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Prophylactic treatment response in bipolar disorder: Results of a naturalistic observation study
Journal of Affective Disorders 104 (2007) 185 – 190 www.elsevier.com/locate/jad
Brief report
Prophylactic treatment response in bipolar disorder: Results of a naturalistic observation study ☆ Julie Garnham a , Alana Munro b , Claire Slaney a , Marsha MacDougall a , Michael Passmore c , Anne Duffy e , Claire O'Donovan d , Andrew Teehan a , Martin Alda e,⁎ a
e
Department of Psychiatry, Capital District Health Authority, Halifax, Canada b School of Medicine, Dalhousie University, Halifax, Canada c University of British Columbia, Vancouver, Canada d Department of Psychiatry, Dalhousie University, Halifax, Canada Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1 Received 8 May 2006; received in revised form 8 March 2007; accepted 12 March 2007 Available online 17 April 2007
Abstract Background: The objective of this study was to evaluate effectiveness of commonly used prophylactic treatments for bipolar disorder in a naturalistic setting and to explore factors associated with treatment response. Methods: We reviewed charts of 120 patients with a confirmed diagnosis of bipolar I or bipolar II disorder. The sample consisted of 37 males and 83 females, in the age range of 20 to 81 years (mean age 45 ± 14 years), treated at an outpatient psychiatry program in a teaching hospital. In contrast to controlled clinical trials, we did not exclude subjects with co-morbid conditions and/or substance abuse. Treatment outcome was evaluated using a scale for retrospective assessment of prophylactic treatment response. The scale rates the degree of improvement in the course of treatment weighted by the likelihood of response being attributable to the treatment. The inter-reliability of the assessments was good with concordance of ratings of 90% and weighted kappa of 0.8. Results: Rates of full response to individual mood stabilizers were: lithium 30%, carbamazepine 0%, valproate 13%, lamotrigine 11%, and olanzapine 25%. Lithium responders were more likely to be bipolar II, and had a typically episodic course of illness with earlier onset in comparison with non-responders. Responders to valproate had higher rates of psychosis. Limitations: Data were obtained by chart reviews. Conclusions: Less than one-third of patients treated with lithium achieved remission; the effectiveness of other treatments in this naturalistic sample was even lower. © 2007 Elsevier B.V. All rights reserved. Keywords: Bipolar disorder; Long-term treatment; Lithium; Valproate; Carbamazepine; Lamotrigine; Olanzapine
☆ Contributors: Julie Garnham designed the study and wrote the protocol; she also coordinated the study, conducted part of the data analysis and wrote the first draft of the paper. Alana Munro, Claire Slaney, Marsha MacDougall, Michael Passmore, Anne Duffy and Claire O'Donovan selected patients for the study, performed chart reviews, and assessments of the treatment response including the inter-rater reliability evaluations. Andrew Teehan was responsible for data management. Martin Alda supervised the design of the study and the data analysis and he wrote the final version of the paper. All authors contributed to and have approved the final manuscript. ⁎ Corresponding author. Tel.: +1 514 398 1781; fax: +1 514 398 4370. E-mail address: [email protected] (M. Alda).
0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.03.003
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1. Introduction Bipolar disorder is a recurrent psychiatric illness affecting approximately 1% of the general population. In order to prevent episodes of mania or depression many patients require long-term treatment. Currently, several treatment modalities are used in the acute and prophylactic management of the illness, including lithium, anticonvulsants, and antipsychotics. Varying degrees of research evidence support the efficacy of these treatments. However, even when treated, BD is considered a poor-outcome condition (Post et al., 2003). Efficacy of individual mood stabilizers has been evaluated in a number of controlled clinical trials. The most systematically studied long-term treatment for bipolar disorder has been lithium (Gnanadesikan et al., 2003). Data from numerous controlled and open clinical trials demonstrate that lithium substantially reduces illness recurrence rates (29% on lithium compared to 74% on placebo — see reviews by Davis et al. (1999) or Baldessarini and Tondo (2000)). Alternatives to lithium include anticonvulsants and antipsychotics. In the anticonvulsant group carbamazepine, lamotrigine, and valproate have all been shown beneficial in treating manic or depressive episodes, rapid cycling, and in preventing recurrences of the illness (Ketter et al., 2003; Muzina et al., 2005). Among antipsychotics the atypical group appears to hold most promise not only for mania, but also for treatment of depression and long-term prophylaxis (Yatham, 2005). Taken together, the results of clinical trials suggest that a substantial proportion of bipolar patients respond fully or partially to treatment with medications from any of the three classes described. In comparison to controlled clinical trials, effectiveness studies present a different picture, congruent with the view of negative outcome of bipolar disorder. Naturalistic follow-up studies of patients treated with lithium since the early 1980s show lower rates (23– 38%) of lithium response than previously seen in controlled and open trials (Grof, 1987; Harrow et al., 1990; Maj et al., 1998; Mander, 1986; Markar and Mander, 1989; O'Connell et al., 1991; Peselow et al., 1994; Prien et al., 1974; Rybakowski et al., 2001; Symonds and Williams, 1981), see also a review by Solomon et al. (1995). In the retrospective study conducted by Markar and Mander (1989), the efficacy of lithium prophylaxis in clinical practice was assessed in 41 patients who were prescribed prophylactic lithium after two admissions in two years or three admissions in five years. Their
morbidity was compared with that of 42 patients who were not treated with lithium. No statistically significant difference was seen between the two groups regarding annual rates of admission or the average time spent in hospital. In a naturalistic follow-up study of manic patients treated under routine clinical conditions Harrow et al. (1990) found that lithium treatment was an effective prophylaxis for a much smaller percentage than the 70% to 80% previously reported in clinical trials. Similarly, Peselow et al. (1994) reported that lithium alone offered an average 83% probability against an affective relapse after one year, 52% after 3 years, and only 37% after 5 years. Maj et al. (1998) found that only 23% of 402 patients followed in a lithium clinic over a five-year period remained episode free. Finally, Rybakowski et al. (2001) examined the frequency of excellent lithium responders defined by the total absence of affective episodes over a ten-year treatment period of lithium prophylaxis. They found that about one third of the patients who were involved in a retrospective study and entered treatment in the 1970s and 1980s met the criteria for complete response. Comparatively few naturalistic studies exist for anticonvulsants. Frankenburg et al. (1988) found that only 2 out of 8 patients treated with carbamazepine alone remained stable over a 3 to 4-year period of treatment. Similarly, Post et al. (1990) found high relapse rates, as well as the need to use additional medication in a majority of carbamazepine treated subjects. A review by Keck and McElroy (2002) also highlights the fact that incomplete response is seen in most patients. In a naturalistic retrospective chart review of 42 bipolar patients treated with oxcarbazepine, 57% derived moderate to significant benefit from this treatment, used either as monotherapy or adjunctive therapy (Ghaemi et al., 2003). Naturalistic and effectiveness studies show poorer results than efficacy studies across all areas of medicine (Guscott and Taylor, 1994). Factors that may contribute to the differences observed in response rates between controlled and naturalistic studies typically include a less restrictive diagnostic spectrum, presence of comorbid conditions, treatment refractoriness, changes in medication-prescribing practices, and variable compliance with prescribed treatment. This study has sought to examine the treatment response rates in bipolar patients treated in an outpatient clinic of a teaching hospital. With all aspects being equal, should we have expected to see differences in treatment response rates and, if so, what would account for those differences? Here we report the outcomes of long-term treatment of bipolar disorder in the ordinary clinical setting. We also explored
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Table 1 Sample characteristics and the response to individual mood stabilizers Treatment
Carbamazepine
Lamotrigine
Lithium
Olanzapine
Valproate
N (males:females) Age ± SD (years) Bipolar I:bipolar II Onset ± SD (years) Pre-treatment episodes Episodic course (%) Rapid cycling (%) Psychosis (%) Suicide attempts (%) Total response score ± SD Full responders (rate) 95% confidence interval Improvement (A) score ± SD N50% improvement 95% confidence interval
21 (9:12) 44.9 ± 9.6 15:6 30.2 ± 9.1 13.3 ± 9.6 3 (14%) 11 (52%) 7 (33%) 7 (33%) 1.86 ± 2.40 0 (0) 0–0.16 3.62 ± 3.26 8 (0.38) 0.18–0.62
19 (5:14) 43.1 ± 12.5 11:8 32.4 ± 12.1 10.7 ± 8.3 4 (21%) 9 (47%) 6 (32%) 9 (47%) 2.58 ± 2.67 2 (0.11) 0.01–0.33 5.11 ± 3.43 11 (0.58) 0.34–0.80
78 (26:52) 45.7 ± 12.9 62:16 32.3 ± 10.5 10.3 ± 8.1 33 (42%) 23 (29%) 37 (47%) 28 (36%) 3.28 ± 3.23 23 (0.30) 0.20–0.41 5.63 ± 3.10 45 (0.58) 0.46–0.69
8 (4:4) 49.6 ± 13.3 7:1 30.5 ± 11.6 14.8 ± 10.5 1 (13%) 6 (75%) 4 (50%) 6 (75%) 4.25 ± 2.60 2 (0.25) 0.03–0.65 6.75 ± 2.96 5 (0.63) 0.24–0.91
69 (20:49) 45.9 ± 15.6 49:20 35.7 ± 14.9 10.3 ± 8.2 31 (45%) 25 (36%) 27 (39%) 31 (45%) 2.28 ± 2.93 9 (0.13) 0.06–0.23 4.29 ± 3.54 29 (0.42) 0.30–0.55
whether treatment response rates to individual mood stabilizers were associated with specific clinical features. 2. Study design We conducted systematic chart reviews on all patient files selected from a general psychiatric outpatient clinic in a tertiary care teaching facility. All charts were reviewed independently in order to determine treatment response to mood stabilizing treatments. 3. Subjects We reviewed charts of all patients treated in general outpatient mental health clinics of Queen Elisabeth II Health Sciences Centre in Halifax, Nova Scotia, Canada, for bipolar I (N = 84) or bipolar II (N = 36) disorders. All diagnoses were based on DSM-IV criteria. The study population included men (N = 37) and women (N = 83) in the age range of 20 to 81 years, average age 44.6 ± 14.1 years. Refractory cases and patients with significant co-morbidity were not excluded. A total of 195 separate treatment trials met the study criteria; the treatments included carbamazepine, lithium, lamotrigine, olanzapine, and valproate. To be included, patients had to have a minimum of 6 months of treatment with one mood stabilizer in a sufficient dose; periods of treatment with two or more mood stabilizers were excluded from the evaluations. The dosage was considered adequate if, for lithium, valproate or carbamazepine, the patients' drug levels were in the therapeutic range. For lamotrigine the daily dose had to be at least 100 mg, and for olanzapine at least 5 mg.
The chart reviews followed a structured procedure. In particular, we documented the clinical course of bipolar disorder including the number, duration, and treatment of mood episodes, history of treatment, documented compliance, drug levels where applicable, and use of concomitant medication, such as antidepressants or benzodiazepines. 4. Treatment response assessment Charts of all included patients were reviewed using a scale described previously (Grof et al., 2002). It was developed specifically for retrospective evaluation of prophylactic treatment response in patients not treated according to a research protocol. The scale quantifies the degree of improvement in the course of treatment (subscale A) expressed as a composite measure of
Fig. 1. Distribution of treatment response scores for lithium and valproate.
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Table 2 Response to lithium and valproate when used as first or second treatment respectively Treatment order
Lithium first
Lithium second
Valproate first
Valproate second
Lithium–valproate
Lithium–valproate
Results reported for N Total response score ± SD Full responders (rate) 95% confidence interval Improvement (A) score ± SD N50% improvement (rate) 95% confidence interval
Lithium 71 3.30 ± 3.21 21 (0.30) 0.19–0.42 5.73 ± 3.00 42 (0.59) 0.47–0.71
Lithium 6 3.50 ± 3.89 2 (0.33) 0.04–0.78 5.00 ± 4.29 3 (0.50) 0.12–0.88
Valproate 37 1.59 ± 2.39 3 (0.08) 0.02–0.22 3.86 ± 3.08 12 (0.32) 0.18–0.50
Valproate 25 2.88 ± 3.26 4 (0.16) 0.05–0.36 4.56 ± 3.97 13 (0.52) 0.31–0.72
Lithium 22 2.14 ± 2.70 2 (0.09) 0.01–0.29 4.59 ± 3.00 9 (0.41) 0.21–0.64
Valproate 22 3.09 ± 3.35 4 (0.18) 0.05–0.40 4.82 ± 3.92 12 (0.55) 0.32–0.76
change in frequency and severity of mood symptoms. The A score is weighted by 5 factors (subscale B) which assist in determining the probability that the observed improvement is a result of the treatment rather than a spontaneous improvement or an effect of additional medication. The total score is obtained by subtracting the B score from the A score. Inter-rater reliability scores were calculated based on reviews of ten randomly selected charts by three independent reviewers. The concordance of ratings was 90% and the weighted κ was 0.8. 5. Statistical analysis We first used descriptive statistics to obtain demographic and clinical data, and the treatment results. For the treatment response scale, we report total scores, the scores on criterion A, and rates of full responders as well as rates of patients who improved. As in our previous study, full responders were defined as patients who had a total score of 7 or higher; these patients were considered in remission as defined by standard criteria such as CGI for all or most of the treatment time (Grof et al., 2002). Those with the A criterion score of 5 or higher were considered improved. The latter criterion corresponds approximately to 50% or better improvement in the course of treatment and thus can serve as a comparison with results of other published studies. For between group comparisons we used chisquare test for categorical, and Mann–Whitney test for continuous variables. Logistic and linear regressions were used to examine demographic and clinical variables associated with the response. 6. Results Demographic and clinical data as well as the average treatment response scores and response rates for individual mood stabilizers, are presented in Table 1. Only two treatments, lithium and valproate, were used frequently enough to allow more detailed analyses. The
distribution of treatment response scores for these two drugs is shown in Fig. 1. The data shows the highest rate of complete response to lithium (almost 30%). A comparably high rate of remission and highest overall score were observed for olanzapine, albeit based on a low number of patients in whom we could evaluate the treatment effect (N = 8). A potential confounder is that different drugs may be used preferentially at different stages of the illness, which might influence the treatment outcome. Therefore, we evaluated the effects of the two most commonly used drugs, lithium and valproate, subdivided by the treatment order. These results are summarized in Table 2. All analyses of these data are limited by the low number of patients treated with lithium as their second mood stabilizer. First, we compared the average total scores, A scores, and remission rates for patients treated with lithium, separately for those where lithium was used as a first and second treatment respectively. There was no significant difference for either variable (χ2 = 0.04, df = 1, p = ns for remission rates; and U = 218.5, p = ns, U = 230.5, p = ns for the total scores and the A scores respectively). We obtained similarly non-significant differences for valproate (χ2 = 0.31, df = 1, p = ns; U = 368 and U = 431.5 respectively, p = ns for each test). Thus, each of these treatments was similarly effective when used as a first or second choice. The average response score, as well as the frequency of remission, were higher for lithium than for valproate when either treatment was used as first (for remission rates χ2 = 5.30, df = 1, p = 0.02; for the total scores U = 1702.5, p = 0.009, and U = 1756.5, p = 0.004 for the A scores). When used as second treatments, lithium and valproate did not differ significantly (χ2 = 0.70, df = 1, p = ns; for average scores U = 79, p = ns, and U = 77, p = ns for the A scores). Finally, we separately analyzed those patients treated first with lithium and then switched to valproate. There were 22 such patients, two of whom remitted on lithium but were switched to valproate for
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reasons other than non-response. Out of the 20 lithium non-responders, four (20%) remitted on valproate, but the two lithium responders failed to respond to valproate. Analysis of factors associated with treatment outcome showed that full response to lithium was better in those with an episodic course of illness prior to treatment (44% responders vs. 15% in those with nonepisodic course, χ2 = 8.55, df = 1, p = 0.004), and in patients with bipolar II disorder (56% responders vs. 23% responders in the bipolar I group, χ2 = 6.93, df = 1, p = 0.009); and the full responders had earlier onset than non-responders (27.9 ± 7.8 years vs. 34.1 ± 11.0 years, U = 832.5, p = 0.03). All three variables remained significant when analyzed jointly in logistic regression. Full response to valproate was better in subjects with a history of psychotic symptoms (22% vs. 5% in patients with no such history, χ2 = 4.38, df = 1, p = 0.04). As the response rates could be influenced by a number of confounding factors, we adjusted the total response scores for lithium and valproate, the two groups with largest numbers of treated subjects, using multiple linear regression. The other treatment groups were too small to allow any detailed analyses. The independent variables included age, sex, age at onset, number of lifetime mood episodes, episodicity of the clinical course, history of rapid cycling, psychosis during mood episodes, and history of suicide attempts. The adjusted treatment response score for lithium was 3.1 ± 1.7, significantly higher than the adjusted score for valproate (2.2 ± 1.4, U = 3184.0, p b 0.001). 7. Discussion Clinical reality often tends to differ from results of controlled clinical trials and our findings support this view. Several conclusions are particularly relevant. Treatment of bipolar disorder leads to improvement in a significant proportion of patients, but most drugs rarely produce full remissions. The highest rates of full response were observed for lithium. Three drugs (olanzapine, lamotrigine, and lithium) led to comparable rates of improvement between 58% and 63%. Two commonly used mood stabilizers, valproate and carbamazepine, produced the lowest rates of response and improvement. We need to exercise caution in interpreting this data. It does not mean that one drug is ‘better’ than the other. Simply, these figures indicate how these treatments work in the hands of individual clinicians for individual patients. In naturalistic studies, treatment is not assigned randomly and thus the outcome depends not only on the efficacy of the drug, but also on other factors such as prior assumptions about
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the type of patients for whom a particular treatment is likely to be effective. Another limitation of this study is that only two treatments, lithium and valproate, were used as first line treatments frequently enough to allow testing of the treatment order and other confounders. Finally, by selecting patients treated with only one principal mood stabilizer, we could not assess effects of mood stabilizer combinations. The response rates for lithium are similar to previously published outcome studies. Baldessarini and Tondo (2000) found that 32.5% of patients treated in a specialized clinic responded fully and another third improved partially for a total of 65.6% of patients who benefited from lithium. These figures are close to the 29% and 58% observed in our data. The analysis of factors associated with treatment response confirms the previously reported relationship between the type of clinical course and the response to lithium (Grof et al., 1993). Similar to our observations, Tondo et al. (1998) noted better outcome of lithium treatment in bipolar II patients compared to bipolar I disorder. At first sight this may appear counterintuitive. Bipolar II patients frequently suffer from comorbid anxiety and substance abuse disorders, and they often have a clinical course characterized by rapid cycling, mood instability, and depression–hypomaniainterval pattern (Koukopoulos et al., 2006). Such features would predict poor response to lithium prophylaxis. However, with the broadening of the concept of bipolar spectrum and with an increasingly common diagnosis of bipolar II disorder (MacQueen et al., 2005) the response to treatment is likely to vary with the type of patients studied. In our data we noticed that 75% of bipolar I, but only 43% of bipolar II subjects received lithium. Among those bipolar II patients who were given lithium a substantial proportion had a recurrent episodic course (12 out of 16 compared to 3 out of 21 who did not receive lithium). Therefore, it seems that it was mainly bipolar II patients perceived as likely to benefit from lithium, who actually received the treatment. Only one clinical feature, namely history of psychosis, was associated with the outcome of valproate treatment. Some authors consider valproate as more effective in patients with predominantly manic symptomatology as well as atypical features such as rapid cycling or mixed episodes (Bowden, 2007). It is conceivable that such patients may have a stronger history of psychosis as well, but we were unable to test this conjecture in our data. Valproate has been successfully used as an adjunctive treatment for a variety of behavioral and mood symptoms in patients with psychotic
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disorders as well (Gobbi et al., 2006); see also Stahl (2004) for a review of possible mechanisms. These naturalistic results confirm that symptom management remains a challenging concern for clinicians who treat bipolar patients. Larger scale capture of how well patients do in day-to-day clinical practice is warranted, and interventions aimed at improving treatment response in the naturalistic setting require closer consideration. Specialized mood disorders clinics and tailored clinical services are but some of the options that might, and should be entertained. Acknowledgment We wish to thank to Ms. Caroline MacDonald for technical assistance with the study and preparation of the manuscript. The study was supported by an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD) to M. Alda. References Baldessarini, R.J., Tondo, L., 2000. Does lithium treatment still work? Evidence of stable responses over three decades. Arch. Gen. Psychiatry 57, 187–190. Bowden, C.L., 2007. Spectrum of effectiveness of valproate in neuropsychiatry. Expert Rev. Neurother. 7, 9–16. Davis, J.M., Janicak, P.G., Hogan, D.M., 1999. Mood stabilizers in the prevention of recurrent affective disorders: a meta-analysis. Acta Psychiatr. Scand. 100, 406–417. Frankenburg, F.R., Tohen, M., Cohen, B.M., Lipinski, J.F.J., 1988. Long-term response to carbamazepine: a retrospective study. J. Clin. Psychopharmacol. 8, 130–132. Ghaemi, S.N., Berv, D.A., Klugman, J., Rosenquist, K.J., Hsu, D.J., 2003. Oxcarbazepine treatment of bipolar disorder. J. Clin. Psychiatry 64, 943–945. Gnanadesikan, M., Freeman, M.P., Gelenberg, A.J., 2003. Alternatives to lithium and divalproex in the maintenance treatment of bipolar disorder. Bipolar Disord. 5, 203–216. Gobbi, G., Gaudreau, P.O., Leblanc, N., 2006. Efficacy of topiramate, valproate, and their combination on aggression/agitation behavior in patients with psychosis. J. Clin. Psychopharmacol. 26, 467–473. Grof, P., 1987. Admission rates and lithium therapy. Br. J. Psychiatry 150, 264–265. Grof, P., Alda, M., Grof, E., Fox, D., Cameron, P., 1993. The challenge of predicting response to stabilising lithium treatment. The importance of patient selection. Br. J. Psychiatry 163 (Suppl. 21), 16–19. Grof, P., Duffy, A., Cavazzoni, P., Grof, E., Garnham, J., MacDougall, M., O'Donovan, C., Alda, M., 2002. Is response to prophylactic lithium a familial trait? J. Clin. Psychiatry 63, 942–947. Guscott, R., Taylor, L., 1994. Lithium prophylaxis in recurrent affective illness: efficacy, effectiveness, and efficiency. Br. J. Psychiatry 164, 741–746. Harrow, M., Goldberg, J.F., Grossman, L.S., Meltzer, H.Y., 1990. Outcome in manic disorders. A naturalistic follow-up study. Arch. Gen. Psychiatry 48, 665–671.
Keck, P.E.J., McElroy, S.L., 2002. Carbamazepine and valproate in the maintenance treatment of bipolar disorder. J. Clin. Psychiatry 63, 13S–17S. Ketter, T.A., Wang, P.W., Becker, O.V., Nowakowska, C., Yang, Y.S., 2003. The diverse roles of anticonvulsants in bipolar disorders. Ann. Clin. Psychiatry 15, 95–108. Koukopoulos, A., Sani, G., Koukopoulos, A.E., Albert, M.J., Girardi, P., Tatarelli, R., 2006. Endogenous and exogenous cyclicity and temperament in bipolar disorder: review, new data and hypotheses. J. Affect. Disord. 96, 165–175. MacQueen, G.M., Hajek, T., Alda, M., 2005. The phenotypes of bipolar disorder: relevance for genetic investigations. Mol. Psychiatry 10, 811–826. Maj, M., Pirozzi, R., Magliano, L., Bartoli, L., 1998. Long-term outcome of lithium prophylaxis in bipolar disorder: a 5 year prospective study of 402 patients at a lithium clinic. Am. J. Psychiatry 155, 30–35. Mander, A.J., 1986. Is lithium justified after one manic episode? Acta Psychiatr. Scand. 73, 60–67. Markar, H.R., Mander, A.J., 1989. Efficacy of lithium prophylaxis in clinical practice. Br. J. Psychiatry 155, 496–500. Muzina, D.J., Elhaj, O., Gajwani, P., Gao, K., Calabrese, J.R., 2005. Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder. Acta Psychiatr. Scand. 111 (Suppl. 426), 21–28. O'Connell, R.A., Mayo, J.A., Flatow, L., Cuthbertson, B., O'Brien, B.E., 1991. Outcome of bipolar disorder on long-term treatment with lithium. Br. J. Psychiatry 159, 123–129. Peselow, E.D., Fieve, R.R., Difiglia, C., Sanfilipo, M.P., 1994. Lithium prophylaxis of bipolar Illness: the value of combination treatment. Br. J. Psychiatry 164, 208–214. Post, R.M., Leverich, G.S., Rosoff, A.S., Altshuler, L.L., 1990. Carbamazepine prophylaxis in refractory affective disorders: a focus on long-term follow-up. J. Clin. Psychopharmacol. 10, 318–327. Post, R.M., Denicoff, K.D., Leverich, G.S., Altshuler, L.L., Frye, M.A., Suppes, T.M., Rush, A.J., Keck, P.E.J., McElroy, S.L., Luckenbaugh, D.A., Pollio, C., Kupka, R., Nolen, W.A., 2003. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. J. Clin. Psychiatry 64, 680–690. Prien, R.F., Caffey, E.M., Klett, C.J., 1974. Factors associated with treatment success in lithium carbonate prophylaxis: report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group. Arch. Gen. Psychiatry 31, 189–192. Rybakowski, J.K., Chlopocka-Wozniak, M., Suwalska, A., 2001. The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disord. 3, 63–70. Solomon, D.A., Keitner, G.I., Miller, I.W., Shea, M.T., Keller, M.B., 1995. Course of illness and maintenance treatments for patients with bipolar disorder. J. Clin. Psychiatry 56, 5–13. Stahl, S.M., 2004. Anticonvulsants as mood stabilizers and adjuncts to antipsychotics: valproate, lamotrigine, carbamazepine, and oxcarbazepine and actions at voltage-gated sodium channels. J. Clin. Psychiatry 65, 738–739. Symonds, R.L., Williams, P., 1981. Lithium and the changing incidence of mania. Psychol. Med. 11, 193–196. Tondo, L., Baldessarini, R.J., Hennen, J., Floris, G., 1998. Lithium maintenance treatment of depression and mania in bipolar I and bipolar II disorders. Am. J. Psychiatry 155, 638–645. Yatham, L.N., 2005. Atypical antipsychotics for bipolar disorder. Psychiatr. Clin. North Am. 28, 325–347.
Brief report
Prophylactic treatment response in bipolar disorder: Results of a naturalistic observation study ☆ Julie Garnham a , Alana Munro b , Claire Slaney a , Marsha MacDougall a , Michael Passmore c , Anne Duffy e , Claire O'Donovan d , Andrew Teehan a , Martin Alda e,⁎ a
e
Department of Psychiatry, Capital District Health Authority, Halifax, Canada b School of Medicine, Dalhousie University, Halifax, Canada c University of British Columbia, Vancouver, Canada d Department of Psychiatry, Dalhousie University, Halifax, Canada Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1 Received 8 May 2006; received in revised form 8 March 2007; accepted 12 March 2007 Available online 17 April 2007
Abstract Background: The objective of this study was to evaluate effectiveness of commonly used prophylactic treatments for bipolar disorder in a naturalistic setting and to explore factors associated with treatment response. Methods: We reviewed charts of 120 patients with a confirmed diagnosis of bipolar I or bipolar II disorder. The sample consisted of 37 males and 83 females, in the age range of 20 to 81 years (mean age 45 ± 14 years), treated at an outpatient psychiatry program in a teaching hospital. In contrast to controlled clinical trials, we did not exclude subjects with co-morbid conditions and/or substance abuse. Treatment outcome was evaluated using a scale for retrospective assessment of prophylactic treatment response. The scale rates the degree of improvement in the course of treatment weighted by the likelihood of response being attributable to the treatment. The inter-reliability of the assessments was good with concordance of ratings of 90% and weighted kappa of 0.8. Results: Rates of full response to individual mood stabilizers were: lithium 30%, carbamazepine 0%, valproate 13%, lamotrigine 11%, and olanzapine 25%. Lithium responders were more likely to be bipolar II, and had a typically episodic course of illness with earlier onset in comparison with non-responders. Responders to valproate had higher rates of psychosis. Limitations: Data were obtained by chart reviews. Conclusions: Less than one-third of patients treated with lithium achieved remission; the effectiveness of other treatments in this naturalistic sample was even lower. © 2007 Elsevier B.V. All rights reserved. Keywords: Bipolar disorder; Long-term treatment; Lithium; Valproate; Carbamazepine; Lamotrigine; Olanzapine
☆ Contributors: Julie Garnham designed the study and wrote the protocol; she also coordinated the study, conducted part of the data analysis and wrote the first draft of the paper. Alana Munro, Claire Slaney, Marsha MacDougall, Michael Passmore, Anne Duffy and Claire O'Donovan selected patients for the study, performed chart reviews, and assessments of the treatment response including the inter-rater reliability evaluations. Andrew Teehan was responsible for data management. Martin Alda supervised the design of the study and the data analysis and he wrote the final version of the paper. All authors contributed to and have approved the final manuscript. ⁎ Corresponding author. Tel.: +1 514 398 1781; fax: +1 514 398 4370. E-mail address: [email protected] (M. Alda).
0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.03.003
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1. Introduction Bipolar disorder is a recurrent psychiatric illness affecting approximately 1% of the general population. In order to prevent episodes of mania or depression many patients require long-term treatment. Currently, several treatment modalities are used in the acute and prophylactic management of the illness, including lithium, anticonvulsants, and antipsychotics. Varying degrees of research evidence support the efficacy of these treatments. However, even when treated, BD is considered a poor-outcome condition (Post et al., 2003). Efficacy of individual mood stabilizers has been evaluated in a number of controlled clinical trials. The most systematically studied long-term treatment for bipolar disorder has been lithium (Gnanadesikan et al., 2003). Data from numerous controlled and open clinical trials demonstrate that lithium substantially reduces illness recurrence rates (29% on lithium compared to 74% on placebo — see reviews by Davis et al. (1999) or Baldessarini and Tondo (2000)). Alternatives to lithium include anticonvulsants and antipsychotics. In the anticonvulsant group carbamazepine, lamotrigine, and valproate have all been shown beneficial in treating manic or depressive episodes, rapid cycling, and in preventing recurrences of the illness (Ketter et al., 2003; Muzina et al., 2005). Among antipsychotics the atypical group appears to hold most promise not only for mania, but also for treatment of depression and long-term prophylaxis (Yatham, 2005). Taken together, the results of clinical trials suggest that a substantial proportion of bipolar patients respond fully or partially to treatment with medications from any of the three classes described. In comparison to controlled clinical trials, effectiveness studies present a different picture, congruent with the view of negative outcome of bipolar disorder. Naturalistic follow-up studies of patients treated with lithium since the early 1980s show lower rates (23– 38%) of lithium response than previously seen in controlled and open trials (Grof, 1987; Harrow et al., 1990; Maj et al., 1998; Mander, 1986; Markar and Mander, 1989; O'Connell et al., 1991; Peselow et al., 1994; Prien et al., 1974; Rybakowski et al., 2001; Symonds and Williams, 1981), see also a review by Solomon et al. (1995). In the retrospective study conducted by Markar and Mander (1989), the efficacy of lithium prophylaxis in clinical practice was assessed in 41 patients who were prescribed prophylactic lithium after two admissions in two years or three admissions in five years. Their
morbidity was compared with that of 42 patients who were not treated with lithium. No statistically significant difference was seen between the two groups regarding annual rates of admission or the average time spent in hospital. In a naturalistic follow-up study of manic patients treated under routine clinical conditions Harrow et al. (1990) found that lithium treatment was an effective prophylaxis for a much smaller percentage than the 70% to 80% previously reported in clinical trials. Similarly, Peselow et al. (1994) reported that lithium alone offered an average 83% probability against an affective relapse after one year, 52% after 3 years, and only 37% after 5 years. Maj et al. (1998) found that only 23% of 402 patients followed in a lithium clinic over a five-year period remained episode free. Finally, Rybakowski et al. (2001) examined the frequency of excellent lithium responders defined by the total absence of affective episodes over a ten-year treatment period of lithium prophylaxis. They found that about one third of the patients who were involved in a retrospective study and entered treatment in the 1970s and 1980s met the criteria for complete response. Comparatively few naturalistic studies exist for anticonvulsants. Frankenburg et al. (1988) found that only 2 out of 8 patients treated with carbamazepine alone remained stable over a 3 to 4-year period of treatment. Similarly, Post et al. (1990) found high relapse rates, as well as the need to use additional medication in a majority of carbamazepine treated subjects. A review by Keck and McElroy (2002) also highlights the fact that incomplete response is seen in most patients. In a naturalistic retrospective chart review of 42 bipolar patients treated with oxcarbazepine, 57% derived moderate to significant benefit from this treatment, used either as monotherapy or adjunctive therapy (Ghaemi et al., 2003). Naturalistic and effectiveness studies show poorer results than efficacy studies across all areas of medicine (Guscott and Taylor, 1994). Factors that may contribute to the differences observed in response rates between controlled and naturalistic studies typically include a less restrictive diagnostic spectrum, presence of comorbid conditions, treatment refractoriness, changes in medication-prescribing practices, and variable compliance with prescribed treatment. This study has sought to examine the treatment response rates in bipolar patients treated in an outpatient clinic of a teaching hospital. With all aspects being equal, should we have expected to see differences in treatment response rates and, if so, what would account for those differences? Here we report the outcomes of long-term treatment of bipolar disorder in the ordinary clinical setting. We also explored
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Table 1 Sample characteristics and the response to individual mood stabilizers Treatment
Carbamazepine
Lamotrigine
Lithium
Olanzapine
Valproate
N (males:females) Age ± SD (years) Bipolar I:bipolar II Onset ± SD (years) Pre-treatment episodes Episodic course (%) Rapid cycling (%) Psychosis (%) Suicide attempts (%) Total response score ± SD Full responders (rate) 95% confidence interval Improvement (A) score ± SD N50% improvement 95% confidence interval
21 (9:12) 44.9 ± 9.6 15:6 30.2 ± 9.1 13.3 ± 9.6 3 (14%) 11 (52%) 7 (33%) 7 (33%) 1.86 ± 2.40 0 (0) 0–0.16 3.62 ± 3.26 8 (0.38) 0.18–0.62
19 (5:14) 43.1 ± 12.5 11:8 32.4 ± 12.1 10.7 ± 8.3 4 (21%) 9 (47%) 6 (32%) 9 (47%) 2.58 ± 2.67 2 (0.11) 0.01–0.33 5.11 ± 3.43 11 (0.58) 0.34–0.80
78 (26:52) 45.7 ± 12.9 62:16 32.3 ± 10.5 10.3 ± 8.1 33 (42%) 23 (29%) 37 (47%) 28 (36%) 3.28 ± 3.23 23 (0.30) 0.20–0.41 5.63 ± 3.10 45 (0.58) 0.46–0.69
8 (4:4) 49.6 ± 13.3 7:1 30.5 ± 11.6 14.8 ± 10.5 1 (13%) 6 (75%) 4 (50%) 6 (75%) 4.25 ± 2.60 2 (0.25) 0.03–0.65 6.75 ± 2.96 5 (0.63) 0.24–0.91
69 (20:49) 45.9 ± 15.6 49:20 35.7 ± 14.9 10.3 ± 8.2 31 (45%) 25 (36%) 27 (39%) 31 (45%) 2.28 ± 2.93 9 (0.13) 0.06–0.23 4.29 ± 3.54 29 (0.42) 0.30–0.55
whether treatment response rates to individual mood stabilizers were associated with specific clinical features. 2. Study design We conducted systematic chart reviews on all patient files selected from a general psychiatric outpatient clinic in a tertiary care teaching facility. All charts were reviewed independently in order to determine treatment response to mood stabilizing treatments. 3. Subjects We reviewed charts of all patients treated in general outpatient mental health clinics of Queen Elisabeth II Health Sciences Centre in Halifax, Nova Scotia, Canada, for bipolar I (N = 84) or bipolar II (N = 36) disorders. All diagnoses were based on DSM-IV criteria. The study population included men (N = 37) and women (N = 83) in the age range of 20 to 81 years, average age 44.6 ± 14.1 years. Refractory cases and patients with significant co-morbidity were not excluded. A total of 195 separate treatment trials met the study criteria; the treatments included carbamazepine, lithium, lamotrigine, olanzapine, and valproate. To be included, patients had to have a minimum of 6 months of treatment with one mood stabilizer in a sufficient dose; periods of treatment with two or more mood stabilizers were excluded from the evaluations. The dosage was considered adequate if, for lithium, valproate or carbamazepine, the patients' drug levels were in the therapeutic range. For lamotrigine the daily dose had to be at least 100 mg, and for olanzapine at least 5 mg.
The chart reviews followed a structured procedure. In particular, we documented the clinical course of bipolar disorder including the number, duration, and treatment of mood episodes, history of treatment, documented compliance, drug levels where applicable, and use of concomitant medication, such as antidepressants or benzodiazepines. 4. Treatment response assessment Charts of all included patients were reviewed using a scale described previously (Grof et al., 2002). It was developed specifically for retrospective evaluation of prophylactic treatment response in patients not treated according to a research protocol. The scale quantifies the degree of improvement in the course of treatment (subscale A) expressed as a composite measure of
Fig. 1. Distribution of treatment response scores for lithium and valproate.
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Table 2 Response to lithium and valproate when used as first or second treatment respectively Treatment order
Lithium first
Lithium second
Valproate first
Valproate second
Lithium–valproate
Lithium–valproate
Results reported for N Total response score ± SD Full responders (rate) 95% confidence interval Improvement (A) score ± SD N50% improvement (rate) 95% confidence interval
Lithium 71 3.30 ± 3.21 21 (0.30) 0.19–0.42 5.73 ± 3.00 42 (0.59) 0.47–0.71
Lithium 6 3.50 ± 3.89 2 (0.33) 0.04–0.78 5.00 ± 4.29 3 (0.50) 0.12–0.88
Valproate 37 1.59 ± 2.39 3 (0.08) 0.02–0.22 3.86 ± 3.08 12 (0.32) 0.18–0.50
Valproate 25 2.88 ± 3.26 4 (0.16) 0.05–0.36 4.56 ± 3.97 13 (0.52) 0.31–0.72
Lithium 22 2.14 ± 2.70 2 (0.09) 0.01–0.29 4.59 ± 3.00 9 (0.41) 0.21–0.64
Valproate 22 3.09 ± 3.35 4 (0.18) 0.05–0.40 4.82 ± 3.92 12 (0.55) 0.32–0.76
change in frequency and severity of mood symptoms. The A score is weighted by 5 factors (subscale B) which assist in determining the probability that the observed improvement is a result of the treatment rather than a spontaneous improvement or an effect of additional medication. The total score is obtained by subtracting the B score from the A score. Inter-rater reliability scores were calculated based on reviews of ten randomly selected charts by three independent reviewers. The concordance of ratings was 90% and the weighted κ was 0.8. 5. Statistical analysis We first used descriptive statistics to obtain demographic and clinical data, and the treatment results. For the treatment response scale, we report total scores, the scores on criterion A, and rates of full responders as well as rates of patients who improved. As in our previous study, full responders were defined as patients who had a total score of 7 or higher; these patients were considered in remission as defined by standard criteria such as CGI for all or most of the treatment time (Grof et al., 2002). Those with the A criterion score of 5 or higher were considered improved. The latter criterion corresponds approximately to 50% or better improvement in the course of treatment and thus can serve as a comparison with results of other published studies. For between group comparisons we used chisquare test for categorical, and Mann–Whitney test for continuous variables. Logistic and linear regressions were used to examine demographic and clinical variables associated with the response. 6. Results Demographic and clinical data as well as the average treatment response scores and response rates for individual mood stabilizers, are presented in Table 1. Only two treatments, lithium and valproate, were used frequently enough to allow more detailed analyses. The
distribution of treatment response scores for these two drugs is shown in Fig. 1. The data shows the highest rate of complete response to lithium (almost 30%). A comparably high rate of remission and highest overall score were observed for olanzapine, albeit based on a low number of patients in whom we could evaluate the treatment effect (N = 8). A potential confounder is that different drugs may be used preferentially at different stages of the illness, which might influence the treatment outcome. Therefore, we evaluated the effects of the two most commonly used drugs, lithium and valproate, subdivided by the treatment order. These results are summarized in Table 2. All analyses of these data are limited by the low number of patients treated with lithium as their second mood stabilizer. First, we compared the average total scores, A scores, and remission rates for patients treated with lithium, separately for those where lithium was used as a first and second treatment respectively. There was no significant difference for either variable (χ2 = 0.04, df = 1, p = ns for remission rates; and U = 218.5, p = ns, U = 230.5, p = ns for the total scores and the A scores respectively). We obtained similarly non-significant differences for valproate (χ2 = 0.31, df = 1, p = ns; U = 368 and U = 431.5 respectively, p = ns for each test). Thus, each of these treatments was similarly effective when used as a first or second choice. The average response score, as well as the frequency of remission, were higher for lithium than for valproate when either treatment was used as first (for remission rates χ2 = 5.30, df = 1, p = 0.02; for the total scores U = 1702.5, p = 0.009, and U = 1756.5, p = 0.004 for the A scores). When used as second treatments, lithium and valproate did not differ significantly (χ2 = 0.70, df = 1, p = ns; for average scores U = 79, p = ns, and U = 77, p = ns for the A scores). Finally, we separately analyzed those patients treated first with lithium and then switched to valproate. There were 22 such patients, two of whom remitted on lithium but were switched to valproate for
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reasons other than non-response. Out of the 20 lithium non-responders, four (20%) remitted on valproate, but the two lithium responders failed to respond to valproate. Analysis of factors associated with treatment outcome showed that full response to lithium was better in those with an episodic course of illness prior to treatment (44% responders vs. 15% in those with nonepisodic course, χ2 = 8.55, df = 1, p = 0.004), and in patients with bipolar II disorder (56% responders vs. 23% responders in the bipolar I group, χ2 = 6.93, df = 1, p = 0.009); and the full responders had earlier onset than non-responders (27.9 ± 7.8 years vs. 34.1 ± 11.0 years, U = 832.5, p = 0.03). All three variables remained significant when analyzed jointly in logistic regression. Full response to valproate was better in subjects with a history of psychotic symptoms (22% vs. 5% in patients with no such history, χ2 = 4.38, df = 1, p = 0.04). As the response rates could be influenced by a number of confounding factors, we adjusted the total response scores for lithium and valproate, the two groups with largest numbers of treated subjects, using multiple linear regression. The other treatment groups were too small to allow any detailed analyses. The independent variables included age, sex, age at onset, number of lifetime mood episodes, episodicity of the clinical course, history of rapid cycling, psychosis during mood episodes, and history of suicide attempts. The adjusted treatment response score for lithium was 3.1 ± 1.7, significantly higher than the adjusted score for valproate (2.2 ± 1.4, U = 3184.0, p b 0.001). 7. Discussion Clinical reality often tends to differ from results of controlled clinical trials and our findings support this view. Several conclusions are particularly relevant. Treatment of bipolar disorder leads to improvement in a significant proportion of patients, but most drugs rarely produce full remissions. The highest rates of full response were observed for lithium. Three drugs (olanzapine, lamotrigine, and lithium) led to comparable rates of improvement between 58% and 63%. Two commonly used mood stabilizers, valproate and carbamazepine, produced the lowest rates of response and improvement. We need to exercise caution in interpreting this data. It does not mean that one drug is ‘better’ than the other. Simply, these figures indicate how these treatments work in the hands of individual clinicians for individual patients. In naturalistic studies, treatment is not assigned randomly and thus the outcome depends not only on the efficacy of the drug, but also on other factors such as prior assumptions about
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the type of patients for whom a particular treatment is likely to be effective. Another limitation of this study is that only two treatments, lithium and valproate, were used as first line treatments frequently enough to allow testing of the treatment order and other confounders. Finally, by selecting patients treated with only one principal mood stabilizer, we could not assess effects of mood stabilizer combinations. The response rates for lithium are similar to previously published outcome studies. Baldessarini and Tondo (2000) found that 32.5% of patients treated in a specialized clinic responded fully and another third improved partially for a total of 65.6% of patients who benefited from lithium. These figures are close to the 29% and 58% observed in our data. The analysis of factors associated with treatment response confirms the previously reported relationship between the type of clinical course and the response to lithium (Grof et al., 1993). Similar to our observations, Tondo et al. (1998) noted better outcome of lithium treatment in bipolar II patients compared to bipolar I disorder. At first sight this may appear counterintuitive. Bipolar II patients frequently suffer from comorbid anxiety and substance abuse disorders, and they often have a clinical course characterized by rapid cycling, mood instability, and depression–hypomaniainterval pattern (Koukopoulos et al., 2006). Such features would predict poor response to lithium prophylaxis. However, with the broadening of the concept of bipolar spectrum and with an increasingly common diagnosis of bipolar II disorder (MacQueen et al., 2005) the response to treatment is likely to vary with the type of patients studied. In our data we noticed that 75% of bipolar I, but only 43% of bipolar II subjects received lithium. Among those bipolar II patients who were given lithium a substantial proportion had a recurrent episodic course (12 out of 16 compared to 3 out of 21 who did not receive lithium). Therefore, it seems that it was mainly bipolar II patients perceived as likely to benefit from lithium, who actually received the treatment. Only one clinical feature, namely history of psychosis, was associated with the outcome of valproate treatment. Some authors consider valproate as more effective in patients with predominantly manic symptomatology as well as atypical features such as rapid cycling or mixed episodes (Bowden, 2007). It is conceivable that such patients may have a stronger history of psychosis as well, but we were unable to test this conjecture in our data. Valproate has been successfully used as an adjunctive treatment for a variety of behavioral and mood symptoms in patients with psychotic
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disorders as well (Gobbi et al., 2006); see also Stahl (2004) for a review of possible mechanisms. These naturalistic results confirm that symptom management remains a challenging concern for clinicians who treat bipolar patients. Larger scale capture of how well patients do in day-to-day clinical practice is warranted, and interventions aimed at improving treatment response in the naturalistic setting require closer consideration. Specialized mood disorders clinics and tailored clinical services are but some of the options that might, and should be entertained. Acknowledgment We wish to thank to Ms. Caroline MacDonald for technical assistance with the study and preparation of the manuscript. The study was supported by an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD) to M. Alda. References Baldessarini, R.J., Tondo, L., 2000. Does lithium treatment still work? Evidence of stable responses over three decades. Arch. Gen. Psychiatry 57, 187–190. Bowden, C.L., 2007. Spectrum of effectiveness of valproate in neuropsychiatry. Expert Rev. Neurother. 7, 9–16. Davis, J.M., Janicak, P.G., Hogan, D.M., 1999. Mood stabilizers in the prevention of recurrent affective disorders: a meta-analysis. Acta Psychiatr. Scand. 100, 406–417. Frankenburg, F.R., Tohen, M., Cohen, B.M., Lipinski, J.F.J., 1988. Long-term response to carbamazepine: a retrospective study. J. Clin. Psychopharmacol. 8, 130–132. Ghaemi, S.N., Berv, D.A., Klugman, J., Rosenquist, K.J., Hsu, D.J., 2003. Oxcarbazepine treatment of bipolar disorder. J. Clin. Psychiatry 64, 943–945. Gnanadesikan, M., Freeman, M.P., Gelenberg, A.J., 2003. Alternatives to lithium and divalproex in the maintenance treatment of bipolar disorder. Bipolar Disord. 5, 203–216. Gobbi, G., Gaudreau, P.O., Leblanc, N., 2006. Efficacy of topiramate, valproate, and their combination on aggression/agitation behavior in patients with psychosis. J. Clin. Psychopharmacol. 26, 467–473. Grof, P., 1987. Admission rates and lithium therapy. Br. J. Psychiatry 150, 264–265. Grof, P., Alda, M., Grof, E., Fox, D., Cameron, P., 1993. The challenge of predicting response to stabilising lithium treatment. The importance of patient selection. Br. J. Psychiatry 163 (Suppl. 21), 16–19. Grof, P., Duffy, A., Cavazzoni, P., Grof, E., Garnham, J., MacDougall, M., O'Donovan, C., Alda, M., 2002. Is response to prophylactic lithium a familial trait? J. Clin. Psychiatry 63, 942–947. Guscott, R., Taylor, L., 1994. Lithium prophylaxis in recurrent affective illness: efficacy, effectiveness, and efficiency. Br. J. Psychiatry 164, 741–746. Harrow, M., Goldberg, J.F., Grossman, L.S., Meltzer, H.Y., 1990. Outcome in manic disorders. A naturalistic follow-up study. Arch. Gen. Psychiatry 48, 665–671.
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