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Comparison of bipolar patients with and without late onset
1Assoc. Dr.,
2Assists. Dr.,
3Psychiatrist, Erenköy Mental and Neurological Diseases Training and Research Hospital, Istanbul - Turkey
Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2012; 3(25): 244-251 DOI: 10.5350/DAJPN2012250307
Full Text PDF Full Text PDF (Turkish)

Abstract

Objective: The aim of this study was to find out if late onset bipolar patients were different from bipolar patients without late onset disorder.

Methods: In this study, we evaluated 144 bipolar cases which met DSM IV diagnosis criteria. Our cut-off for late onset bipolar disorder was 40 years of age. Seventeen cases who were retrospectively determined as having late onset disease were compared with 127 non late onset cases.

Results: Psychotic and mixed episodes, rapid cycling, seasonality and switch with antidepressants were more frequent and hyperthymic temperament scores were higher in patients with late onset disease. Comorbid diseases were more frequent in the late onset patient group: 83% had hypertension, 71% had diabetes mellitus and 23% had cerebrovascular disease. Family history for medical illness was more frequent among late onset patients also.

Conclusions: In bipolar disorder, age of onset is accepted as an important marker in determining different subtypes and in predicting different clinical courses and comorbidity. Vascular pathologies which were determined more frequently, especially in late onset cases must be evaluated carefully and the necessity for a general medical examination must not be ignored.

INTRODUCTION

Early onset is frequently been related to tendency to bipolar spectrum (1). Late-onset bipolar disorder is relatively rare and related data were retrieved from retrospective chart reviews and cohort studies (2). Treatment recommendations are generally as case reports. 

Prevalence of mood disorders was reported 10-25% among geriatric population and 5% at inpatient units. According to US data, prevalence of late-onset (over 60 years) mood disorder was reported 0.1-0.4%. When three databases (Medline, 1966-2009, PsycINFO 1967-2009 and Embase 1980-2009) were reviewed, late-onset criterion was often accepted as being 60 years old or over. In a few studies, 40, 50 and 55 years were taken as cut-off ages (2). 

Severity of late-onset mania generally requires hospitalization and is related with neurological lesions and particularly ischemic lesions in which specific regions of brain related with mood are involved. However a vulnerability for mood disorder is also present (3). At the first episode of late-onset mania, more cognitive impairment and resistant symptoms and signs are observed. “Vascular mania” had been described as a vascular lesion of brain in the past. Right hemispheric and orbito-frontal cortical involvement is frequently observed in these cases. Course of bipolar disorder is worse in these cases and morbidity and mortality increases. 

Recurrent depression may sometimes present as mania at advanced age. Benazzi (4) suggested that bipolar diagnosis should be kept in mind in cases of recurrent depression in the elderly. Polarity is the cornerstone of unipolar and bipolar differentiation and classification. However, age of onset and recurrence are other variables important for continuity and are suggested to increase clinical and genetic benefits in description and classification of mood disorders. In this study comparing bipolar and unipolar cases, most prominent predictive characteristic was recurrence. Recurrence was followed by atypical depression and hypomania or mania-positive family history. Distinguishing features were psychomotor agitation for unipolar disorder and hypersomnia for bipolar disorder (4). In another study, when inpatients hospitalized due to major depressive disorder over 60 years old were evaluated retrospectively, bipolar disorder was found in 36.8% of cases (5). Among these cases, 81.3% were evaluated as type 2 or bipolar disorder, not otherwise specified . Bipolar cases were relatively early-onset cases and had more frequent episodes. 

Treatment of late-onset cases which requires close monitoring due to their general medical conditions and high prevalence of comorbidity is frequently neglected or overlooked. There is need for specific treatment algorithms in this field; however, it is noteworthy that pharmacotherapy does not contain any standardization and covers all medication groups. Monotherapy is generally followed by polypharmacy. Psychotherapy was added to drug treatment in resistant cases or electroconvulsive therapy (ECT) option was used (2). Mood stabilizers recommended in late-onset mania is particularly lithium carbonate and sodium valproate; however, sodium valproate is better tolerated. Not using antipsychotics will be appropriate except the period from onset to recovery. In cases with excessive psychomotor activity or in resistant cases, ECT can be very effective (2).

Number of studies investigating clinical characteristics of late-onset bipolar cases is quite few (3). No study was published in Turkey comparing late-onset bipolar cases with non-late-onset cases. Aim of this study was to investigate the differences of socio-demographic characteristics, temperament, clinical characteristics and comorbid conditions between late-onset and non-late-onset patients.

METHODS

Sample

One hundred and forty-four cases with bipolar disorder according to DSM-IV criteria and being followed-up from our outpatient clinic were evaluated. Cases were required to be at the healthy period. For this purpose, cases who received scores under 8 from Hamilton Depression Rating Scale and under 5 from Young Mania Rating Scale were included in the study. In this study, late-onset cut-off age for bipolar disorder was selected as 40. Seventeen cases who were found to be late-onset after retrospective examination and 127 cases who were not late-onset were compared according to socio-demographic characteristics, temperament features, clinical characteristics and comorbid conditions.

Tools

SCID-I (Structured Clinical Interview for DSM-Axis 1 Disorders-SCID-I): Turkish version of clinical interview form structured for DSM-IV axis I disorders (6). 

Bipolar Disorders Diagnosis and Follow-up Form - SKIP-TURK: Age of onset of the disease, disease duration, age of treatment onset, physical and sexual abuse in the history, academic and social functionality, premenstrual syndrome, initial type of disease, severity and duration of the episode, postpartum onset, seasonality, sub-type of depression, episode with psychotic symptoms, suicidal attempt, hospitalization, duration and number of episodes, predominant course pattern, sudden onset and termination, chronicity and rapid-cycling, switches, tobacco, alcohol and substance abuse are interviewed by this form (7).

TEMPS-A Scale (Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire): This scale consists of 100 items to determine depressive, cyclothymic, hyperthymic, irritable and anxious temperament (8). Subject answers scale items as yes or no by considering all his/her life. Its validity and reliability study in Turkish was done (9). 

Administration 

Required approval was taken from Training and Planning Committee of Erenköy Training and Research Hospital for Mental Health and Diseases. Bipolar cases agreed to participate in the study and gave informed consent were recruited consecutively during normal outpatient clinic follow-up. No individual rejected to participate in the study. 

Diagnostic interviews were performed by SCID-I. An open interview aimed to obtain information about disease followed this. Relatives of the patients were interviewed when there are unclear points. Patients at remission were required to complete TEMPS-A Temperament Scale according to instructions. Patients are required to answer “no” when they are not sure and review all their lives during this procedure. 

Statistical Analysis

Comparison of numerical variables were performed by t test (due to SD/mean<0.3), comparison of categorical variables were performed by chi-square test. Statistical significance was taken as p<0.05 and all tests were two tailed.

RESULTS

Proportion of late-onset cases were found 13.4% (n=17). This figure was 5.5% (n=7) for over 50 years old and 2.3% (n=3) for over 60 years old. Mean age of disease onset was 51.4±4.5 for late-onset cases and male gender (n=14) was predominant at late-onset group (p<0.001). Male/female ratio over 50 years was 4/1 and all cases over 60 were male. Educational levels of late-onset cases were not different from other bipolar cases and proportion of being married was higher (p=0.037). 

Psychotic episodes (p=0.011), mixed episodes (p=0.027), rapid-cycling (p=0.041), seasonality (p=0.014) and switch by antidepressants (p=0.031) were found significantly more frequent in late-onset cases. Psychiatric comorbidity was more frequent among late-onset cases (p<0.001). These comorbidities were anxiety disorders (n=19) and substance use disorders (n=14). Comorbid psychiatric diagnosis of one case among late-onset cases was evaluated as panic disorder. Physical illness comorbidity was more frequent among late-onset cases (p=0.015). Comorbid diagnoses were hypertension at 83%, diabetes at 71% and cerebrovascular disease at 23% of cases.

No difference was found between late- and non-late-onset bipolar cases for family history of psychiatric disease (p=0.722). Bipolar disorder was found in siblings of two of three late-onset cases over 60 years old. Family history of physical illness was found significantly more frequent in late-onset cases (p=0.035). Proportions for family history of physical illness were 74% for hypertension, 61% for diabetes and 23% for cerebrovascular disease, and ranking was similar as it was for the cases. Hyperthymic temperament scores were found higher in late-onset cases (p=0.045) (Table 1).

DISCUSSION

Age of onset is considered as an important determinant to determine different sub-types and predict different clinical courses and comorbid diagnoses (10). This is the first-ever study comparing late-onset bipolar cases with non-late-onset cases and brought up some differences. According to findings of our study, there are differences between late-onset and non-late-onset cases with bipolar disorder for psychotic episodes, mixed episodes, rapid-cycling, seasonality, switch by antidepressants, comorbid physical illness and family history of physical illness.

Male gender was found more prevalent in late-onset group in our study. When related literature is reviewed, there are study findings reporting both higher prevalence of late-onset bipolar disorder in women and equal prevalence in both genders between early and late-onset cases as well (11,12). In the study of Almeida and Fenner (13) which evaluated inpatients with bipolar disorder in Western Australia between 1980 and 1998, no gender difference was reported in late-onset cases over 65 years old. Robb et al. (14) reported later onset of manic episode in female bipolar cases. Male predominance in late-onset cases of our study may be due to composition of our sample of only type I bipolar cases. In the study of Benazzi (15) which evaluated 211 cases with early and late-onset atypical depression, early-onset atypical depression was related with female gender and type II bipolar disorder. Early-onset in female cases with type II bipolar disorder and male predominance in late-onset cases are consistent findings. 

Late-onset cases made up 13.4% of all bipolar cases. This figure was 5.5% for cases whose onset was over 50 years old and 2.3 % for cases over 60 years old. In the sample of Almeida and Fenner (13) consisting of 6182 cases, bipolar disorder with onset over 65 years old was found 8%. However, this figure is substantially over prevalence of bipolar disorder reported in US data. This difference may be due to not being conducted a field study and difficulties of elderly population to access to bigger centers and receiving psychiatric help. Differences in prevalence and frequency may be related with sample sizes and limitations of retrospective evaluations as well. We also think that prevalence and incidence of bipolar disorder in geriatric population cannot be evaluated independent of survival analyses. Likewise, despite different prevalence and incidence figures in different studies, a similar difference was not observed between age of onset averages (16). On the other hand, temperament and other characteristics providing tendency and risk factors such as substance abuse may vary between societies and cultures. 

Higher prevalence of being married may be explained by being completed the social development phases of these people whom disease onset is later. Similarly, early-onset bipolar disorder may impair family relations and functionality more and result in termination of marriages during disease course. If this interpretation was correct, then a similar case should be true for mean education duration as well. However, educational levels of late-onset cases were not found different from non-late-onset cases. In the study of Lieberman et al. (17) which examined gender-dependent variables in bipolar disorder, age of onset of disease was not found to have an effect on being married or not in women but early onset was found to decrease marriage rates only in male cases. 

In the EMBLEM (The European Mania in Bipolar Longitudinal Evaluation of Medication) study (18) which compared late- onset and non-late-onset cases, rapid-cycling was found to be more frequent in late-onset cases consistent with our findings. Another finding which we found to be more frequent among late-onset cases was presence of mixed episodes which is consistent with literature (19,20). There are studies which showed that rapid-cycling and mixed episodes are more prevalent among early-onset cases (21). However, rapid-cycling and mixed episode may either be considered as a poor-prognostic form of bipolar disease or as a complication occurring during process complicated by physical illnesses and related medication use observed more frequently in geriatric population. More frequent switch with antidepressants in addition to rapid-cycling and mixed episode as shown in our study suggest that mood is less stable and more sensitive in geriatric population. This condition may be related to neurodegenerative processes. 

Likewise, hypertension, diabetes and cerebrovascular disease were found to be risk factors for neurodegenerative processes of brain in our study. Hypertension and diabetes were particularly of note due to being risk factors for cerebrovascular disease as well. Bipolar disease emerging at later ages is related with damages to mood-specific brain regions and particularly with ischemic insult and this had been called as “vascular mania” in the past (3). Right hemispheric and orbito-frontal cortical involvement is particularly observed in these cases. In our study, higher prevalence of hypertension, diabetes and cerebrovascular diseases in late-onset bipolar cases and their families are consistent with the well-known literature data of higher prevalence of comorbid physical illness diagnoses in late-onset cases. It is important to mention that older age is a risk factor itself for comorbid physical illness. In our study, prevalence of hypertension, diabetes and cerebrovascular diseases increase with age in late-onset cases. Late-onset cases were older than non-late-onset cases in our study. On the other hand, in a retrospective study done with inpatients over 60 years old with major depressive disorder, prevalence of bipolar disease was found 36.8% (5). The most important predictor of bipolar disorder is diabetes and is present in 61.5% of cases. Pathological conditions such as diabetes and hypertension which impair vascular structure in long-term may lead to development of mood disorders. Diagnosis of comorbid somatic disease may be an important factor responsible for clearly defining the clinical presentation, difficulties to form a treatment protocol, inadequate response to treatment or frequent recurrences in late-onset mood disorder. 

Rapid-cycling, mixed episode and shifting may be interpreted as indicators of severity of bipolar disorder (10). For this reason, psychotic symptoms were reported more frequently in late-onset cases than non-late-onset cases (15,18,20). Seasonality was also found more frequent in late-onset cases than non-late-onset cases in our study. There is no report in the literature about seasonality in late-onset cases and in the study of Goikolea et al. (22) which compared seasonal and non-seasonal cases, no difference was found between two groups for age of onset. While these findings seem to be contradictory, when seasonality being a factor increasing severity and duration of episode is taken into consideration, it is easier to understand its higher frequency in late-onset cases. Moreover, mania and depression occurring at later ages is severe enough which frequently requires hospitalization (3). At the first episode of bipolar disorder at later ages, more severe cognitive impairment and persistent symptoms and signs are present.

Psychiatric comorbidity in late-onset bipolar cases in our study was found less than other cases. These comorbidities were generally anxiety and substance use disorders. This finding is consistent with comorbid diagnosis of panic disorder more frequently observed in early-onset cases by Schürhoff et al. (20). Our findings are consistent with the finding of more frequent comorbidity of substance abuse in bipolar cases with onset in early adolescence or childhood as mentioned by Akiskal (1). More frequent psychiatric comorbidity in early-onset cases may be a presentation of a sub-type phenomenologically or may be considered as a non-specific reflection of higher prevalence of substance abuse disorders in adolescence and early adulthood to bipolar disorder. 

As present more frequently in late-onset cases, indifference of family history of psychiatric disorder between late-onset and non-late onset cases in our study is consistent with Todd (23) which proposed that positive family history is rarer in late-onset cases rather than Akiskal (1) who proposed the opposite (24). Further studies with wider sample sizes are certainly needed in order to consider family history as predictor of a different sub-type among late-onset cases. On the other hand, higher hyperthymic temperament scores in late-onset cases in our study is a finding subject to debate. Prevalence rates for hyperthymic temperament in bipolar disorder were substantially over than figures reported for healthy population (9, 25) and unipolar disorder (26, 27) similar to results of studies done in Turkey and abroad. Moreover, manic switch was reported to be more frequent in cases with hyperthymic temperament (28). Cyclothymic and hyperthymic temperament are sub-threshold presentations of bipolar spectrum according to Akiskal and is inherited by bipolar disorder. Higher hyperthymic temperament scores in late-onset cases may be interpreted as a familial tendency indicator for bipolar disorder at these cases. 

Bipolar disorders spectrum offers therapeutic benefits for atypical and complex cases. Various comorbidities and common pathophysiological mechanisms are defined for bipolar disorder and dementia in the literature because mood disorder to a certain extent is already observed at dementia cases. Secondary depressive conditions are also frequent. Moreover, behavioral complications of dementia are also ordinary. Ng et al. (24) most frequently reported mixed episodes in their series of 10 cases whom have late-onset mood disorder and related behavioral problems and which onset of bipolar and cognitive disorder was definitely differentiated. All of these cases had premorbid cyclothymic, hyperthymic or irritable temperament structure. Their family histories were generally positive. Symptoms which were generally refractory and deteriorate by antidepressants or acetyl cholinesterase inhibitors respond successfully to mood stabilizers and atypical antipsychotics. Recovery of mood generally accompanies cognitive improvement. Mood disorder in cases with cognitive disorder or impaired cognitive functions was called as “late-onset bipolar spectrum disorder – bipolar disorder type VI”. Dementia or another cognitive impairment and antidepressant and anti-dementia medications used in these conditions may exacerbate potential bipolarity in some cases. Evaluating premorbid mood structure and family history in these cases may be beneficial for treatment selection. No case with comorbid dementia exists in our study among late-onset cases in our study. 

Retrospective determination and cross-sectional evaluation of bipolar cases in our study is an important limitation. Another limitation of our study is lower number of late-onset cases than non-late-onset ones. This increases possibility of type 1 error. Moreover, taking the age of 40 as cut-off point but variation of this point in the literature and the age of 40 years being the lower limit of this interval may lead to confusion in interpreting the findings. Studies with higher age cut-off point and with higher number of late-onset cases together with wider sample sizes should be planned. In addition to these, prospective clinical studies which compare cases with comorbid late-onset bipolar disorder and somatic disease with non-late-onset bipolar disorder and also new study designs testing possible shared etiologies of somatic diseases and bipolar disorder are needed. On the other hand, our study is the first study comparing late-onset bipolar cases to non-late-onset ones in Turkey. Age of onset is considered as an important indicator to predict different sub-types, different disease courses and comorbidities (10). According to results of our study, late-onset bipolar cases and non-late-onset ones differ for episode with psychotic episodes, mixed episode, rapid cycling, seasonality, switch with antidepressants, comorbid somatic disease and family history of somatic disease. Hypertension, diabetes and cerebrovascular disorders found to be more prevalent in late-onset cases should be carefully examined in these cases and need for a detailed general medical evaluation should be kept in mind.



REFERENCES 

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2. Aziz R, Lorberg B, Tampi RR. Treatments for late-life bipolar disorder. Am J Geriatr Pharmacother 2006; 4:347-364. 

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4. Benazzi F. Classifying mood disorders by age-at-onset instead of polarity. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:86-93. 

5. Lopez JD, Arauxo A, Paramo M. Late onset bipolar disorder: following right thalamic injury. Acta Eur Psychiatry 2009; 37: 233-235.

6. Çorapçıoğlu A, Aydemir Ö, Yıldız M ve ark. (1999) DSM-IV Eksen I Bozuklukları (SCID-I) için yapılandırılmış klinik görüşme, klinik versiyon. Ankara, Hekimler Yayın Birliği (Article in Turkish).

7. Özerdem A, Yazıcı O, Oral ET and the Mood Disorders Study Group Psychiatric Association of Turkey. Establishment of a registry program for bipolar illness in Turkey. International Society of Affective Disorders 2nd Biennial Conference-Cancun, Mexico. J Affective Disord 2004; 78 (Suppl.1): 86. 

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16. Wylie ME, Mulsant BH, Pollock BG, Sweet RA, Zubenko GS, Begley AE, Gregor M, Frank E, Reynolds CF 3rd, Kupfer DJ. Age at onset in geriatric bipolar disorder. Effects on clinical presentation and treatment outcomes in an inpatient sample. Am J Geriatr Psychiatry 1999; 7:77-83.

17. Lieberman DZ, Massey SH, Goodwin FK. The role of gender in single vs married individuals with Bipolar Disorders. Compr Psychiatry 2010, 51: 380-385.

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27. Hecht H, van Calker D, Spraul G, Bohus M, Wark HJ, Berger M, von Zerssen D. Premorbid personality in patients with uni- and bipolar affective disorders and controls: assessment by the Biographical Personality Interview (BPI). Eur Arch Psychiatry Clin Neurosci 1997; 247:23-30.

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Geç Başlangıçlı Olan ve Olmayan İki Uçlu Bozukluk Hastalarının Karşılaştırılması
1Doç. Dr.,
2Asist. Dr.,
3Psikiyatrist, Erenköy Ruh ve Sinir Hastalıkları Eğitim ve Araştırma Hastanesi, İstanbul - Türkiye
Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2012; 3(25): 244-251 DOI: 10.5350/DAJPN2012250307

Amaç: Bu çalışmanın amacı, geç başlangıçlı iki uçlu bozukluğu olan olguların, geç başlangıçlı olmayan olgulardan farklılaşıp farklılaşmadığının incelenmesidir.

Yöntem: Bu çalışmada, DSM-IV ölçütlerine göre iki uçlu bozukluk tanılı ve polikliniğimizde izlenmekte olan 144 olgu değerlendirilmiştir. İki uçlu bozuklukta geç başlangıç sınırı olarak 40 yaş seçilmiştir. Geriye dönük olarak geç başlangıçlı olduğu saptanan 17 olgu, geç başlangıçlı olmayan 127 olgu ile karşılaştırılmıştır.

Bulgular: Geç başlangıçlı olgularda psikotik bulgulu dönem, karma dönem, hızlı döngülülük, mevsimsellik ve antidepresan ile kayma daha sık, hipertimik mizaç puanları daha yüksek bulundu. Bedensel hastalık eştanısı geç başlangıçlı olgular arasında daha sıktı. Olguların %83’ünde hipertansiyon, %71’inde diyabet, %23’ünde ise serebrovasküler hastalık eştanısı belirlendi. Ailede bedensel hastalık öyküsü de geç başlangıçlı olgularda daha sıktı.

Sonuç: İki uçlu bozuklukta başlangıç yaşı, farklı alttipleri belirlemede, hastalığın farklı klinik gidişlerini ve eştanıları öngörmede önemli bir belirleyici olarak değerlendirilmektedir. Özellikle, geç başlangıçlı olgularda daha sık bulunduğu saptanan vasküler patolojiler, bu olgularda dikkatle incelenmeli, ayrıntılı bir genel tıbbi durum değerlendirmesinin gerekliliği göz ardı edilmemelidir.