Special issues in trial design and use of placebo in bipolar illness.
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Antidepressive Agents↗
Biomedical subjects
G S Leverich
Publications and source records attributed to G S Leverich.
The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study.
BACKGROUND: Few studies have approached the subject of polypharmacotherapy systematically. This retrospective review of 178 patients with refractory bipolar disorder or unipolar depression (Research Diagnostic Criteria or DSM-III-R criteria) discharged from the National Institute of Mental Health (NIMH) Biological Psychiatry Branch between 1974 and 1996 was conducted to assess the degree and efficacy of "add-on" pharmacotherapy. METHOD: Following completion of formal structured blinded research protocols, patients entered a treatment phase (often again on a blind basis) in which all agents available in the community could be utilized. Each patient's retrospective life chart and all prospective double-blind nurse- and self-rated NIMH data were reviewed. The overall degree of improvement at discharge was assessed by rating on the Clinical Global Impressions scale (CGI) as modified for bipolar illness (CGI-BP). RESULTS: A 78% improvement rate (moderate or marked on the CGI) was achieved at the time of discharge. There was a significant relationship between number of medications utilized at discharge as a function of discharge date (r = 0.45, p < .0001). The percentages of patients discharged on treatment with 3 or more medications were 3.3% (1974-1979), 9.3% (1980-1984), 34.9% (1985-1989), and 43.8% (1990-1995). No correlation was found between polypharmacy and age (r = -0.03, p = .66). Patients more recently discharged from the NIMH had an earlier age at illness onset, more lifetime weeks depressed, and a higher rate of rapid cycling than patients in the earlier cohorts. CONCLUSION: Increasing numbers of medications in more recent NIMH cohorts were required to achieve the same degree of improvement at hospital discharge. More systematic approaches to the complex regimens required for treatment of patients with refractory mood disorder are clearly needed.
Adult↗
High exposure to neuroleptics in bipolar patients: a retrospective review.
BACKGROUND: Acute and long-term use of neuroleptics to treat bipolar disorder remains prevalent despite safety concerns. Neuroleptic-treated patients with bipolar disorder have been reported to have rates of tardive dyskinesia, akathisia, and acute dystonia as high as or higher than patients with schizophrenia. Moreover, the pattern of repeated, intermittent use of neuroleptics in bipolar disorder may increase rather than decrease the risk of tardive dyskinesia. METHOD: Retrospective life charts of 133 treatment-refractory patients with bipolar disorder (diagnosed according to Research Diagnostic Criteria or a clinical interview with the Schedule for Affective Disorders and Schizophrenia-Lifetime Version or the Structured Clinical Interview for DSM-IV Axis I Disorders) admitted to the National Institute of Mental Health (NIMH) were reviewed for prior neuroleptic use, medication exposure, and course of illness variables. Patients' medication response and degree of improvement while at NIMH were also assessed. RESULTS: A total of 72.2% (N = 96) of the bipolar patients examined had exposure to neuroleptics prior to referral to NIMH. Neuroleptic-treated patients had a mean of 5.6 neuroleptic trials with a mean duration of 166.4 days for each trial and a dose range of 25 to 960 mg in chlorpromazine equivalents. Life chart data showed that the neuroleptic-exposed and nonexposed bipolar patients were distinguished by 1 course-of-illness variable: increased suicidality in the neuroleptic-treated group. Patients with and without prior neuroleptic exposure experienced the same high degree of improvement at discharge from NIMH. Only 12.5% (N = 12) of the group previously treated with typical neuroleptics (N = 96) required neuroleptics at discharge. CONCLUSION: Our data suggest that the majority of even treatment-refractory bipolar patients can be stabilized without neuroleptics. Given the high risk of tardive dyskinesia and the availability of other novel agents, the routine intermittent use of typical neuroleptics to treat patients with bipolar disorder should be minimized.
Adult↗
Lamotrigine for the treatment of bipolar disorder: a clinical case series.
BACKGROUND: Recently, a number of new agents have become available to treat bipolar disorder, however many patients may not respond fully even when used in combination. Early reports in epilepsy studies suggested mood-related effects of lamotrigine treatment, as have preliminary reports in bipolar patients. METHODS: Seventeen patients meeting DSM-IV criteria for bipolar I (n = 9) or bipolar II (n = 8) disorder displaying affective symptoms and a past history of inadequate response or tolerability to at least two standard mood stabilizing agents were recruited through the Stanley Foundation Bipolar Network and treated with the new anticonvulsant lamotrigine in an add-on, open-label study. Response to therapy was assessed using the Clinical Global Impression Scale modified for bipolar disorder. RESULTS: The mean dose of lamotrigine was 187+/-157 mg/day (range 50-600 mg/day) for a mean duration of 159+/-109 days (range 14-455 days). Eleven (65%) patients were rated as very much or much improved. Lamotrigine was well tolerated, and may have mood stabilizing and antidepressant properties in some patients with bipolar disorder. LIMITATIONS: The study is hypothesis generating because it was uncontrolled and open. Controlled studies are warranted. CONCLUSIONS: This preliminary report supports clinical improvement for both mood cycling and depression in patients with bipolar disorder treated with lamotrigine.
Adolescent↗
Relationship between prior course of illness and neuropsychological functioning in patients with bipolar disorder.
BACKGROUND: This study investigated the relationship between prior course of illness and neuropsychological deficits in relatively high functioning outpatients with bipolar disorder. METHOD: Forty-nine bipolar I or II patients, in a relatively euthymic state during treatment with mood stabilizers, were administered neuropsychological tests that assessed a variety of functions, including verbal memory, sustained attention and vigilance, and intelligence. A detailed retrospective life chart was completed for each patient using the NIMH Life Chart Method" to define variables reflecting duration and severity of illness, and frequency of episodes. RESULTS: Stepwise multiple regression analyses show that several different measures of a more severe course of prior illness related to greater duration and a larger number of affective episodes and hospitalizations were associated with poorer performance on tests of abstraction, attention and memory. CONCLUSION: The results indicate that bipolar patients with a more severe prior course of illness and a greater number of affective episodes have more impaired neuropsychological functioning. The direction of causality and the pathophysiological mechanisms remain to be explored.
Adult↗
Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients.
OBJECTIVE: This investigation evaluated the relationship between changes in thyroid indices and mood stability during lithium and carbamazepine prophylaxis for bipolar disorder. METHOD: In the first 2 years, 30 patients with bipolar mood disorder were randomly assigned to 1 year of lithium and then 1 year of carbamazepine, or vice versa; in the third year, they received lithium plus carbamazepine. By stepwise regression analysis, the degree and timing of lithium- and carbamazepine-induced thyroid changes and their subsequent relationship to long-term mood stability were evaluated. RESULTS: During the lithium phase, there was a significant inverse relationship between morbidity and mean serum level of free T4, i.e., a lower mean serum level of free T4 was associated with more affective episodes and greater severity of depression as shown by the Beck Depression Inventory. During the carbamazepine phase, there was an inverse relationship between mean level of total T4 and global severity rating. During the combination phase, no relationships between thyroid indices and clinical outcome were significant. CONCLUSIONS: In the lithium phase, a low level of free T4 was associated with more affective episodes and greater severity of depression. Whether this mood instability is causally related to low free T4 levels and whether it can be attenuated with T4 replacement remain to be studied in a controlled setting.
Affect↗
Sensitization components of post-traumatic stress disorder: implications for therapeutics.
Behavioral sensitization to psychomotor stimulants and stressors involves increasing reactivity to repetition of the same dose (or intensity) of the stimulus over time. In cocaine-induced behavioral sensitization, conditioned components are prominent and the underlying pharmacological and neuroanatomical substrates differ as a function of stage of its evolution. Since there is cross-sensitization between cocaine-induced behavioral sensitization and stress-induced behavioral sensitization and, as well, a high comorbidity of stimulant abuse with post-traumatic stress disorder, many of the mechanisms and principles of cocaine-induced behavioral sensitization may be pertinent to post-traumatic stress disorder. The extent and duration of cocaine-induced behavioral sensitization/stress-induced behavioral sensitization are a function of age, genetic strain, and gender of the organism, as well as magnitude, frequency, duration, quality, and environmental contingencies of the inducing stimuli. These effect a spatiotemporal evolution of cascades of alterations in gene expression involving a host of immediate early and late effector genes, including neurotrophic and apoptotic factors. They may change the physiology, biochemistry, and neuroanatomy of the developing brain and, in adults, substrates critical for learning and memory. Suggestions are made for differential strategies of therapeutic intervention as primary prevention, in the immediate post-traumatic period, and in the late phases of post-traumatic stress disorder evolution.
Animals↗
Antidepressant discontinuation-related mania: critical prospective observation and theoretical implications in bipolar disorder.
BACKGROUND: Development of manic symptoms on antidepressant discontinuation has primarily been reported in unipolar patients. This case series presents preliminary evidence for a similar phenomenon in bipolar patients. METHOD: Prospectively obtained life chart ratings of 73 bipolar patients at the National Institute of Mental Health were reviewed for manic episodes that emerged during antidepressant taper or discontinuation. Medical records were utilized as a corroborative resource. Six cases of antidepressant discontinuation-related mania were identified and critically evaluated. RESULTS: All patients were taking conventional mood stabilizers. The patients were on antidepressant treatment a mean of 6.5 months prior to taper, which lasted an average of 20 days (range, 1-43 days). First manic symptoms emerged, on average, 2 weeks into the taper (range, 1-23 days). These 6 cases of antidepressant discontinuation-related mania involved 3 selective serotonin reuptake inhibitors (SSRIs), 2 tricyclic antidepressants (TCAs), and 1 serotonin-norepinephrine reuptake inhibitor. Mean length of the ensuing manic episode was 27.8 days (range, 12-49 days). Potential confounds such as antidepressant induction, phenomenological misdiagnosis of agitated depression, physiologic drug withdrawal syndrome, and course of illness were carefully evaluated and determined to be noncontributory. CONCLUSION: These 6 cases suggest a paradoxical effect whereby antidepressant discontinuation actually induces mania in spite of adequate concomitant mood-stabilizing treatment. These preliminary observations, if replicated in larger and controlled prospective studies, suggest the need for further consideration of the potential biochemical mechanisms involved so that new preventive treatment approaches can be assessed.
Adrenergic Uptake Inhibitors↗
Statistical approaches to trial durations in episodic affective illness.
In light of the high variability in illness characteristics and patterns among patients with bipolar illness, parallel group designs present severe methodologic difficulties. Crossover, off-on-off-on (B-A-B-A), and other individualized designs may be a useful substitute, but no consensus exists about how to estimate the individual trial durations required in these instances. Several methods for determining optimum trial lengths in crossover designs are presented, illustrated, and discussed. These include: chi-square (chi2) for the expected versus observed number of either episodes or days well; exceeding two standard deviations for average duration of episodes or euthymic intervals; or the Sequential Probability Ratio Test (SPRT), which detects when mean values differ from prior statistical expectations. Each method was applied to three demonstration cases using data from actual clinical trials of three patients with different patterns of recurrent affective illness. Each method detected changes in illness severity, although different tests appeared to be sensitive to differing cycle patterns in the patients illustrated. We suggest that these types of analyses and others can be used as indicator statistics to augment global impressions and clinical judgment, and to assist in determining individualized trial durations, both in formal clinical trials and in clinical treatment settings. Once individual responsivity is confirmed with an appropriate interplay of trial design and statistical analysis, the percentage response in a given population can then be compared to other agents or in other populations. Moreover, meta-analytic techniques based on addition of z scores from individuals' effect sizes can then be used to assess overall significance of a drug effect in a given population or subpopulation. The need for further development of appropriate and alternate study designs and analysis methods for bipolar illness is highlighted. Approaches to estimating required trial durations in individuals with different cycle frequencies in crossover and B-A-B-A designs constitute one element of that exploration.
Acute Disease↗
Olanzapine in treatment-resistant bipolar disorder.
BACKGROUND: We evaluated the response to olanzapine in 14 consecutive patients with bipolar I disorder who were inadequately responsive to standard psychotropic agents. METHODS: Fourteen patients with bipolar I disorder by DSM-IV criteria experiencing persistent affective symptoms inadequately responsive to at least one standard mood stabilizer were treated with open-label olanzapine by one of the authors. Response was assessed with the Clinical Global Impression Scale modified for use in bipolar disorder (CGI-BP). RESULTS: The 14 patients received olanzapine at a mean (SD dosage of 14.1+/-7.2 (range 5-30) mg/day for a mean+/-SD of 101.4+/-56.3 (range 30-217) days of treatment. Of the 14 patients, 8 (57%) displayed much or very much overall improvement in their illness. In general, olanzapine was well tolerated. The most common side effects were sedation, tremor, dry mouth, and appetite stimulation with weight gain. LIMITATIONS: Data were obtained nonblindly and without a randomized control group, and olanzapine was added to ongoing psychotropic regimens. CONCLUSION: Olanzapine may have antimanic and mood-stabilizing effects in some patients with bipolar disorder, and is generally well tolerated. Controlled studies of olanzapine in bipolar disorder appear warranted.
Antipsychotic Agents↗
Beyond lithium in the treatment of bipolar illness.
Dramatic changes have recently occurred in the availability of treatment options for bipolar illness. Second generation mood stabilizing anticonvulsants carbamazepine and valproate are now widely used as alternatives or adjuncts to lithium. High potency benzodiazepines are also used as alternatives to typical neuroleptics, and now atypical neuroleptics are demonstrating efficacy and better side-effects profiles than the typicals. Thyroid augmentation strategies and dihydropyridine L-type calcium channel blockers require further clinical trials to define their role. Putative third generation mood stabilizing anticonvulsants lamotrigine, gabapentin, and topiramate have unique mechanisms of action and deserve further systematic study, as does the potential role for nonconvulsive brain stimulation with repeated transcranial magnetic stimulation (rTMS). These and a host of other potential treatment options now require a new generation of clinical trials to help identify clinical and biological markers of response and optimal use alone and in complex combination therapeutic regimens.
Antimanic Agents↗
Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness.
Of 30 patients with treatment-refractory affective illness, 10 showed a moderate to marked response to blind nimodipine monotherapy compared with placebo on the Clinical Global Impressions Scale. Fourteen inadequately responsive patients (3 unipolar [UP], 11 bipolar [BP]) were treated with the blind addition of carbamazepine. Carbamazepine augmentation of nimodipine converted four (29%) of the partial responders to more robust responders. Patients who showed an excellent response to the nimodipine-carbamazepine combination included individual patients with patterns of rapid cycling, ultradian cycling, UP recurrent brief depression, and one with BP type II depression. When verapamil was blindly substituted for nimodipine, two BP patients failed to maintain improvement but responded again to nimodipine and remained well with a blind transition to another dihydropyridine L-type calcium channel blocker (CCB), isradipine. Mechanistic implications of the response to the dihydropyridine L-type CCB nimodipine alone and in combination with carbamazepine are discussed.
Adult↗
A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century.
Anticonvulsants have moved into an important position as alternatives and adjuncts to lithium carbonate in the treatment of bipolar illness. Work with the nonhomologous model of kindled seizures helped in the choice of carbamazepine as a potential mood stabilizer and in the study of the mechanisms of action of the second generation anticonvulsants carbamazepine and valproate, as well as the putative third generation psychotropic anticonvulsants lamotrigine and gabapentin. Anticonvulsant neuropeptides such as TRH and nonconvulsant approaches with repeated transcranial magnetic stimulation (rTMS) also appear promising.
Anticonvulsants↗
Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP.
The Clinical Global Impressions Scale (CGI) was modified specifically for use in assessing global illness severity and change in patients with bipolar disorder. Criticisms of the original CGI were addressed by correcting inconsistencies in scaling, identifying time frames for comparison, clarifying definitions of illness severity and change, and separating out assessment of treatment side effects from illness improvement during treatment. A Detailed User's Guide was developed to train clinicians in the use of the new CGI-Bipolar Version (CGI-BP) for rating severity of manic and depressive episodes and the degree of change from the immediately preceding phase and from the worst phase of illness. The revised scale and manual provide a focused set of instructions to facilitate the reliability of these ratings of mania, depression, and overall bipolar illness during treatment of an acute episode or in longer-term illness prophylaxis. Interrater reliability of the scale was demonstrated in preliminary analyses. Thus, the modified CGI-BP is anticipated to be more useful than the original CGI in studies of bipolar disorder.
Bipolar Disorder↗
Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients.
BACKGROUND: Therapeutic effects of the tripeptide protirelin (thyrotropin-releasing hormone) have been postulated in the affective disorders, but direct assessment in humans has been hindered by poor blood-brain barrier permeability. METHODS: Eight medication-free inpatients with refractory depression received 500 micrograms of protirelin via a lumbar intrathecal injection and an identical sham lumbar puncture procedure, separated by 1 week, in a double-blind crossover design. RESULTS: Five of eight patients responded to intrathecal protirelin, defined as a 50% or greater reduction in an abbreviated Hamilton Rating Scale for Depression score. Suicidality also was reduced significantly (P < .05). Responses were rapid and clinically robust, but short-lived. CONCLUSION: Administration of protirelin by an intrathecal route induced a rapid improvement in mood and suicidality in these refractory depressed patients, supporting the hypothesis that thyrotropin-releasing hormone could be a positive modulator of mood.
Affect↗
Algorithms for bipolar mania.
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Algorithms↗
Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder.
BACKGROUND: We compared the prophylactic efficacy of lithium, carbamazepine, and the combination and identified possible clinical markers of response. METHOD: Fifty-two outpatients who met DSM-III-R criteria for bipolar illness were randomly assigned in a double-blind design for an intended 1 year of treatment with lithium or carbamazepine, a crossover to the opposite drug in the second year, and then a third year on the combination. Patients received monthly detailed evaluations, and daily life chart ratings of the degree of functional incapacity associated with mania or depression were completed. RESULTS: For evaluable patients: 13 (31.0%) of 42 failed to complete a full year of lithium therapy owing to lack of efficacy, and 2 dropped out because of side effects; 13 (37.1%) of 35 withdrew from carbamazepine within the first year owing to lack of efficacy, and 10 dropped out because of side effects (9 of the 10 had a rash); 7 (24.1%) of 29 withdrew from the combination therapy owing to lack of efficacy. The percentage of the evaluable patients who had marked or moderate improvement on the Clinical Global Impressions scale was 33.3% on lithium. 31.4% on carbamazepine, and 55.2% on the combination treatment, which was not significantly different. By a variety of measures, lithium was more effective than carbamazepine in the prophylaxis of mania. Patients with a past history of rapid cycling did poorly on monotherapy (28.0% responded to lithium; 19.0% responded to carbamazepine), but significantly better on the combination (56.3%, p < .05). CONCLUSION: These prospective, randomized data suggest a high incidence of inadequate response to either mood stabilizer or their combination despite use of adjunctive agents as needed. Additional novel treatment regimens are needed to better decrease affective morbidity in large numbers of bipolar outpatients.
Adult↗
Alternative approaches to refractory depression in bipolar illness.
Thus, there appears to be a large variety of approaches to refractory bipolar depression. In contrast to several decades ago, wherein augmentation of lithium with antidepressants and neuroleptics was essentially the only treatment mode available, a panoply of treatment options now exist. However, their relative efficacy in different illness subtypes and stages remains to be better delineated, as do their optimal sequencing and use in combination in individual patients. It is the opinion of these authors and many of our colleagues in the field that initial use of several mood stabilizer drugs in combination may have a preferable long-term outcome in some rapid cycling patients, compared with the immediate use of a unimodal antidepressant with an inadequate single mood stabilizer, although this remains to be systematically studied. The use of thyroid augmentation strategies would appear to have merit in relationship to not only the potential treatment of lithium-related hypothyroidism, but also in augmenting antimanic and antidepressant effects. As one moves toward some of the complex combination treatment strategies discussed in this chapter, one has to be particularly careful about drug interactions and their potential for toxicity as well as therapeutic effects. Perhaps a prevailing guideline would be to use these agents more carefully in combination therapy than in monotherapy, with slow upward titration of dose to individual patients' side effects thresholds, even in preference to targeting of conventional blood level windows. In this way, side effects can be avoided during the assessment of complex combination regimens. In addition, one should be aware of potential pharmacokinetic interactions. For example, with the addition of valproate to carbamazenine, one should reduce the dose of carbamazepine, as valproate will not only increase the free fraction of carbamazepine based on displacement of protein binding, but will lead to increased accumulation of carbamazepine-10,11-epoxide. This epoxide is not measured in conventional assays but could contribute to the side effects profile (Ketter and Post, 1994). Similarly, valproate will markedly increase blood levels of lamotrigine; the starting dose of this agent should be substantially lower than conventional dosage when these two drugs are used in combination. We suggest the utility of detailed mapping with a formal system-such as the Life Chart Methodology (LCM) (Leverich and Post, 1996)-of mood fluctuation vs. medications in order to optimize and rationalize complex combination therapy. In this way, not only can the nuances of partial response be better defined, but also basic decisions about the therapeutic index and relative likelihood of response can be more readily assessed. We have discussed the other merits of the life chart method as an important clinical treatment tool as well as a research tool in other venues, but reemphasize its potential great importance in the treatment of refractory cyclic bipolar patients, in whom an initial period of remission of depression may, in many instances, be as likely attributable to the natural course of illness as the current intervention being offered. As such, it behooves the clinician to have a systematic database for the more subtle issues of dose titration and sequential addition of medications in complex combination regimens. In the face of inefficiency to one combination strategy, how one moves to the next strategy remains a highly individualized, clinically-based algorithm. We suggest the potential utility of moving towards a new set of mood stabilizers and then repeating some of the unimodal antidepressant additions and augmentation trials in an attempt to overcome refractory depression. Refractory depression in bipolar patients should be viewed as a medical emergency in light of the high potential for suicide in the illness in general (Chen and Dilsaver, 1996) and in patients who have either sustained or episodic refracto
Bipolar Disorder↗