Lithium Prophylaxis Research Articles

Protective effect of pregnancy in women with lithium-responsive bipolar disorder

Background: Recent psychiatric literature, while indicating a high incidence of postpartum depression, contains a few clinical reports which support our observations that women with episodic bipolar disorder often remain well without treatment during pregnancy. Our retrospective study statistically examines the clinical course of 28 women with RDC typical bipolar disorder, type I, who became pregnant prior to receiving successful lithium prophylaxis. Methods: We derived all data from the International Group for the Study of Lithium-treated Patients (IGSLI) database of excellent lithium responders. Data were compared both intraindividually, using data from three 9-month periods — immediately prior to pregnancy, pregnancy and postpartum — and interindividually, using never-pregnant women as controls. Results: Intraindividual data show that women with typical bipolar disorder, type I, experience significantly fewer and shorter recurrences during pregnancy than either before or after. Interindividual comparisons indicate that the recurrence risk during pregnancy is markedly lower than the clinical course would predict. Moreover, the few recurrences observed during pregnancy all took place in the last 5 weeks. Limitations: Limiting cases to lithium responsive patients could have reduced heterogeneity and perhaps generalizability. Conclusions: The findings, nonetheless, indicate a marked improvement of the clinical course of typical bipolar disorder, type I, lithium-responsive, during pregnancy. Exploring the underlying protective mechanisms may lead to new understanding of the pathophysiology of mood disorders and to new approaches to treatment and prevention.

Is There a Loss of Efficacy of Lithium in Patients Treated for Over 20 Years?

Diminishing efficacy of lithium prophylaxis in initially well-responding patients during long-term treatment as well as after interruption of prophylaxis has been described repeatedly in the past. For the present analysis, 22 patients with bipolar and unipolar affective disorder continuously treated and documented in a specialized lithium outpatient clinic over at least 20 years were included. The cumulative affective morbidity of the first 10 years versus the second 10 years of prophylactic treatment was subjected to statistical and single-case (life chart method) analysis. There was no statistical evidence for diminishing efficacy of lithium prophylaxis. The increase in the Morbidity Index in single patients in a case-related individual approach could be revealed as not necessarily due to an alleged loss of efficacy of lithium, but more likely to be due to the atypical features in the psychopathology and course of illness.

The impact of lithium prophylaxis on the course of bipolar disorder: a review of the research evidence

A critical review is provided of the available research evidence concerning the efficacy and effectiveness of lithium prophylaxis in bipolar disorder. It is emphasized that, in spite of the limitations of available placebo-controlled trials and naturalistic studies, lithium is the only drug whose prophylactic activity in bipolar disorder is convincingly proved, and remains the first-choice medication in the long-term treatment of bipolar patients. The impact of lithium prophylaxis is likely to be less significant on atypical and comorbid cases of bipolar disorder than in typical manic depressive illness, but the superiority of other medications over lithium in the long-term treatment of those cases is at present not convincingly proved by research. Currently available research evidence does not seem to support the idea that lithium exerts its prophylactic effect on relapses but not on recurrences of bipolar disorder. Clinicians should be aware of the fact that the drop-out rate in bipolar patients receiving long-term lithium prophylaxis is high even if treatment surveillance is accurate, and that complete suppression of recurrences is a relatively rare outcome of prophylaxis.

Does 'rebound mania' occur after stopping carbamazepine? A pilot study.

Withdrawal of lithium prophylaxis in patients with bipolar affective disorder has been shown to precipitate 'rebound mania', an effect which may negate its benefits in the poorly compliant. No studies have looked for similar effects on withdrawal of carbamazepine, an alternative and adjunctive prophylactic treatment. This retrospective study examined the effects of withdrawal of carbamazepine prophylaxis in patients with bipolar disorder. A systematic search for patients with bipolar disorder who stopped carbamazepine therapy whilst in remission was conducted, followed by case note review and interview. In a case series of six patients who stopped carbamazepine, four remained well for at least 3 months, one developed an episode of moderate depression and one remained well before resuming treatment after 1 month. None required admission or suffered a manic episode in the 3 months following cessation. This study does not support the existence of a carbamazepine 'rebound' effect. It raises the possibility that recurrence after stopping carbamazepine may be less severe than the 'rebound mania' seen on lithium withdrawal. If this is the case, it may be a better choice of mood stabilizer in the poorly compliant. To date, there is insufficient evidence on which to base this choice. There is a need to examine this issue further through larger prospective and experimental studies on the effects of anticonvulsant withdrawal.

Does effective lithium prophylaxis result in a symptom-free state of manic-depressive illness? Some thoughts on the fine-tuning of mood stabilization

Recovered depressive or manic-depressive patients on long-term lithium medication may show oscillations in their state of well-being, neuropsychological impairment, and subclinical mood disturbances. It remains an open question as to whether such changes should be labeled as "subthreshold" symptoms of depression or mania, as a particular syndromal entity not directly related to the "mood disorder," or as subtle side effects of lithium. Within a psychological theory of the action of lithium, mental effects of lithium must be postulated and should not be simply considered as side effects. Depending on medical common sense and economic restrictions, the optimization and fine-tuning of lithium prophylaxis may be advisable in selected cases, including counseling, family therapy, cognitive therapy, well-being therapy, or interpersonal psychotherapy. Also, a change of medication may be considered in patients with subjective or objective cognitive impairment.

Serotonin receptor 2A, 2C, 1A genes and response to lithium prophylaxis in mood disorders

The aim of this study was to investigate the influence of serotonin receptors 2A, 2C and 1A gene variants on lithium prophylactic efficacy in mood disorders. One hundred and twenty-four subjects affected by bipolar ( n=102) and major depressive ( n=22) disorder were followed prospectively for an average of 52 months and were typed for 5-HT2A (T102C: n=111, HTP: n=104), 5-HT2C ( n=110) and 5-HT1A ( n=61) variants. Both 5-HT2A and 5-HT2C variants were not associated with lithium outcome. Consideration of possible stratification effects like gender, polarity, family history, age at onset and duration of lithium treatment did not influence results. No 5-HT1A gene variant was identified. 5-HT2A and 2C variants are not, therefore, associated with lithium prophylactic efficacy in mood disorders.

Melancholic features and response to lithium prophylaxis in mood disorders

Clinical predictors of the efficacy of lithium prophylaxis in mood disorders have great potential value. Melancholic features during depressive phases have been both proposed and rejected as valid predictors of favorable outcome. The aim of the present study is to describe the validity of melancholic features during depressive phases as predictors of the prophylactic efficacy of lithium. Sixty-one subjects affected by bipolar (n = 51) and major depressive (n = 10) disorder were followed prospectively for an average of 53 months. All subjects were evaluated as a lifetime perspective at intake, by the Operational Criteria checklist for psychotic illness (OPCRIT). Melancholic features were correlated with outcome only when controlling for time of first lithium administration. These two variables accounted for more than 30% of the total variance in lithium response. Others clinical factors such as polarity, delusions, gender, onset, personality disorders, and family history of mood disorders did not influence the observed association. Our preliminary findings suggest that melancholic features may be associated with favorable lithium prophylactic outcome in mood disorders.

Non-adherence with long-term prophylaxis: a 6-year naturalistic follow-up study of affectively ill patients

In a retrospective 6-year follow-up, we assessed the reasons for and the frequency and consequences of non-adherence in 76 affectively ill patients receiving lithium prophylaxis in two lithium clinics. Thirty-eight bipolar (50%), 21 unipolar (27.6%) and 17 schizoaffective patients (22.4%) diagnosed according to DSM-III-R, were investigated with a specialized follow-up documentation. Of the patients 53.9% discontinued prophylaxis at some time; 43.2% of the discontinuations occurred during the first 6 months. In contrast to other studies the main reason reported for non-adherence was resistance against long-term treatment. According to the Lithium Attitudes Questionnaire non-adherent patients showed significantly less acceptance of the prophylaxis in general, of the effectiveness of lithium and of the severity of their illness than adherent patients. In a multivariate analysis of various parameters, only the negative attitude to prophylaxis correlated significantly with non-adherence. Significant correlation was found between treatment outcome and duration of initial prophylaxis. During the 6-year follow-up only the adherent patients showed a significant reduction of the number and duration of admissions. Our findings confirmed non-adherence as a major problem in the effectiveness of lithium prophylaxis. The authors recommend prospective investigations of attitudes and the impact of psychoeducation on long-term adherence.

Early onset of lithium prophylaxis as a predictor of good long-term outcome.

The recurrence rates during lithium preventive treatment were investigated in a sample of 270 Mood Disorder subjects subdivided according to their onset time for lithium prophylaxis as very early (within 5 years from the onset of illness), early (6-10 years), late (11-20 years) and very late (more than 21 years). 131 subjects of the sample followed for 4 years prolonged the observation for a further period of 8 years. Results indicated that beginning lithium therapy within the first ten years of illness predicts better preventive outcomes than beginning prophylaxis later, both in major depression, recurrent and bipolar patients.

Predictors of lithium prophylaxis in bipolar patients

Background. This study aimed to investigate the demographical and clinical factors and their predictive powers before and at the end of the 6th and 12th month of lithium prophylaxis. Methods. Subjects meeting the following criteria were included in the investigation: (1) bipolar patients (DSM-IV); (2) having at least a 3-year lithium prophylaxis; (3) being in either the `definite poor' or `definite good' response groups. Both groups were compared regarding sociodemographic and clinical variables. Results. At the pretreatment point of the prophylaxis, four variables that could predict poor response with 74.1% power were severe episodes, higher ratio of mania/depression, psychotic index episode and being unmarried. At the end of the 6th month, the five variables having 84.89% predictive power for poor response were again the previous three variables and additionally bipolar I diagnosis and poor response to the first 6 months of lithium. At the end of the 12th month, the three variables for poor response had 91.37% predictive power and these were again the previous first two variables and a poor response to the first 12 months of lithium. Limitations. This was a retrospective study; psychosocial stress was not evaluated by standardized criteria; and the predictive value of personality disorders could not be tested thoroughly. Conclusions. This study suggests that it is possible to predict, rather reliably, the response to prophylactic lithium regarding clinical variables.

Rapid cycling bipolar affective disorder in people with intellectual disability: a systematic review.

Rapid cycling bipolar affective disorder has attracted renewed interest in the general adult psychiatric literature, particularly as the response to lithium prophylaxis is poor in this subgroup of patients. The present paper describes a systematic Medline/Psyclit review of case studies and small series of patients with rapid cycling bipolar affective disorder in people with intellectual disability (ID). Rapid cycling bipolar affective disorder in people with ID may differ from its occurrence in the non-ID population in terms of a relative preponderance of males, an increased likelihood of rapid cycling onset in those with an early (prepubertal) onset of affective disorder and a different response to prophylactic drugs. The efficacy of treatment and prophylaxis of rapid cycling illnesses needs further investigation in the population with ID.

Reliability and validity of four alternative definitions of rapid-cycling bipolar disorder.

This study tested the reliability and validity of four definitions of rapid cycling. Two trained psychiatrists, using the Schedule for Affective Disorders and Schizophrenia, independently assessed 210 patients with bipolar disorder. They checked whether each patient met four definitions of rapid cycling: one consistent with DSM-IV criteria, one waiving criteria for duration of affective episodes, one waiving such criteria and requiring at least one switch from mania to depression or vice versa during the reference year, and one waiving duration criteria and requiring at least 8 weeks of fully symptomatic affective illness during the reference year. The interrater reliability was calculated by Cohen's kappa statistic. Patients who met each definition according to both psychiatrists were compared to those who did not meet any definition (nonrapid-cycling group) on demographic and clinical variables. All patients were followed up for 1 year. Kappa values were 0.93, 0.73, 0.75, and 0.80, respectively, for the four definitions of rapid cycling. The groups meeting the second and third definitions included significantly more female and bipolar II patients than did the nonrapid-cycling group. Those two groups also had the lowest proportion of patients with a favorable lithium prophylaxis outcome and the highest stability of the rapid-cycling pattern on follow-up. The four groups of rapid-cycling patients did not differ significantly among themselves on any of the assessed variables. The expression "rapid cycling" encompasses a spectrum of conditions. The DSM-IV definition, although quite reliable, covers only part of this spectrum, and the conditions that are excluded are very typical in terms of key validators and are relatively stable over time.

Tryptophan hydroxylase gene and response to lithium prophylaxis in mood disorders

Lithium is an effective prophylactic agent in mood disorders but not all patients with mood disorders respond to lithium therapy; it is therefore necessary to identify responders prior to treatment. Clinical predictors account for about half of the variance and it is probable that genetic factors play a substantial role. The aim of this study was to investigate the possible association between the tryptophan hydroxylase (TPH) gene and prophylactic efficacy of lithium in mood disorders. One hundred and eight subjects affected by bipolar ( n=90) and major depressive ( n=18) disorder were followed prospectively for an average of 50.4 months and were typed for their TPH variant using polymerase chain reaction techniques. TPH variants were marginally associated with lithium outcome ( F=3.16; d.f.=2,105; P=0.046). Subjects with the TPH∗A/A variant showed a trend toward a worse response compared to both TPH∗A/C and TPH∗C/C variants. Consideration of possible stratification effects such as gender, polarity or age at onset did not influence the observed association. TPH variants may be a possible factor influencing the prophylactic efficacy of lithium in mood disorders.

Therapeutic strategies in refractory bipolar disorder

Lithium is still regarded as the first choice substance in the prophylactic treatment of bipolar disorder. However, approximately one third of patients with a "classic" course of bipolar affective disorder do not adequately respond to lithium prophylaxis. The introduction of carbamazepine and valproic acid allowed a more differential syndrome- and course-orientated approach to the prophylactic treatment of bipolar disorder for the first time. However, about 10 to 20 percent of patients still remain refractory to standard regimes. Therefore, criteria for resistance to prophylactic treatment have to be further established. It has been suggested that at least two adequate trials of more than 12 months duration with sufficient drug blood levels have to be performed before refractoriness should be assumed. A severe subtype of affective disorder with poor response to lithium and other treatment approaches is a rapid cycling course which is characterised by at least four affective episodes per year. Here we present an overview of the currently available alternatives for prophylactic treatment, i.e. anticonvulsants, combination treatment, adjunctive thyroxine, calcium channel blockers, and more experimental approaches for treating refractory bipolar disorder patients. Suggestions for optimizing the prophylactic treatment of bipolar disorder are summarized in an algorithm.

Ethnic differences in the presentation of bipolar affective disorder

There have been repeated reports that Afro-Caribbean people living in the UK are more prone than white people to be diagnosed as having schizophrenia and mania, along with some evidence that they are less likely to receive a diagnosis of depression. We attempted to replicate these findings in a population of patients on lithium prophylaxis. We therefore assessed the clinical characteristics of people under the age of 55 from three ethnic groups attending a lithium clinic in south London, those of (1) white British ( n = 88); (2) Afro-Caribbean ( n = 31); and, (3) African ( n = 15) origin. Nineteen of the white patients met DSM-IV criteria for unipolar depression (UP) and eight met the criteria for bipolar II disorder (BP II); in contrast, only two black patients met the criteria for unipolar depression and none met the criteria for BP II. Among patients diagnosed as BP I, Africans were significantly more likely than whites to show exclusively or mainly manic presentations while Afro-Caribbeans were more likely to have had mood-incongruent delusions. On the other hand, white patients were significantly more likely than Afro-Caribbeans to have had suicidal ideas or actions, and showed a similar but not significant excess when compared with Africans. Our findings could reflect either genuine ethnic differences in the presentation of severe affective disorder or be produced by the failure of British doctors to detect depression and deliver appropriate treatment to their black patients. The frequency with which Afro-Caribbean patients with mania present mood-incongruent delusions probably contributes to the high rates of diagnosed schizophrenia in this population.

Dopamine receptor D2 and D4 genes, GABA A alpha-1 subunit gene and response to lithium prophylaxis in mood disorders

Lithium is an effective prophylactic agent in mood disorders, and genetic factors are likely to modulate individual susceptibility to lithium treatment. The aim of this study is to investigate the influence of dopamine receptor D2 (DRD2), D4 exon 3 (DRD4), and γ-aminobutyric acid type A (GABA A) receptor alpha-1 subunit (GABRA1) gene variants on the efficacy of lithium prophylaxis in mood disorders. Patients with mood disorders ( N=125: bipolar subtype, n=100; major depressive disorder subtype, n=25) were followed prospectively for an average of 53 months and were typed for DRD2 (Ser311/Cys311: n=121, VNTR: n=63), DRD4 ( n=125) and GABRA1 ( n=61) variants using polymerase chain reaction (PCR) techniques. DRD2, DRD4 and GABRA1 variants were not associated with response to lithium. A trend was observed toward a better outcome of DRD4*2/4 subjects, but it was due to only two subjects. Consideration of possible stratification effects like gender, polarity, family history, age at onset and duration of lithium treatment did not reveal any association either. DRD2, DRD4 and GABRA1 variants therefore do not appear to be associated with the outcome of lithium prophylaxis in mood disorders.

Lithium prophylaxis of recurrent bipolar affective disorder: Long-term outcome and its psychosocial correlates

Background: Discrepancy between efficacy of prophylactic lithium and its effectiveness in ordinary clinical practice necessitates long-term follow-up data from specialised lithium clinics. Also, role of psychosocial factors in influencing the outcome is unclear. Methods: One hundred and eighteen patients of bipolar affective disorder attending a lithium clinic were followed-up for ∼11 years (range 2–27 years). Demographic and clinical data, measures of social support and psychosocial stress were obtained at the intake in 1989–1990. Study design combined retrospective chart-review (till the time of intake) with prospective follow-up till July 1995. Results: On lithium, the patients had a mean of 0.43 relapses per year (manic, 0.26; depressive, 0.17) which was significantly less ( p<0.01) than the pre-lithium episode frequency. The figure for entirely relapse-free patients was 24%, and 62% had relapses up to one episode per year (median=0.3 per year). Fifty-eight (49%) patients were good responders to lithium (relapses≤0.30 per year). In comparison to good responders, partial/poor responders had a significantly greater number of pre-lithium depressive episodes, poor lithium compliance, more psychosocial stress and lower social support at intake. These variables correlated well with relapses and explained 32% of the variance of the data. Conclusions: Lithium had a definite prophylactic effect on long-term outcome. Social support and stressful life events are significant correlates of response to lithium. Clinical Implications: Lithium prophylaxis of bipolar affective disorders seems justified though psychosocial factors appear to modulate its effectiveness. Limitations: Other psychotropic medications were used during relapse and the assessment of psychosocial factors was cross-sectional.

Patterns of DST positivity in remitted affective disorders

Background: While the Dexamethasone Suppression Test (DST) has been extensively used in cross–sectional observations of patients with major affective disorders, studies have tended to ignore the longitudinal application of the DST in patients stabilized on long–term prophylactic medication.Methods: Monthly DST’s were performed on 19 patients, 16 with bipolar disorder and 3 with recurrent major depression. All cases had an excellent response to lithium treatment, and family history positive for bipolar disorder. The average duration of observation was 4 years.Results: All patients remained clinically stable throughout the period of observation. Eleven patients showed intermittent DST positivity ranging from 10% to 60% of tests, and 2 patients exhibited no positivity. Six patients had fewer than 10% positive DST’s. Females showed significantly higher positivity than males. The frequency of positivity did not correlate with current age, age of illness onset, duration of illness, duration of lithium treatment, or season. The risk of primary affective disorders in first–degree relatives was also unrelated to the frequency of positivity.Conclusions: While the highly selected and small sample population limits generalizability, our observations suggest that clinically sufficient lithium prophylaxis does not automatically prevent intermittent HPA dysregulation. We hope that a better understanding of this phenomenon will offer new approaches to the long–term management of mood disorders.

Subclinical symptoms in mood disorders: pathophysiological and therapeutic implications.

The aim of this review was to survey the available literature on prodromal and residual symptoms of unipolar major depression and bipolar disorder. Both a computerized (Medline) and a manual search of the literature were performed. In a substantial proportion of patients with affective disorders a prodromal phase can be identified. Most patients report residual symptoms despite successful treatment. Residual symptoms upon remission have a strong prognostic value. There appears to be a relationship between residual and prodromal symptomatology (the rollback phenomenon). Appraisal of subclinical symptomatology in mood disorders has important implications for pathophysiological models of disease and relapse prevention. In depression, specific treatment of residual symptoms may improve long-term outcome, by acting on those residual symptoms that progress to become prodromes of relapse. In bipolar disorder, decrease of subclinical fluctuations and improvement of level of functioning by specific therapeutic strategies may add to the benefits provided by lithium prophylaxis.

Dopamine receptor D3 gene and response to lithium prophylaxis in mood disorders.

Lithium has established itself as an effective prophylactic agent in mood disorders, but not all patients respond to lithium therapy. It is probable that genetic factors play a substantial role in determining the differences in response to lithium. The aim of this study was to investigate the association between the dopamine receptor D3 (DRD3) gene and prophylactic efficacy of lithium in mood disorders. Fifty-five subjects affected by bipolar (n=43) and major depressive (n=12) disorder were followed prospectively for an average of 49 months and were also typed for their DRD3 variant, using polymerase chain reaction techniques. DRD3 variants were not associated with lithium outcome. Consideration of possible stratification effects, such as gender, polarity, family history, age at onset or duration of lithium treatment, also did not reveal any associations. DRD3 variants are not, therefore, a major factor influencing the prophylactic efficacy of lithium in mood disorders.