Bipolar Disorder Research

compiled by Patty E. Fleener M.S.W.

(The Below Bipolar Disorder Research Comes From Bipolar Network News & Various Other Resources)

Last Five Years of Research Summarized

Demographic and clinical characteristics of individuals in a bipolar disorder case registry.

Family Intervention

Health Media Ltd - March 04, 2002 
It has been shown that positive intervention by families combined with medication has made a positive difference for the bipolar consumer in terms of relapse and hospitalization.

A variety of research was found but few controlled studies.

Gaba Receptor Implicated in Bipolar Disorder

Health Media Ltd - March 04, 2002 
"...the GABRA polymorphism, or other genes linked to this polymorphism, appears to contribute to bipolar affective disorder."

Genetics

378 genetic markers were examined and a linkage was found "between bipolar illness vulnerability and loci on chromosomes 15q14 and 7q11.

Lithium

Lithium: The literature was reviewed of patients taking lithium long term to patients that discontinued it. "Suicidal acts rose 22-fold, and fatalities increased 14-fold, within the first year after discontinuing the lithium." There are increased cases of goiter in 100 patients taking lithium that was related to dose and duration. This was prevented by thyroxine.

The Annals of Pharmachotheraphy
Vol. 36, No. 3, pp. 427�429.
Increased Lithium Dose Requirement in a Hyperglycemic Patient
"Glycosuria associated with hyperglycemia induces an osmotic diuresis that increases the renal clearance of lithium, necessitating higher lithium doses to maintain therapeutic lithium plasma concentrations."

Bipolar Disord 1999 Sep;1(1):5-10
Perspectives on lithium treatment of bipolar disorder: action, efficacy, effect on suicidal behavior.
Schou M.
The Psychiatric Hospital, Risskov, Denmark
In bipolar disorder the choice of prophylactic drug must be based on a weighing of efficacy against tolerability, interactions, ease of management, use during pregnancy and lactation, and expense. Lithium should be the preferred prophylactic drug in patients with typical bipolar disorder and in patients who are at high risk of committing suicide, that is, patients with severe depressions or depressions combined with persistent suicidal ideas or with suicide attempts in the past.

Antidepressants

Mood stabilizers taken with newer (second generation) antidepressants induce mania less than older antidepressants - tricyclics and MAOI.

Bupropion (Wellbutrin), sertraline (Zoloft), and venlafaxine (Effexor) are examined in consumers with the bipolar disorder who experience "break through depression," even though medicated. 

There is a moderate antidepressant response in 33% and a 12% rate of triggering mania in this study of 100 bipolars.

Buproprion (Wellbutrin) vs. Desipramine (Norpramin) were studied. The rate of cycling between mania and hypomania was significantly greater in the Desipramine group (37%). Buproprion (13%,p<0.05).

Paxil studied in a randomized, controlled six week trial. It was found to be "equally effective for depression breaking through ongoing mood stabilizer treatment as an addition of a second mood stabilizer, typically valproate to lithium, or vice versa."

"...the risk of depressive relapse for 27 bipolar patients after antidepressant discontinuation was 67% versus 39% in the 18 patients who" stayed on their antidepressants.

Wellbutrin

2001 by the Society of Biological Psychiatry
Wellbutrin "...was shown to be effective and well tolerated in decreasing the risk for relapse of depression for up to 44 weeks."

The Annals of Pharmacotherapy: Vol. 34, No. 5, pp. 619�621.
Mania with Bupropion: A Dose-Related Phenomenon?
It was questioned since this drug has less chance of triggering mania than other antidepressants if it is ok to exceed the recommended dosage of 450mg/d to treat depression resistant patients. It was shown that excess dosages triggered mania, so that excess doses should be used with caution. Apparently its efficacy is dose related.

Celexa

J Clin Psychiatry 2001 Dec;62(12):985-90
Kupfer DJ, Chengappa KN, Gelenberg AJ, Hirschfeld RM, Goldberg JF, Sachs GS, Grochocinski VJ, Houck PR, Kolar AB.
Celexa has a high response rate, and a high rate of sustained remission. It also has low side effects. This makes it a good treatment for bipolar I or bipolar II disorder. "These findings should stimulate a controlled double-blind trial to demonstrate even more clearly the usefulness of this drug in the therapeutic regimen for bipolar disorder."

Mood Stabilizers

The treatment of combining one or more mood stabilizers with an antidepressant to prevent manic episodes, needs to be explored further.

"...using the newer antidepressants earlier to supplement mood stabilizers should be considered."

New medication and combining medications can produce remarkable improvement. 

Lamotrigine (Lamictal)

Lamotrigine (Lamictal) has assisted many consumers whose illness has not responded to other treatments. (Frye et al, 2000, J Clin Psychopharmacol, in press; Calabrese et al., 1999, J Clin Psychiatry 60: 79-88). 

Proceed slowly with Lamictal to reduce risk of rash and other side effects.

Lamotrigine (Lamictal) was superior to both gabapentin and placebo in a six-week monotherapy trial for refractory patients.

437 outpatient study, double-blind, placebo-controlled; Lamotrigine is equal to desipramine and superior to placebo in unipolar depression.

Gabapentin (Neurontin)

Gabapentin (Neurontin) is helpful for residual manic and depressive symptoms, but not rapid cycling. Neurontin has better response with patients who are associated with younger age, shorter duration of illness, and lower initial body weight. Gabapentin failed to exceed placebo in an outpatient study of acute mania.

Gabapentin is not an effective medication for acute mania. Study: 10 wk., double-blind, placebo-controlled trial dosed between 900 and 3600 mg/day. Gabapentin was "not superior to the placebo for bipolar I symptoms of hypomania, mania, or mixed states."

Gabapentin has also been "effective in some anxiety disorders including social phobia and is widely used for adjunctive treatment in pain syndromes."

218 patient study of Gabapentin in the treatment of bipolar disorder shows that if it is "combined with antidepressants, neuroleptics, lithium, and other anticonvulsants, had a high rate of response in combination (69%) and in monotherapy (42%)."

The Annals of Pharmacotherapy: Vol. 35, No. 10, pp. 1264�1269.
Gabapentin Treatment for Bipolar Disorders
Ian D Maidment
Medline literature (January 1985�November 2000) was examined with the search terms "gabapentin, mood stabilizer, and bipolar disorder." From this examination it was determined that gabapentin cannot be recommended for treatment of bipolar disorder.

Bipolar Disord 1999 Sep;1(1):61-5
Altshuler LL, Keck PE Jr, McElroy SL, Suppes T, Brown ES, Denicoff K, Frye M, Gitlin M, Hwang S, Goodman R, Leverich G, Nolen W, Kupka R, Post R.
UCLA Mood Disorders Research Program, UCLA Medical Plaza, CA 90095-7057, USA
Gabapentin appears to have acute anti-manic and anti-depressant properties as an adjunctive agent for refractory bipolar illness. Prospective double-blind studies are needed to further delineate its acute efficacy when used as monotherapy and its prophylactic efficacy as monotherapy or in conjuction with other mood stabilizers.

Divalproex (Depakote)

Divalproex (Depakote) vs. Lithium were both equally effective in 43 patients. The patients that did not respond to Lithium, responded to Depakote and vice versa. "Depakote monotherapy was notably effective in treating depressive symptoms."

Topiramate (Topamax)

Topiramate (Topamax) find a 56% much or very much improved response in "16 patients after 6 weeks, four of the 16 had unpleasant sense of touch and two had word finding difficulties," in the treatment of bipolar disorder. All patients lost weight at an average of 10 pounds.

"Dr. R. McIntyre and colleagues at the Centre for Addiction and Mental Health, Toronto, compared topiramate (50-300 mg/day) to bupropion SR (Wellbutrin, 100-400 mg/day) for eight weeks as adjuncts to mood stabilizers in 26 bipolar out patients with major depression. Both bupropion SR and topiramate showed a significant reduction in depressive symptoms and were not statistically different from each other. No patients switched into a manic episode on either treatment. These preliminary results suggest that topiramate may have comparable antidepressant activity to bupropion SR, a remarkable finding if replicated."

Mexiletine (Mexitil)

Mexiletine (Mexitil) has anticonvulsant, antiarrhythmic, and analgesic properties. In a study of 13 treatment resistant bipolars at doses from 200 - 1200 mg/day had a full response in 45% of patients. Another study:  8 out of 26 patients treated with Mexiletine had a positive therapeutic effect.

ECT (Electro Convulsive Therapy)

"...low dose, right unilateral (one-sided) was ineffective in two different studies of major depression (i.e., 23% improvement or 17% improvement respectively). However, high dose right unilateral ECT was as effective as bilateral (two-sided) ECT, and bilateral ECT clearly produced more lasting amnesia and memory defects. (Sackeim et al, 2000; Arch Gen Psychiatry 57: 425-434).

rTMS and ECT are generally equally effective in "patients with nondelusional major depression.

ECT superior to patients with delusional depression than rTMS.

Bipolar Brains

Study of 10 bipolar brains during autopsy compared with "11 nonpsychiatric control subjects.

Dr. Rajkowska found decreased density of layer 3 in the dorsolateral pre-frontal cortex (Brodman's area nine), comprised of a decrease in the numbers of pyramidal cells but not other neuronal elements, a decrease in glial cell density, and an increase in glial size."

"...bipolar patients showed: 1) decreased dorsolateral prefrontal cortex NAA bilaterally; 2) decreased prefrontal white matter NAA bilaterally; and, 3) increased thalamic NAA bilaterally.

These data thus supplement a growing amount of structural imaging data suggesting alterations in size or chemistry of the prefrontal cortex, amygdala, and hippocampus in bipolar patients compared with controls."

Neuroleptics - Antipsychotics

Atypicals

J Clin Psychiatry 2001 Dec;62(12):975-80
Miller DS, Yatham LN, Lam RW.
Due to their superior effectiveness and side effect profile when compared with typical antipsychotics. atypical antipsychotics are an excellent choice as add-on therapy to mood stabilizers for the treatment of patients with mania.

Olanzapine (Zyprexa)

Olanzapine (Zyprexa) was statistically significantly superior to placebo in the treatment of rapid cycling Bipolar I patients.

Arch Gen Psychiatry 2002 Jan;59(1):62-9
Tohen M, Chengappa KN, Suppes T, Zarate CA Jr, Calabrese JR, Bowden CL, Sachs GS, Kupfer DJ, Baker RW, Risser RC, Keeter EL, Feldman PD, Tollefson GD, Breier A.
"Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes."

Bipolar Disord 2000 Sep;2(3 Pt 1):196-9
Ghaemi SN, Cherry EL, Katzow JA, Goodwin FK.
Harvard Bipolar Research Program, Massachusetts General Hospital, Consolidated Department of Psychiatry, Boston 02114, USA.
"Olanzapine appears to be moderately effective in open add-on treatment in patients with mainly depressive symptoms. Accumulating evidence suggests that olanzapine, and atypical antipsychotics in general, possess mild to moderate adjunctive antidepressant properties."

"Dr. R. Baker and co-workers from Lilly Research Laboratories and Harvard Medical School found that in two inpatient double-blind, randomized trials investigating the efficacy of olanzapine for acute mania, worsening of mania occurred more often on placebo than on olanzapine, in contrast to previous reports in open trials that olanzapine induced or exacerbated mania."

"Dr. J. Frazier from Harvard Medical School and colleagues conducted a study of olanzapine monotherapy (2.5-20 mg/day) in 23 juvenile bipolar patients (ages 5-14) with mania or mixed symptoms. Sixty-one percent of patients responded, and 22 (96%) of 23 completed the study. Clinically significant increases in weight occurred in some patients, however."

"Dr. M. Tohen of Lilly Research Laboratories and Harvard Medical School, along with colleagues from a variety of universities, performed several studies with olanzapine. A three-week, double-blind study of olanzapine (5-20 mg/day) versus valproate (500-2500 mg/day) in hospitalized manic patients showed a statistically significant greater improvement on olanzapine."

Risperidone

Risperidone Monotherapy Quickly Reduces Manic Symptoms in Bipolar Disorder 
Patients hospitalized for a manic episode due to type I bipolar disorder respond rapidly to monotherapy with the antipsychotic agent risperidone, psychiatrists reported today. The drug also relieves concurrent symptoms of depression.
Reuters Health Information 2002

Cognitive Therapy

6 month follow up showed fewer bipolar episodes, higher social functioning, and better coping strategies "compared with the control group that received treatment as usual. There was no evidence that the improvement in the therapy group was due to more medications being prescribed."

Being able to identity early stages of relapse is very effective in regards to the length of time the relapse lasts.

"To date there are six controlled studies of CBT interventions with children. All are school-based studies of children with self-reported (but not with diagnosed) depression. Five of the six support the efficacy of CBT in reducing depressive symptoms. There is considerable variation in the nature of the CBT interventions.

"There are nine controlled or comparative studies of CBT for adolescent depression, seven of which found CBT efficacious at the end of acute treatment. Most include adolescents with diagnosed depressive disorders, and only one was conducted in a school setting.

"...there is a question about whether CBT, medication, or combination treatment is more efficacious with depressed teenagers or with certain subgroups of these young people."
John F. Curry, Duke University Medical Center "Specific Psychotherapies for Childhood and Adolescent Depression"

Dermatoglyphic (study of the epidermal ridges and the pattern formed by them) Characteristics 

Med J Malaysia 2001 Jun;56(2):223-6
Chakraborty D, Mazumdar P, Than M, Singh R.
"The dermatoglyphic characteristics of subjects with bipolar mood disorder when compared with control group revealed significant differences... The radial loop were increased in bipolar mood disorder, but there were little changes in 'atd' angles between normal and bipolar mood disorder."

Women

J Clin Psychiatry 2002;63 Suppl 4:42-55
The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics.
Ernst CL, Goldberg JF.
Department of Medicine, Cambridge Hospital-Harvard Medical School, Mass, USA.
Several concerns were looked at in this study. 1) Valproate as it how it affects polycystic ovary syndrome (PCOS), 2) new psychotropic medications on pregnancy and breastfeeding. Are these medications safe? PCOS likely represents "a complex neuroendrocrine disorder with multiple determinants..." Women with bipolar disorder, even without taking psychotropic medications, frequently have "menstrual irregularities." 3) The risk of Valproate and Carbamazepine causing central nervous system damage to the fetus is substantial during the first trimester of pregnancy. 4) While it has not been definitive, olanzapine and lamotrigine safety data is the most abundant. There is much less known about other atypical antipsychotics or newer anticonvulsants in regards to the safety to the fetus. 5) In regards to breast feeding:  "substantial with lithium, are of potential concern with lamotrigine and clozapine, are quite likely minimal with valproate or carbamazepine, and are indeterminate with most other new anticonvulsants or atypical antipsychotics"

New Research

17 to 24 year olds with bipolar spectrum disorders "reported higher lifetime rates of anxiety, substance abuse, Attention Deficit-Hyperactivity Disorder (ADHD), and eating disorders in bipolar than in unipolar depressed participants. Women with bipolar disorder had higher rates of anxiety (85% vs. 41%), ADHD (18% vs. 5%), and eating disorders (15% vs. 0%) than men with bipolar disorder, but not substance abuse disorders (41% vs. 32%)."

"A recent National DMDA [Depressive and Manic-Depressive Association] survey of people with bipolar disorder indicated that the average length of time from onset of symptoms to correct diagnosis was 10 years."
Lydia Lewis, National DMDA "Unmet Needs in Diagnosis and Treatment of Mood Disorder in Children and Adolescents"

"More than 400 case reports and small trials have been reported on the treatment of bipolar children and adolescents...Positive reports have been published for lithium, divalproex, and carbamazepine; however, many reports have been based on retrospective chart reviews and small open-label studies...few placebo-controlled trials for bipolar, manic or mixed, in children and adolescents have been conducted."
Graham J. Emslie and Tarym L Mayes, University of Texas Southwestern Medical Center "Mood Disorder in Children and Adolescents: Psychopharmacological Treatment"

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The following is an excerpt of "A Five-Year Prospectus of the Stanley Foundation Bipolar Network (SFBN)" at Stanley Foundation Bipolar Network. You can get your own PDF copy there.

The last five years of research summarized:

...Treatment Findings:
8. An ongoing double-blind, randomized comparative trial of three of the newer antidepressants (bupropion [Wellbutrin�], sertraline [Zoloft�], and venlafaxine [Effexor�]) for bipolar depression (the largest comparative study to date) has already indicated a good overall efficacy and a much lower than anticipated switch rate into mania with the use of any of the three antidepressants when they are added to an ongoing mood stabilizer for the treatment of breakthrough depression.
9. The atypical antipsychotic olanzapine (Zyprexa�) was suggested to have utility in the open add-on treatment of inadequately stabilized patients with bipolar illness. These new data preceded and predicted its current status as an FDA approved drug for the treatment of mania.
10. A number of the prominent antidepressant and potential mood-stabilizing effects identified for the newly-approved anticonvulsant lamotrigine (Lamictal�) have now been replicated in double-blind controlled clinical trials in the literature and in the Stanley Foundation-supported clinical trials in the NIMH Biological Psychiatry Branch.
11. A suggestive role for gabapentin (Neurontin�) as an adjunctive treatment, but not in monotherapy, has been revealed.
12. Topiramate (Topamax�) appears to have useful adjunctive effects in patients with unstable mood cycling, but does not appear to be a useful acute antidepressant. Its prominent positive side-effects profile of inducing weight loss has now been documented in a large cohort of affectively-ill patients similar to that first noted in patients with seizure disorders.
13. An apparent lack of efficacy of the new anticonvulsant tiagabine (Gabitril�) and the potential for serious side effects, such as the occurrence of seizures in patients without a prior history of seizure disorder, has been rapidly elucidated. 
14. Placebo-controlled trials of the potential antidepressant, antimanic, and moodstabilizing effects of the specific omega-3 fatty acid EPA (eicosapentaenoic acid) are in progress with more than 50 patients randomized.
15. Protocols for a new series of clinical trials with novel agents are in place and are being reviewed by local IRBs.
16. The ongoing study and treatment of this large and well-characterized cohort of patients makes recruitment for clinical trials much more efficient and rapid than could be accomplished by usual cumbersome single-study recruitment techniques in the field. In fact, the Network strategy for following a large cohort of patients in continuous follow-up has been adopted by two large NIMH funded programs in unipolar depression (STAR*D) and in bipolar illness (the STEPBP program).
17. Based on the computerized longitudinal database we are evaluating optimal medication combination treatments based on long-term treatment outcome..."

Demographic and clinical characteristics of individuals in a bipolar disorder case registry.

Kupfer DJ, Frank E, Grochocinski VJ, Cluss PA, Houck PR, Stapf DA.

Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, PA 15213, USA. [email protected]

BACKGROUND: The goal of this analysis was to characterize a cohort of 3000 persons who self-identified as having bipolar disorder by demographic, clinical, and treatment characteristics and to document the burden that this disorder imposed on their lives. METHOD: The Stanley Center Bipolar Disorder Registry used a variety of recruitment methods to reach people with bipolar disorder. The cohort included those currently in treatment and those active in support groups. Registrants completed an interviewer-administered questionnaire to obtain information on demographic characteristics, clinical history, and treatment history. RESULTS: The median age of the 2839 patients who were analyzed was 40.1 years, 64.5% were women, and over 90% were white. The median age at onset was 17.5 years, and the mean was 19.8 years. Despite the fact that over 60% completed at least some college and 30% completed college, 64% were currently unemployed. The patients' family histories point to a high prevalence of mental disorder in the families, especially mood disorders. Patients were concurrently taking multiple medications, and more than one third were taking at least 3 types of psychotropic medications. This pattern of pharmacotherapy was consistent with participants' overall mood ratings, which demonstrated how unusual it was for them to be symptom-free over a 6-month period. CONCLUSION: Our present findings point to the chronicity and severity of bipolar disorder as experienced in the community. We still need to develop better interventions, ensure access to care consistent with current consensus guidelines, and initiate care as early as possible in the course of the condition.

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The above information is used only for educational purposes and not for profit.

"(The BNN is published four times a year by an international group of investigators working with patients with bipolar disorder to better understand the long-term course and treatment of the illness. The goal of the Network is to help develop new and more effective treatments for bipolar disorder. http://www.bipolarnews.org/.

Additional Information outside of the BNN is include above.

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