1 Biological Psychiatry Branch, National
Institute of Mental Health, Bethesda, Maryland, USA
2 HC Rümke Group
and University Medical Centre, Utrecht, The Netherlands
3 Stanley Center, Cincinnati, Ohio, USA
4 Stanley Center, University of Texas
Southwestern Medical Center, Dallas, Texas, USA
5 Stanley Center, UCLA, Los Angeles,
California, USA
6 Department of Psychiatry, University of
Munich
7 Department of Psychiatry and Psychotherapy,
University of Freiberg, Germany
Correspondence: Dr Robert M. Post, Biological Psychiatry Branch, NIMH Building 10, Room 35239, 10 Center Drive MSC 1272, Bethesda, MD 20892-1272, USA. Tel: +1 301 496 4805
Declaration of interest Support received from the Theodore and Vada Stanley Foundation.
See Paper 2, pp.
s177s183.
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ABSTRACT |
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Aims To describe the rationale and methods of the SFBN.
Method The SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates.
Results The reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilisers and 93 to omega-3 fatty acids. A number of open clinical case series have been published.
Conclusions Well-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.
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INTRODUCTION |
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RATIONALE FOR THE SFBN |
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Two of the major reasons cited as underlying the inadequate study of bipolar illness were the erroneous perception that lithium had adequately treated the illness and, more importantly, major methodological arguments about what measures and studies were optimal for this uniquely variable illness and its panoply of presentations. When prominent investigators submitted grant requests on pharmacological treatment of bipolar illness, extramural NIMH review committees would almost invariably reject them because of disagreements about optimal design and assessment methods. Similar problems are now occurring in the NIMH intramural review of work in bipolar illness. Acute studies in bipolar illness are difficult and expensive, especially given the heterogeneity of the illness and its multiple comorbidities.
These problems were further magnified in maintenance trials, and with a general lack of agreement about the best longitudinal measures for trials, NIMH-sponsored maintenance drug studies on bipolar illness virtually ceased following the study of Prien et al (1974), despite the increasing recognition of the inadequacy of existing treatment for a very large proportion of patients with the illness (Goldberg et al, 1995; Denicoff et al, 1997a). One of the few funded studies of which we are aware is the ongoing comparison of lithium v. valproate monotherapy after stabilisation on the combination in patients with rapid-cycling bipolar disorder, undertaken by Calabrese et al (2001). However, in that study only one-quarter of the candidates in the intent-to-treat analysis ever became eligible for randomisation, largely because of the poor response even to this combination of two of the most widely used drugs for bipolar illness. These data continue to reflect the need for new approaches to the illness.
Given this lack of acute and long-term controlled clinical trials, Theodore and Vada Stanley were very generous in asking what they could do to help. The idea of a research network had been generally endorsed at the 1989 and 1994 NIMH bipolar meetings, so we proceeded on this basis. The SFBN was organised so that novel clinical treatments could be explored on a case series basis, and formal trials could be conducted on a randomised basis with either open or blind methodology, using similar core assessments at different levels of rating intensity (Fig. 1). It is hoped that information gleaned at one methodological level could help inform the other (Benson & Hartz, 2000; Concato et al, 2000; Leverich et al, 2001).
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DESIGN AND METHODS OF THE SFBN |
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There are principal investigators at five core or original sites, including Dr Lori Altshuler and Dr Mark Frye (in Los Angeles); Dr John Rush and Dr Trisha Suppes (in Dallas); Dr Paul Keck and Dr Susan McElroy (in Cincinnati); Dr Kirk Denicoff and Ms Gabriele Leverich (in Bethesda); and Dr Willem Nolen and Dr Ralph Kupka (in Utrecht). In 2000, affiliated sites in Freiburg (Dr Jörg Walden) and Munich (Dr Heinz Grunze) were added, sharing common methodology and entering patients in both double-blind and open studies. European sites were included not only because of their shared interest and expertise, but also because of the early availability of some drugs for study that are not yet obtainable in the USA.
The concept of the SFBN is that studies can be conducted at all levels of the pyramidal structure as appropriate to the knowledge of a drug or phase of its development (Fig. 1). At the top of the pyramid are well-controlled studies with relatively small sample sizes where patients are studied in detail longitudinally. Each study requires separate consent and approval by local institutional review boards. At the base are open, randomised and naturalistic case series that can inform and help design studies at the higher levels (Post et al, 2000a). Patients also give written consent to participate in this ongoing evaluation and naturalistic treatment. Instead of limiting studies to the traditional randomised controlled trials in academic settings, we decided to employ the same core methodology, but at a reduced level of detail and rating intensity at level III with open randomised studies assessing only global outcomes. Open assigned drug studies are represented at level IV, and naturalistic case series and opportunistic case studies at level V.
Thus, at levels I and II we use intensive clinician and patient daily ratings from the prospective NIMH Life Chart Method (NIMH-LCM; Leverich & Post, 1996, 1998) (Fig. 2(a)). In the SFBN we follow all 500 patients with daily prospective LCM ratings, which gives us a precise measure of type, severity and frequency of mood fluctuations, and the response to treatment both immediately and in the long term. In some clinical setting, it is proposed that at level III and below patients will complete their LCM ratings themselves and then their clinicians will make use of this assessment in their global ratings. These levels are thus designed to minimise the amount of time that clinicians would need to spend on the ratings. A Clinical Global Impressions (CGI) scale as revised for bipolar illness (the CGI-BP; Spearing et al, 1997) is completed at all levels of the SFBN; at level III and below, this global outcome measure may be the only assessment that requires a physician (Fig. 2(b)).
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Reliability and validity
The initial data of the NIMH-LCM generated at the NIMH and in the SFBN
indicate good reliability and clear validity. The Hamilton Rating Scale for
Depression (Hamilton, 1960)
and the Inventory of Depressive Symptomatology (IDS; Rush et al,
1986,
1996) were highly correlated
(r=0.86 and r=0.78, respectively) with the depression scale
of the NIMH-LCM (Denicoff et al,
1997b,
2000). The Young Mania Rating
Scale (Young et al,
1978) was also highly correlated with the LCM mania rating
(r=0.66) (Denicoff et al,
2000), and a robust correlation (r=0.81 and
r=0.73) was found in the same two studies (Denicoff et al,
1997a,
2000) between the LCM average
severity of illness (combined depression and mania ratings based on the degree
of mood-related functional incapacity) and the Global Assessment of
Functioning (GAF) scale (American
Psychiatric Association, 1994). This longitudinal rating system
(Leverich & Post, 1996,
1998;
Leverich et al, 2001)
was chosen because the same measure of symptom-driven functional impairment
can be used retrospectively when the specific symptoms (required for more
detailed cross-sectional rating scales) cannot be easily remembered
(Squillace et al,
1984; Roy-Byrne et
al, 1985; Post et
al, 1988). Moreover, in contrast to the GAF, the LCM allows
dimensional assessments of mild, moderate and severe mania and depression to
be made separately.
Inadequacy of current mood stabilisers
The need for new treatment approaches for patients with bipolar disorder
was further highlighted by a recent out-patient clinic study in the Biological
Psychiatry Branch of the NIMH. Using most of the core methods noted above,
Denicoff et al
(1997a) treated
patients with lithium or carbamazepine on a blind randomised basis for 1 year,
switched to the other drug the next year, and then gave both drugs in
combination in the third year. As illustrated in
Fig. 3, counting a responder as
someone who was rated as either very much improved (essentially asymptomatic)
or much improved (with some residual symptoms) on the CGI scale, response
rates to either lithium or carbamazepine monotherapy for 1 year were less than
a third, but on the combination of both drugs in the third year, the response
rate was over 50% (Denicoff et al,
1997a).
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These data emphasise that these two widely used drugs are very often not effective either alone or in combination, even in a population recruited as out-patients in the Washington, DC area, two-thirds of whom were employed or in higher education. Thus, these data on poor outcome are not based on the highly treatment-resistant group of patients recruited and studied in our in-patient unit (Frye et al, 2000a,b). Another discouraging aspect of the former study was that it allowed short-term benzodiazepine/neuroleptic augmentation for mania and antidepressant therapy for breakthrough depression, as needed (Denicoff et al, 1997a). Thus, these traditional regimens of lithium or carbamazepine or combination treatment, even with augmentation treatments, still did not yield a high degree of efficacy. Compared with the baseline year, lithium substantially reduced the amount of time in manic phase, as did the combination of carbamazepine and lithium, but none of these treatments was notably effective on average for the overall amount of time spent in depression.
As revealed in Fig. 3, even including data from an additional year on lithium and valproate plus augmentation treatment, and a fifth year on the triple combination (lithium, carbamazepine and valproate plus augmentation), 36% of the original cohort of patients still remained inadequately responsive during any of the 5 years of treatment (Denicoff et al, 1997c). In particular, treatment of the depressive component of the illness remained more problematic than the manic component, and did not achieve an overall significant decrease in average time depressed in any of the 5 prospective years of treatment compared with the baseline year.
Double-blind comparison of bupropion, sertraline and venlafaxine
Because of these results and similar data from many other clinics in
academic centres (reviewed in Gitlin
et al, 1995; Goldberg
et al, 1995), as well as the paucity of comparative data
in bipolar depression, the first decision of the SFBN was to set up a
double-blind randomised clinical trial comparing the acute and long-term
efficacy of three of the newer antidepressant drugs with different putative
mechanisms of action bupropion (dopaminergic), sertraline
(serotonergic) and venlafaxine (serotonergic and noradrenergic) as
adjunctive treatment to previously inadequate mood stabiliser regimens,
similar to that designed by Sachs et al
(1994). Over 125 patients have
been randomised in this ongoing study. In the first 64 patients randomised to
95 acute trials in the blind study there was a 14% rate of switch into acute
mania (n=6) or hypomania (n=7) in the first 10 weeks of the
study. Another 33% have so far switched into mania or hypomania in the
intended 1-year continuation phase. Without breaking the blind, a data safety
monitoring inquiry yielded evidence that no one drug of the three was under-
or overrepresented in either rate of improvement or switch into mania.
Another important goal of the SFBN is evaluation of the profusion of medicines that are potentially either mood stabilisers or unimodal antimanic or antidepressant treatments. We hope to address the question of the optimal sequencing of these drugs for the individual patient as a function of different clinical presentations, subtypes, comorbidities and neurobiological markers.
Thus, the SFBN has a series of embedded randomised trials in which a patient who does not respond to any of the agents in the crossover phases of the first comparative antidepressant trial described above can go on to another randomised trial of, for example, lamotrigine v. tranylcypromine, a monoamine oxidase inhibitor (MAOI). This will be one of the first randomised trials comparing a potential mood stabiliser (lamotrigine) to an MAOI for refractory bipolar depression. Each of these drugs will be used adjunctively to a mood stabiliser.
Exploratory case series on novel anticonvulsants as mood
stabiliser
The SFBN also decided to examine open pilot data at level V for each of the
anticonvulsants newly approved by the Food and Drug Administration for add-on
treatment of epilepsy as potential mood stabilisers. These retrospective case
series could then inform more formal comparative trials at higher levels of
the Network. These anticonvulsants include lamotrigine
(Suppes et al, 1999),
gabapentin (Altshuler et al,
1999) and topiramate (McElroy
et al, 2000), which have shown promise in different
symptom areas as open adjuncts to previously ineffective treatments. Thus, the
SFBN has started to examine the potential effectiveness of a series of new
agents in naturalistic treatment, both for breakthrough depression and
persistent cycling. Although several of these drugs appear promising, further
controlled clinical trials are now needed
(Table 1).
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Clinical and biological correlates of treatment response
Biological correlates of clinical response are also sought. Consistent data
from more than 12 studies (reviewed in
Post et al,
2000b) indicate that people with bipolar disorder have
increased intracellular calcium in their blood elements (platelets,
neutrophils or B lymphoblasts), as originally described by Dubovsky et
al (1989). It may be
important to know which patients have increased calcium levels and whether
this will help identify those likely to respond to a calcium channel blocker
or other calcium-active treatment. Hough et al
(1999) have developed a
microassay for intracellular calcium that will allow the Network to address
this question. In another example, Frye et al
(1997) have found that a low
baseline level of somatostatin in cerebrospinal fluid is associated with
nimodipine response. This is interesting, because nimodipine is one of the few
drugs that increase the concentration of somatostatin in the cerebrospinal
fluid (Pazzaglia et al,
1995).
In addition to these types of neuro-chemical markers, brain imaging and genetic markers are also potentially useful in clinical response prediction. Initial trends from NIMH in-patient data indicate that frontal and paralimbic hypoactivity seems to be more associated with response to nimodipine (Ketter et al, 1999), gabapentin and lamotrigine (personal communication, T.A. Kimbrell et al, 1997), whereas hyperactivity, particularly in the left insula, seems to be associated with carbamazepine response (Ketter et al, 1999). Whether such measures will be useful in helping to choose the most appropriate pharmacotherapy or parameters of repeated transcranial magnetic stimulation (rTMS) in the clinic remains to be seen (Kimbrell et al, 1999; Post & Speer, 2000; Speer et al, 2000).
It is likely, however, that single nucleotide polymorphisms (SNPs) will provide information on prediction of individual treatment response and drug tolerability, even prior to their ability to identify new gene markers of illness vulnerability that will become targets for therapeutic intervention. The SFBN focus on detailed aspects of acute and long-term treatment outcome should fit well with the use of SNPs, made available by the sequencing of the human genome.
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CONCLUSION |
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Children and adolescents with very early onset of bipolar disorder are increasingly being recognised, and we hope to develop parallel assessments for this age group, using a Kiddie LCM designed to be continuous with the adult version (Leverich & Post, 1998) (Fig. 5).
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A newly launched NIMH initiative, the Systematic Treatment Enrichment Program for Bipolar Disorder (STEP-BD), aims to recruit 10 000 patients to participate in a series of open and randomised clinical trials headed by Drs G. Sachs and M. Thase. The SFBN is working in close coordination with STEP-BD to prevent overlap and to ensure maximum exploitation of new therapeutic opportunities.
Given the large number of new putative antimanic, antidepressant and mood-stablising drugs now available for study (Post et al, 1998a,b), we look forward to rapid advances in pharmacotherapy and better matching of individuals to optimal therapies. Now that several drug companies are beginning to study bipolar disorder, one can be hopeful that the proliferation of new information will rapidly improve the therapeutic outcome for patients with this potentially devastating illness.
In summary, the SFBN addresses many of the recommendations of the NIMH conferences on bipolar illness held in 1989 and 1994. Now that we have well-recognised and validated longitudinal outcome measures, such as the prospective NIMH-LCM, and a substantial number of patients in continuous longitudinal treatment and followup, we look forward to advances in the therapeutics for bipolar disorder.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: APA.
Benson, K. & Hartz, A. J. (2000) A
comparison of observational studies and randomised, controlled trials.
New England Journal of Medicine,
342, 1878
-1886.
Calabrese, J. R., Shelton, M. D., Bowden, C., et al (2001) Bipolar rapid cycling: focus on depression as its hallmark. Journal of Clinical Psychiatry (suppl.), in press.
Concato, J., Shah, N. & Horwitz, R. I.
(2000) Randomized, controlled trials, observational studies,
and a hierarchy of research designs. New England Journal of
Medicine, 342, 1887
-1892.
Denicoff, K. D., Smith-Jackson, E. E., Disney, E. R., et al (1997a) Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. Journal of Clinical Psychiatry, 58, 470 -478.
Denicoff, K. D., Smith-Jackson, E. E., Disney, E. R., et al (1997b) Preliminary evidence of the reliability and validity of the prospective life-chart methodology (LCM-p). Journal of Psychiatric Research, 31, 593 -603.[CrossRef][Medline]
Denicoff, K. D., Smith-Jackson, E. E., Bryan, L. A., et al (1997c) Valproate prophylaxis in a prospective clinical trial of refractory bipolar disorder. American Journal of Psychiatry, 154, 1456 -1458.[Abstract]
Denicoff, K. D., Leverich, G. S., Nolen, W. A., et al (2000) Validation of the prospective NIMH-Life-Chart Method (NIMH-LCMTM-p) for longitudinal assessment of bipolar illness. Psychological Medicine, 30, 1391 -1397.[CrossRef][Medline]
Dubovsky, S. L., Christiano, J., Daniell, L. C., et al (1989) Increased platelet intracellular calcium concentration in patients with bipolar affective disorders. Archives of General Psychiatry, 46, 632 -638.[Abstract]
Frye, M. A., Pazzaglia, P. J., Luckenbaugh, D., et al (1997) Baseline CSF somatostatin predictive of nimodipine treatment response (abstract). Biological Psychiatry, 41, 33S.
Frye, M. A., Ketter, T. A., Kimbrell, T. A., et al (2000a) A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. Journal of Clinical Psychopharmacology, 20, 607 -614.[CrossRef][Medline]
Frye, M. A., Ketter, T. A., Leverich, G. S., et al (2000b) The increasing polypharmacotherapy of refractory mood disorders: 22 years of study. Journal of Clinical Psychiatry, 61, 9 -15.
Gitlin, M. J., Swendsen, J., Heller, T. L., et al (1995) Relapse and impairment in bipolar disorder. American Journal of Psychiatry, 152, 1635 -1640.[Abstract]
Goldberg, J. F., Harrow, M. & Grossman, L. S. (1995) Course and outcome in bipolar affective disorder: a longitudinal follow-up. American Journal of Psychiatry, 152, 379 -384.[Abstract]
Hamilton, M. (1960) A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56 -62.
Hough, C., Lu, S. J., Davis, C. L., et al (1999) Elevated basal and thapsigargin-stimulated intracellular calcium of platelet and lymphocytes from bipolar affective disorder patients measured by a fluorometric microassay. Biological Psychiatry, 46, 247 -255.[CrossRef][Medline]
Ketter, T. A., Kimbrell, T. A., George, M. S., et al (1999) Baseline cerebral hypermetabolism associated with carbamazepine response, and hypometabolism with nimodipine response in mood disorders. Biological Psychiatry, 46, 1364 -1374.[CrossRef][Medline]
Kimbrell, T. A., Little, J. T., Dunn, R. T., et al (1999) Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism. Biological Psychiatry, 46, 1603 -1613.[CrossRef][Medline]
Kupka, R., Nolen, W., Altshuler, L., et al
(2001) The Stanley Foundation Bipolar Network. 2. Preliminary
summary of demographics, course of illness and response to novel treatments.
British Journal of Psychiatry,
178 (suppl. 41), s177
-s183.
Leverich, G. S. & Post, R. M. (1996) Life charting the course of bipolar disorder. Current Review of Mood and Anxiety Disorders, 1, 48 -61.
Leverich, G. S. & Post, R. M. (1998) Life charting of affective disorders. CNS Spectrums, 3, 21-37.
Leverich, G. S., Nolen, W. A., Rush, A. J., et al (2001) The Stanley Foundation Bipolar Treatment Outcome Network: I. Longitudinal methodology. Journal of Affective Disorders, in press.
McElroy, S. L., Frye, M., Denicoff, K., et al (1998) Olanzapine in treatment-resistant bipolar disorders. Journal of Affective Disorders, 49, 119 -122.[CrossRef][Medline]
McElroy, S. L., Suppes, T., Keck, P. E., et al (2000) Open-label adjunctive topiramate in the treatment of bipolar disorder: a clinical case series. Biological Psychiatry, 47, 1025 -1033.[CrossRef][Medline]
McElroy, S. L., Altshuler, L., Suppes, T., et al
(2001) Axis I psychiatric comorbidity and its relationship to
historical illness variables in 288 patients with bipolar disorder.
American Journal of Psychiatry,
158, 420
-426.
Pazzaglia, P. J., George, M. S., Post, R. M., et al (1995) Nimodipine increases CSF somatostatin in affectively ill patients. Neuropsychopharmacology, 13, 75-83.[CrossRef][Medline]
Post, R. M. & Speer, A. M. (2000) Speculations on the future of rTMS and related therapeutic modalities. In Transcranial Magnetic Stimulation in Neuropsychiatry (eds M. S. George & R. H. Belmaker), pp. 269-287. Washington, DC: American Psychiatric Press.
Post, R. M., Roy-Byrne, P. P. & Uhde, T. W., et al (1988) Graphic representation of the life course of illness in patients with affective disorder. American Journal of Psychiatry, 145, 844 -848.[Abstract]
Post, R. M., Frye, M. A., Leverich, G. S., et al (1998a) The role of complex combination therapy in the treatment of refractory bipolar illness. CNS Spectrums, 3, 66 -86.
Post, R. M., Frye, M. A., Denicoff, K. D., et al (1998b) Beyond lithium in the treatment of bipolar illness. Neuropsychopharmacology, 19, 206 -219.[CrossRef][Medline]
Post, R. M., Denicoff, K. D. & Leverich, G. S. (2000a) Special issues in trial design and use of placebo in bipolar illness. Biological Psychiatry, 47, 727 -732.[CrossRef][Medline]
Post, R. M., Pazzaglia, P. J., Ketter, T. A., et al (2000b) Carbamazepine and nimodipine in refractory affective illness: efficacy and mechanisms. In Pharmacotherapy for Mood, Anxiety and Cognitive Disorders (eds U. Halbreich & S. Montgomery), pp. 77-110. Washington, DC: American Psychiatric Press.
Prien, R. F. & Potter, W. Z. (1990) National Institute of Mental Health workshop on treatment of bipolar disorder. Psychopharmacology Bulletin, 26, 409 -426.[Medline]
Prien, R. F. & Rush, A. J. (1996) National Institute of Mental Health workshop report on the treatment of bipolar disorder. Biological Psychiatry, 40, 215 -220.[CrossRef][Medline]
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. Archives of General Psychiatry, 31, 189 -192.[CrossRef][Medline]
Roy-Byrne, P. P., Post, R. M., Uhde, T. W., et al (1985) The longitudinal course of recurrent affective illness: life charting data from research patients at NIMH. Acta Psychiatrica Scandinavica, 71 (suppl.), 5-34.
Rush, A. J., Giles, D. E., Schlesser, M. A., et al (1986) The Inventory for Depressive Symptomatology (IDS): preliminary findings. Psychiatry Research, 18, 65-87.[CrossRef][Medline]
Rush, A. J., Gullion, C. M., Basco, M. R., et al (1996) The Inventory of Depressive Sumptomatology (IDS): psychometric properties. Psychological Medicine, 26, 477 -486.[Medline]
Sachs, G. S., Lafer, B. & Stoll, A. L. (1994) A double-blind trial of bupropion versus desipramine for bipolar depression. Journal of Clinical Psychiatry, 55, 391 -393.
Spearing, M. K., Post, R. M., Leverich, G. S., et al (1997) Modification of the Clinical Global Impressions (CGI) scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Research, 73, 159 -171.[CrossRef][Medline]
Speer, A. M., Kimbrell, T. A., Wasserman, E. M., et al (2000) Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biological Psychiatry, 48, 1133 -1141.[CrossRef][Medline]
Squillace, K., Post, R. J., Savard, R., et al (1984) Life charting of the longitudinal course of recurrent affective illness. In Neurobiology of Mood Disorders (eds R.J. Post & J.C. Ballenger), pp. 38-59. Baltimore: Williams & Wilkins.
Stoll, A. L., Severus, E., Freeman, M. P., et al
(1999) Omega-3 fatty acids in bipolar disorder: a preliminary
double-blind, placebo-controlled trial. Archives of General
Psychiatry, 56, 407
-412.
Suppes, T., Brown, E. S., McElroy, S. L., et al (1999) Lamotrigine for the treatment of bipolar disorder: a clinical case series. Journal of Affective Disorders, 53, 95-98.[CrossRef][Medline]
Suppes, T., Leverich, G. S., Keck, P. E., et al (2001) The Stanley Foundation Bipolar Treatment Outcome Network: II. Demographics and illness characteristics of the first 261 patients. Journal of Affective Disorders, in press.
Young, R. C., Biggs, J. T., Ziegler, V. E., et al (1978) A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry, 133, 429 -435.[Abstract]