffective disorder. The authors found that the presence of psychotic features was negatively associated with age of onset for the group as a whole, and bipolar affective disorder (manic or mixed type) specifically. The clinical implications of the findings are discussed.     

Age at onset of affective disorders in Italian and Swedish patients

Variability of age at onset in affective disorder is a complex event where several variables play a role, resulting in a detectable observed distribution which can be viewed as related to the structural mechanism of the disease. To confirm previous results on factors affecting the distribution of onset in affective disorders, we studied its distribution pattern in two different populations, Italian and Swedish, with an analytic approach that does not require specifications of any a priori hypothesis. The findings in this study, however, tend to confirm the biological nature of the age of onset phenomenon and to exclude cultural determinants. On the other hand, it does not exclude that other factors, not considered in this study, may be operating. This result is very important under the hypothesis of a genetic ethiopathogenesis of affective disorders, and some of its implications are discussed.     

Outcome of schizoaffective disorder at two long-term follow-ups: comparisons with outcome of schizophrenia and affective disorders

OBJECTIVE: This research assessed whether the outcome of schizoaffective disorder is more similar to that of schizophrenia or that of affective disorders. METHOD: The authors conducted a prospective follow-up study of 101 schizoaffective, schizophrenic, bipolar manic, and depressed patients assessed at three times: during hospitalization and 2 and 4-5 years later. The follow-up test battery involved detailed assessment of social functioning, work performance, symptoms, posthospital treatment, and rehospitalization. RESULTS: Outcome for schizoaffective patients 4-5 years after hospitalization differed significantly from that for patients with unipolar depression. However, the differences between schizoaffective and bipolar manic patients were more equivocal. Unlike the patients with bipolar disorder, only a limited number of patients with schizoaffective disorder showed complete recovery in all areas throughout the year preceding the 2-year follow-up and the year preceding the 4- to 5-year follow-up. The differences in outcome between schizoaffective and schizophrenic patients were also mixed. These two groups showed some similarities in outcome, but there were fewer schizoaffective than schizophrenic patients with uniformly poor outcome in all areas. CONCLUSIONS: Overall, schizoaffective patients showed some similarities to both schizophrenic and bipolar manic patients. Schizoaffective patients had somewhat better overall posthospital functioning than patients with schizophrenia, somewhat poorer functioning than bipolar manic patients, and significantly poorer functioning than patients with unipolar depression. The data suggest that when mood-incongruent, schizophrenic-like psychotic symptoms are present in the acute phase, they predict considerable difficulty in outcome, even when affective syndromes are also present, as in schizoaffective disorder. It is likely that schizoaffective disorder is not just a simple variety of affective disorder.     

Antiepileptic drugs: affective use in autism spectrum disorders

Antiepileptic drugs are widely administered to individuals with autistic spectrum disorders. There are several reasons for the use of antiepileptic drugs in autistic spectrum disorders, including the high incidence of epilepsy in these individuals, the anecdotal reports suggesting an improvement of communication and behavior in autistic subjects with epileptic discharges, and the increased awareness that some disruptive behaviors may be manifestations of an associated affective disorder. In this study, data on the current use of antiepileptic drugs in the treatment of autism, and on the association of affective disorders with epilepsy and autism, are reviewed. The evidence supporting the hypothesis that there may be a subgroup of autistic children with epilepsy and affective disorders that preferentially respond to antiepileptic drugs is still very preliminary, and further investigations with double-blind controlled studies are needed. Although the role of antiepileptic drugs at the present time is not established, there is evidence that autism, epilepsy, and affective disorders commonly co-occur, and that they may share a common neurochemical substrate, which is the common target of the psychotropic mechanism of action of different antiepileptic drugs.     

Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations

Objective

To investigate a possible association of mutations in the PTEN‐induced putative kinase 1 (PINK1) gene with psychiatric disorders in a large family with monogenic parkinsonism.

Method

20 members of a family (4 homozygous, 11 heterozygous and 5 non‐mutation carriers) were investigated for the presence of psychiatric disorders using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM‐IV); information on three additional heterozygous mutation carriers was obtained according to the family history research diagnostic criteria.

Results

We found predominantly affective and schizophrenia spectrum disorders in 11 (61%) of the 18 mutation carriers and in 1 (20%) of the 5 mutation‐negative cases.

Conclusions

First, affective and psychotic symptoms may be part of the phenotypic spectrum or even the sole manifestation of PINK1 mutations. Second, patients with familial movement disorders associated with psychiatric conditions may serve as a valuable study population to explore (genetic) causes of neuropsychiatric disease.In patients with Parkinson''s disease (PD), a wide range of psychiatric disorders has been described including depression (20–50%),¹ psychosis (15–40%),^2,3 anxiety disorder (20–40%) and cognitive impairment (20%).² Psychiatric disorders may be the first or even the only manifestation in carriers of Parkin gene mutations, the most‐frequent known cause of early‐onset parkinsonism (EOP).⁴ Likewise, psychiatric problems have been reported in patients and their motor‐asymptomatic relatives with mutations in the recently detected PTEN‐induced kinase 1 (PINK1) gene, the second‐commonest cause of EOP.^5,6,7,8,9Two homozygous mutations in the PINK1 gene were initially described in three consanguineous families with EOP.⁶ The frequency of PINK1 mutations ranges from 1% to 8% in patients with PD of different ethnicities who are often selected for young age of onset and for family history (for review see Klein and Schlossmacher¹⁰). Most of the currently described mutations are localised near or within the functional serine/threonine kinase domain of PINK1 and are expected to result in a loss‐of‐function effect in vivo. Wild‐type PINK1 functions as a protein kinase that is mainly located within the mitochondria.Although PINK1‐associated parkinsonism is generally considered an autosomal recessive condition, a growing body of evidence has been accumulating that supports the notion of a single heterozygous mutation conferring disease susceptibility in at least a subset of patients.^6,8,9,10,11Currently, no studies have systematically assessed psychiatric symptoms in monogenic EOP. To investigate this possible association, we evaluated a large family with EOP with PINK1 mutations for the presence of psychiatric disorders.     

Social rhythm regularity and the onset of affective episodes in bipolar spectrum individuals

Objectives:  Research suggests that bipolar disorder individuals may have less social rhythm regularity than normal controls and that this may contribute to their affective symptoms and episodes. This study examined whether regularity prospectively predicted time to onset of major depressive, hypomanic and manic episodes in a sample with bipolar spectrum disorders.
Methods:  We recruited 414 undergraduate students from Temple University and University of Wisconsin diagnosed with cyclothymia, bipolar II disorder, or with no affective disorder (normal controls). Participants completed the Social Rhythm Metric at Time 1 and structured interviews approximately every four months for an average follow-up period of 33 months.
Results:  Participants diagnosed with cyclothymia and bipolar II disorder reported significantly fewer regular activities than normal controls, and approximately half of these participants experienced a worsening course of their illness over the study duration. Survival analyses indicated that both diagnosis and social rhythm regularity significantly predicted the time to participants' first prospective onset of major depressive, hypomanic and manic episodes.
Conclusion:  Consistent with the social zeitgeber theory, bipolar spectrum participants reported less social rhythm regularity than normal controls, which prospectively predicted the survival time to affective episodes.     

早发型和晚发型情感性障碍的遗传效应比较

为了解早发型和晚发型情感性障碍间是否存在遗传效应的差异，对同时符合中国精神疾病分类方案与诊断标准第２版和美国精神障碍诊断和统计手册第４版情感性障碍诊断标准的１８０例患者，以３０岁为界，划分为早发组（１１３例）和晚发组（６７例）。所得资料行单因素分析，用多基因阈值理论进行遗传率的估算。结果显示，早发组有精神疾病家族史多，一级亲属中情感性障碍的发病风险率高，一级亲属的加权平均遗传率高，脑部ＣＴ显示有器质性改变者少，与晚发组比较，差异均有显著性。提示二者存在着遗传异质性。     

The broad autism phenotype predicts child functioning in autism spectrum disorders

Background

Broad autism phenotype (BAP) is a milder expression of the social and communication impairments seen in autism spectrum disorders (ASD). While prior studies characterized the BAP in unaffected family members of probands with ASD, the relationship between parental BAP traits and proband symptomatology remains poorly understood. This study utilizes the Broad Autism Phenotype Questionnaire (BAPQ) in parents and the Social Responsiveness Scale (SRS) in children to examine this connection. We hypothesized that in families affected by ASD, elevated maternal and paternal BAPQ scores would correlate with greater autism symptomatology in diagnosed children. In an extension of prior research, we also explored this relationship in families with typically developing children (TDC).

Methods

Two hundred and forty-five children with ASD, 129 TDC and all parents were recruited as part of a larger study investigating relationships between genes, brain and behavior. The Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and expert clinical judgment confirmed ASD diagnoses in children. SRS was collected for all children. Parents completed a self-report BAPQ and an informant report BAPQ for their spouse; an average of self-report and informant report for each parent was used in all analyses.

Results

Mothers and fathers of children with ASD had significantly higher rates of BAP traits as compared to parents of TDC. Maternal and paternal BAPQ total scores were not correlated with child IQ in either group. In the ASD group, 10% of mothers and 21% of fathers scored above the established BAP threshold compared to 4% of TDC parents. Crude regression analyses showed that maternal and paternal BAPQ total scores accounted for significant variance in child SRS scores in both ASD (17.1%) and TDC (19.8%) families.

Conclusions

Our results suggest that broad autism symptomatology in parents is moderately associated with their child’s autism symptomatology. This result extended to TDC families, suggesting that the BAPQ and SRS capture subtle, subclinical social variation in both children and adults. These findings could help define multi-generational social impairments in future phenotypic and genetic studies.     

Two-year longitudinal study of poststroke mood disorders: diagnosis and outcome at one and two years

As part of a prospective study of mood disorders in stroke patients, interviews were obtained from 37 patients at 1 year and 48 patients at 2 years follow-up. In-hospital evaluations for these 65 follow-up patients found that 9 patients (14%) had symptom clusters of major depression, 12 patients (18%) had symptom clusters of dysthymic or minor depression, and 44 patients (68%) did not meet the DSM III diagnostic criteria for depression. Although overall prevalence of depression did not change significantly over time, the prognosis for individual patients, depending on diagnostic group, was different. All of the follow-up patients with major depression in-hospital were improved by 2 years, with a significant reduction in their mean depression scores and improvement in their activities of daily living, whereas only 30% of follow-up patients with dysthymic depression improved by this time. There was no significant improvement in their mean depression scores or mean activities of daily living score. Of the patients followed up who were not depressed in-hospital, 34% had developed major or minor depression by 2 years, and their mean depression scores were significantly increased. These data suggest that the prevalence of depression among the follow-up patients remains high (between 30 and 40%) for the first 2 years after stroke, but that untreated poststroke major depression has a natural course of about 1-2 years, with associated improvement in activity of daily living scores, whereas the prognosis for poststroke dysthymic depression is frequently unfavorable and often persists for greater than 2 years.     

Gait unsteadiness and fall risk in two affective disorders: a preliminary study

Background

In older adults, depression has been associated with increased fall risk, but the reasons for this link are not fully clear. Given parallels between major depression and Parkinson's disease, we hypothesized that major depression and related affective disorders would be associated with impairment in the ability to regulate the stride-to-stride fluctuations in gait cycle timing.

Methods

We measured stride-to-stride fluctuations of patients with two forms of mood disorders, unipolar major depressive disorder (MDD) and bipolar disorder, and compared their gait to that of a healthy control group. The primary outcomes were two measures of gait unsteadiness that have been associated with fall risk: stride time variability and swing time variability.

Results

Compared to the control group, the two patient groups tended to walk more slowly and with decreased swing time and increased stride time. However, none of these differences was statistically significant. Compared to the control group, swing time variability was significantly larger in the subjects with bipolar disorder (p < 0.0001) and in the subjects with MDD (p < 0.0004).

Conclusions

Patients with MDD and patients with bipolar disorder display gait unsteadiness. This perturbation in gait may provide a mechanistic link connecting depression and falls. The present findings also suggest the possibility that measurement of variability of gait may provide a readily quantifiable objective approach to monitoring depression and related affective disorders.

     

Mode of inheritance in families of patients with lithium-responsive affective disorders

A better understanding of the role of genetic factors in affective disorders is likely to result from investigating more homogeneous populations. To achieve this goal, we have systematically studied patients who are excellent responders to long-term lithium treatment and their relatives. In the families of 71 such probands, we have analyzed the mode of inheritance by comparing the observed morbidity risks with the risks expected under different genetic models. The results demonstrate major-gene effects in the transmission of primary affective disorders; the polygenic model with sex-specific thresholds could be rejected. Discrimination between the autosomal and X-chromosome models was not possible, but the autosomal recessive model predicts more realistic, gender-specific frequencies of affective disorders in the general population. These results suggest that autosomal recessive inheritance deserves serious consideration in molecular genetic investigations.     

Factors affecting the distribution of age at onset in patients with affective disorders

We analyzed the age-at-onset distributions in a group of 285 patients diagnosed as having major affective disorder, recurrent, either unipolar or bipolar, in order to detect the possible existence of genetic and epidemiological factors affecting their age-at-onset distribution. In fact, since it is known that affective disorders are genetically heterogeneous with respect to the liability systems involved, methodological considerations support the hypothesis of the existence of different ages at onset also. We thus investigated several variables and the significant findings of our study were that bipolarity, at least one affected parent and a low position in the sibship are each associated with earlier age at onset of affective disease.     

Adult quality of life and associated factors in adolescent onset schizophrenia and affective psychotic disorders

BACKGROUND: Subjects in treatment for affective disorders are usually less satisfied with life compared to subjects with schizophrenia. AIMS: The aims of this study were to compare subjective quality of life (QoL) at adult age of adolescent onset psychotic disorders and analyse associated factors. METHOD: Fifty-three patients with adolescent onset psychotic disorders were followed up at age 25, diagnostically re-evaluated according to the DSM-IV and assessed with the Positive and Negative Symptoms Scale, the Strauss-Carpenter Scale and the Lancashire Quality of Life Profile. RESULTS: Subjects diagnosed with schizophrenia or schizoaffective disorder (n = 27) experienced significantly lower overall QoL than subjects with psychotic mood disorders (n = 26). Overall QoL was strongly associated to depressed mood (R2 = 0.49) in the schizophrenia group and to degree of employment (R2 = 0.39) in the mood disordered group. CONCLUSION: Depression is a major concern in the evaluation and treatment of patients with schizophrenia, while vocational support seems particularly important after an episode of psychotic mood disorder.