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.     

Cognitive-behavioral management of patients with bipolar disorder who relapsed while on lithium prophylaxis

BACKGROUND: The application of cognitive-behavioral treatment (CBT) to patients with bipolar disorder who had an affective episode while on lithium prophylaxis has received little research attention. The aim of this preliminary study was to test whether reduction of residual symptomatology by cognitive-behavioral methods could yield long-term beneficial effects in patients with bipolar disorder, as was found to be the case in recurrent unipolar depression. METHOD: Fifteen patients with RDC bipolar disorder, type I, who relapsed while on lithium prophylaxis despite initial response and adequate compliance were treated by cognitive-behavioral methods in an open trial. A 2- to 9-year follow-up was performed. RESULTS: Five of the 15 patients had a new affective episode during follow-up. CBT was associated with a significant reduction of residual symptomatology. CONCLUSION: These preliminary results suggest that a trial of CBT may enhance lithium prophylaxis and improve long-term outcome of bipolar disorder.     

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.     

The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s

Objectives: The aim of the study was to assess the prophylactic effect of long-term lithium administration in patients with bipolar mood disorders entering treatment in the 1970s and 1980s at the outpatient clinic of the Department of Psychiatry, University of Medical Sciences, Poznan, Poland. Methods: The clinical characteristics of two groups of patients before and during lithium therapy were compared, namely, the 60 bipolar patients who entered lithium prophylaxis in the 1970s and 49 patients who entered in the 1980s. Both groups received the drug over a 10-year period. Results: The patients who entered lithium in the 1970s had fewer previous episodes of depression and more of mania than the patients who entered the therapy in the 1980s, although the total number of affective episodes was similar in both groups. The overall prophylactic efficacy of lithium over a 10-year period of administration was similar in both groups, except for a trend towards a greater number of depressive episodes in the first year of lithium prophylaxis in the 1980s group. The excellent lithium responders constituted 35% of the 1970s patients and 27% of those in the 1980s group. The 1970s patients were maintained on a higher level of serum lithium compared to the patients in the 1980s group and had more lithium-induced side effects. Conclusions: A decrease in lithium prophylactic efficacy in consecutive decades was not observed. Small differences between the bipolar patients entering lithium therapy in the 2 decades were observed in terms of the previous history of illness and during the course of lithium administration.     

Effectiveness and outcome predictors of long-term lithium prophylaxis in unipolar major depressive disorder

OBJECTIVE: To determine the effectiveness of lithium prophylaxis in unipolar major depressive disorder (MDD) and to identify predictors of outcome including comedication. METHODS: In this long-term naturalistic study, clinical data from 55 patients with MDD (DSM-III-R) were collected prospectively in an outpatient clinic specializing in the treatment of affective disorders. OUTCOME MEASURES: Change in hospital admission rate (number and duration) during prophylaxis compared with the period before prophylaxis, Morbidity-Index during prophylaxis and time to first recurrence after initiation of lithium treatment. RESULTS: During an average follow-up period of 6.7 years, a significant decline in the number of days spent in hospital (p<0.001; 52 d/yr less; 95; CI 31-73 d) and a low Morbidity-Index (mean 0.07) was observed. Only in 6 patients did medication have to be changed because of side-effects (n=4) or a lack of efficacy (n=2). None of the independent variables we analyzed proved to be important in predicting the outcome of lithium prophylaxis. Comedication was necessary in 21 patients. The overall outcome of their prophylactic treatment, however, did not differ from the group that did not receive comedication in the symptom-free intervals. CONCLUSIONS: The results of this study, with its long observation period and the inclusion of comedication as a confounding variable, indicate that lithium is a potent prophylactic agent for unipolar MDD in a naturalistic setting. In contrast to the findings of others, age was not associated with the outcome of prophylaxis, and latency did not predict outcome. Contrary to doubts that have been raised in recent years with regard to the effectiveness of lithium in everyday clinical practice, lithium appears to be a safe and potent alternative to antidepressants.     

Behandlungsstrategien bei prophylaxeresistenten bipolaren Störungen

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.     

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment

Suicidal behavior is strongly associated with depression, especially if accompanied by behavioral activation, dysphoria, or agitation. It may respond to some treatments, but the design of scientifically sound, ethical trials to test for therapeutic effects on suicidal behavior is highly challenging. In bipolar disorder, and possibly also unipolar major depression, an underprescribed medical intervention with substantial evidence of preventive effects on suicidal behavior is long-term treatment with lithium. It is unclear whether this effect is specifically antisuicidal or reflects beneficial effects of lithium on depression, mood instability, and perhaps aggression and impulsivity. Antisuicidal effects of anticonvulsant mood stabilizers (carbamazepine, lamotrigine, valproate) appear to be less than with lithium. Further evaluation is needed for potential antisuicidal effects of atypical antipsychotics with growing evidence of efficacy in depression, particularly acute bipolar depression, while generally lacking risk of inducing agitation, mania, or mood instability. Short-term and long-term value and safety of antidepressants are relatively secure for unipolar depression but uncertain and poorly tested for bipolar depression; their effects on suicidal risk in unipolar depression may be age-dependent. Sedative anxiolytics are virtually unstudied as regards suicidal risks. Adequate management of suicidal risks in mood disorder patients requires comprehensive, clinically skillful monitoring and timely interventions.     

The clinical usefulness of lithium as an antidepressant

Much attention has been directed toward the use of lithium in bipolar depressive illness (manic-depressive illness), but fewer studies have evaluated lithium's efficacy in unipolar depressive disorders. This paper critically reviews the literature dealing with the use of lithium for the treatment of acute unipolar depression as well as for prophylaxis against future depressive episodes. Differences in study design, entry criteria, serum lithium level, dose, patient population, and diagnosis are highlighted; these variations help explain some of the controversy surrounding the use of lithium in unipolar depression. The available information indicates that lithium should be seriously considered as an effective alternative for the treatment of unipolar depression when other antidepressant medications are ineffective or contraindicated.     

The influence of successful prophylactic drug treatment on cognitive dysfunction in bipolar disorders

Background:  Cognitive variables such as negative self-evaluations have been discussed as vulnerability factors for depressive syndromes. In the context of bipolar disorders dysfunctional cognitive structures have received little interest as these patients seem to be less disturbed during the euthymic interval than patients with major depression.
Methods:  In the present study, the self-esteem of remitted patients with DSM-III-R diagnosis of major depression (n=20), bipolar disorder (n=20) and healthy controls (n=20) was measured with the Frankfurt Self-concept Scale (FSKN).
Results:  1) Statistical analysis by analysis of variance (ANOVA) showed no significant differences as to age, sex, etc. between the psychiatric groups. The clinical groups showed lower self-esteem ratings in comparison to healthy controls. 2) Four groups (T1–T4) of remitted patients with bipolar disorders (20 in each group) were successfully maintained on mood stabilizers (lithium or carbamazepine) and classified by the duration of their episode-free period. T1 included those who were episode-free for only the week before discharge from hospital. T2 were symptom-free for <30 months. T3 were episode-free for >30 months and <60 months. T4 were episode-free for >60 months. The comparison of their FSKN self-esteem ratings by ANOVA suggests that self-esteem improves during successful prophylactic treatment. A posteriori contrasts indicate a normalized self-esteem after a bipolar episode-free period of at least 47 months.
Conclusions:  Dysfunctional cognitions can be demonstrated in unipolar as well as in bipolar patients. Successful episode-preventive medication with mood stabilizers seems to counteract lowered self-esteem. Adjunctive cognitive therapy might help to optimize the long-term course of bipolar disorder.     

Atypical antipsychotics for bipolar disorder.

Atypical antipsychotic agents have been widely investigated for their efficacy in acute mania. The data to date suggest that olanzapine,risperidone, quetiapine, aripiprazole, and ziprasidone are effective, with no significant differences in antimanic efficacy among these agents. These agents are effective as an alternative to lithium or divalproex as monotherapy or in combination with these mood stabilizers. The data concerning their utility in acute bipolar depression and maintenance treatment of bipolar disorder are limited. The studies to date suggest that olanzapine has modest acute antidepressant properties but probably has efficacy comparable to lithium and divalproex in preventing manic and depressive episodes. Quetiapine seems to have robust antidepressant properties, but these data need to be replicated in further trials before quetiapine can be recommended as a first-line agent for acute bipolar depression. Aripiprazole has shown promise in preventing manic episodes in one 6-month study, but further studies with at least 1-year duration and larger sample sizes are needed before this agent can be recommended as a monotherapy for prophylaxis of bipolar disorder. It is currently unknown if risperidone, aripiprazole, and ziprasidone have any efficacy in treating acute bipolar depression. Similarly, long-term studies are needed to ascertain the role of risperidone, quetiapine, and ziprasidone in the maintenance treatment of bipolar disorder. Overall, the atypical antipsychotic agents as a group represent an effective and relatively safe addition to the armamentarium for the treatment of bipolar disorder.     

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.     

The treatment of bipolar depression

Objectives: The treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management.

Methods: A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'.

Results: If effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate.

Conclusions: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.     

Lithium and anticonvulsants in bipolar depression

For decades, lithium and anticonvulsants have been widely used in the treatment of bipolar disorder. Their efficacy in the treatment of mania is recognized. These drugs have been initially evaluated in old and methodologically heterogeneous studies. Their efficacy in bipolar depression has not always been confirmed in more recent and methodologically more reliable studies. Thus, lithium's efficacy as monotherapy was challenged by the study of Young (2008) that showed a lack of efficacy compared with placebo in the treatment of bipolar depression. In two recent meta-analyses, valproate has shown a modest efficacy in the treatment of bipolar depression. As for lithium, valproate appeared to have a larger antimanic effect for acute phase and prophylaxis of bipolar disorder. In contrast, lamotrigine is more effective on the depressive pole of bipolar disorder with better evidence for the prevention of depressive recurrences. The guidelines include these recent studies and recommend lamotrigine as a first-line treatment of bipolar depression and for maintenance treatment. Because of more discordant data concerning lithium and valproate, these two drugs are placed either as first or as second line treatment of bipolar depression. The different safety/efficacy ratios of mood stabilizers underlie the complementarity and the importance of combination between them, or with some second-generation antipsychotics, in the treatment of patients with bipolar disorder.     

Anticonvulsants in bipolar disorder.

In recent years, a number of anticonvulsants have been more rigorously investigated for their potential mood-stabilizing properties. They are heterogeneous in their mechanisms of action and in their efficacy in the various mood states in bipolar illness (Table 3). At present, evidence from well-controlled studies supports the role of DIV and CBZ in the treatment of acute mania. DIV seems to have better efficacy than lithium in mixed mania or mania associated with depressive symptoms and is recommended as a first-line pharmacologic option in acutely manic or mixed manic patients. Neither CBZ nor DIV have robust evidence supporting their efficacy in the treatment of acute bipolar depression, although DIV clearly possesses beneficial effects on depressive symptomatology and prophylaxis against depressive episodes during long-term treatment. Results from a large study indicate that LAM has significant efficacy in bipolar depression without the associated risks of cycle acceleration or manic/hypomanic switches. LAM should be considered a primary option in patients with bipolar depression and in bipolar II patients with rapid cycling. DIV is recommended as a first-line option in bipolar I patients with rapid cycling. LAM has proven efficacy in the prophylaxis of bipolar I disorder and should be considered along with lithium or DIV as treatment of choice in the long-term management of bipolar disorder. For the other anticonvulsants, including CBZ and OXC, there is still inadequate evidence of efficacy as monotherapy in the long-term management of bipolar disorder. Even less data exist for other available AEDs, and consensus is growing that someAEDs (eg, GBP) have little or no specific effect in bipolar disorder. Despite the progress made in the past decade, a wider therapeutic armamentarium is critically needed, because a large proportion of bipolar patients do not respond to acute treatments during a manic or depressive episode and have frequent relapse and recurrences during long-term treatment. As additional AEDs become available, rigorously designed and large-scale studies examining AEDs as monotherapy and AEDs in combination therapies versus placebo must be undertaken to assess efficacy and safety more adequately to provide better guidance for the clinician faced with the management of this challenging mood disorder.     

Lithium augmentation in treatment-resistant depression: clinical evidence, serotonergic and endocrine mechanisms

For now more than 50 years, lithium has been the gold standard for the pharmacologic treatment of bipolar disorder. However, its utility is not restricted to acute mania and prophylactic treatment of bipolar disorder. A relatively new indication for its use is the addition to an antidepressant in the acute treatment phase of unipolar major depression. To date, this treatment approach called lithium augmentation is the best-documented approach in the treatment of refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment. In a recent double-blind, placebo-controlled trial, lithium augmentation has demonstrated to also be effective in the continuation treatment phase to prevent early relapses. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. In contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants, neuroendocrine studies on the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined DEX/CRH test. Here we review new data on the efficacy and mechanism of action of lithium augmentation.     

What do patients in a lithium outpatient clinic know about lithium therapy?

OBJECTIVE: To determine how much patients know about lithium therapy and to examine factors that might influence this knowledge. SETTING: Lithium outpatient clinic. PATIENTS: Patients (n = 123) affiliated with a lithium outpatient clinic (mean treatment duration of 12 years). Diagnoses, according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised, included bipolar disorder, recurrent unipolar depression and schizoaffective disorder. OUTCOME MEASURES: Quantitative assessment of lithium-related knowledge, obtained by responses to a questionnaire adapted from the Lithium Knowledge Test, and factors affecting this knowledge. RESULTS: Age was negatively correlated with lithium therapy knowledge scores, whereas duration of treatment, sex, education and diagnosis appeared to be unrelated to knowledge. CONCLUSION: Patient education about lithium treatment should be intensified, especially for older patients taking lithium because adverse drug reactions pose a greater risk to the elderly.     

Bipolar II disorder: symptoms, course, and response to treatment

The authors provide an overview of the diagnosis, course, and treatment of bipolar II disorder, a distinct subtype that is often misdiagnosed as unipolar depression or bipolar I disorder. They discuss research suggesting that underdiagnosis of bipolar II disorder reflects a failure to identify subthreshold expression of mania (hypomania). The course of bipolar II disorder is different from that of bipolar I disorder or unipolar depression, with distinct differences in rates of recovery, clinical features, and number of episodes. The risk of suicide appears to be particularly elevated. High rates of comorbid disorders have been reported, including substance abuse or dependence, anxiety disorders, and personality disorders. Few definitive studies exist on which to base conclusions about the differential efficacy of various treatment strategies in bipolar II disorder and bipolar I disorder. Preliminary studies suggest that the newer anticonvulsants may be of benefit for patients with bipolar II disorder, while other data suggest that there may be a greater role for antidepressant medications.     

Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison

Twenty-seven patients with recurrent unipolar depression and 22 with bipolar II illness in remission for at least six months were randomly assigned on a double-blind basis to treatment regimens using lithium carbonate, imipramine hydrochloride, lithium carbonate plus imipramine, or placebo. Lithium carbonate was found to help prevent depressive relapse among patients with unipolar disease, and relapse of any type among those with bipolar II disease. No effect or interaction of imipramine was found in either group. These results add to a growing body of data that suggest the usefulness of lithium carbonate in the prophylaxis of unipolar depressive illness. The relative usefulness of lithium carbonate and imipramine requires further study.