Gabapentin is an anticonvulsant that is chemically
unrelated to any other anticonvulsant or mood
regulating medication.
Gabapentin received final approval for marketing in
the USA on 30 December 1993 and is labeled only for use
as an anticonvulsant. It is also widely used to treat
individuals suffering from many kinds of pain problems,
tremors, restless legs syndrome, hot flashes associated with
menopause, and various psychiatric disorders.
Generic forms of gabapentin are available in the USA as the
manufacturer no longer has patent protection.
Gabapentin differs from other mood stabilizing drugs in two
major ways:
1. Gabapentin is sometimes effectiveness for patients
who have failed to respond to antidepressants or
mood stabilizers;
2. Gabapentin's relatively benign side-effect profile.
Gabapentin has had been successful in controlling rapid
cycling and mixed bipolar states in a few people who have not
received adequate relief from carbamazepine and/or valproate.
It also appears that gabapentin has significantly more
antianxiety and antiagitation potency than either carbamazepine
or valproate. Gabapentin also may be useful as a treatoent for
people with antipsychotic-induced tardive dyskinesia.
It is too early to be very specific about which mood disorders
are most likely to respond to treatment with gabapentin.
There are very few published reports on gabapentin's
use in psychiatry. Patients with hard-to-treat bipolar
syndromes seem to have been treated more often than patients
with "treatment-resistant" unipolar disorders, although a few
people with such hard to treat unipolar depressions have been
treated with good results. It is possible that gabapentin will
prove to be a useful treatment for people with other mood
disorders.
Gabapentin also seems to have significant activity as a way of
controlling various anxiety disorders.
The initial use of gabapentin was to treat people with
depressed, manic and mixed states that did not respond to
existing medications. Some patients are now being maintained
on gabapentin on a long term basis in an attempt to prevent
future episodes. The effectiveness of gabapentin as a
long-term prophylactic agent is currently being investigated.
Before gabapentin is prescribed the patient should
have a thorough medical evaluation, including blood
and urine tests, to rule out any medical condition,
such as thyroid disorders, that may cause or exacerbate
a mood disorder.
Gabapentin is usually started at a dose of 300 mg once a day,
usually at bed time. Every three to five days the dose is
increased. In some people a response is seen with 600 mg/day . . .
other people must increase the dose as high as 4,800 mg/day.
No interactions between gabapentin and lithium, carbamazepine
or valproate have been reported.
When used as an antidepressant or as a mood-stabilizing
agent the final dose of gabapentin is most often between
900 and 2,000. Some people require doses as high as
4,800 mg/day to achieve a good results.
As gabapentin has a half-life of about six hours it must
be administered three or four times a day,
While some people notice the antimanic and antidepressant
effects within a week or two of starting treatment, others
have to take a therapeutic amount of gabapentin for up to
a month before being aware of a significant amount of improvement.
Here is a listing of gabapentin's side effects that affected
5% or more of the 543 people taking the drug during clinical
trials and the frequency of those side effects in the 378
people treated with placebo in those trials:
The side effects most often associated with discontinuation of
gabapentin are sleepiness (1.2%), unsteadiness (0.8%),
fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness
(0.6%).
Among the rarely reported side effects of gabapentin are
depersonalization, mania, agitation, paranoia, and increased
or decreased libido.
Only a few interactions between gabapentin and other drugs
have been identified. Antacids may decrease the absorption
of gabapentin and lower the blood level of gabapentin by 20%
Gabapentin may increase the concentration of some oral
contraceptives by 13%. This probably is not clinically significant.
Alcohol may increase the severity of the side-effects of
gabapentin.
Gabapentin is has been placed in the FDA pregnancy Category C:
"Animal studies have shown an adverse effect on
the fetus but there are no adequate studies in
humans; The benefits from the use of the drug in
pregnant women may be acceptable despite its
potential risks . . . ."
Gabapentin has been used with children and young adolescents
in other countries other than the USA. In the USA gabapentin is
only approved for use in those over the age of 12.
Older people seem to handle gabapentin similarly to younger
ones. There is little experience using gabapentin for
the treatment of psychiatric disorders in the elderly.
Like other psychopharmacologic agents, gabapentin should be
discontinued gradually. Withdrawal reactions have been
occasionally treported, mostly in people who have abruptly
stopped taking large doses of gabapentin. Only when necessary
because of a serious side effect, should gabapentin be suddenly
discontinued.
Data on overdoses are scarce. Overdoses of up to 49,000 mg of
gabapentin have been survived without sequelae.
Yes, the combination has been used without any special
problems.
As of 24 February 2007, the per tablet cost of generic
gabapentin, when ordered in lots of 100 tablets from
an on-line pharmacy (drugstore.com) was:
The major use of gabapentin in psychiatry is with people
who have mood or anxiety disorders that have not been adequately
controlled by other medications.
Gabapentin seems to be effective in some people with
bipolar mood disorders that have not responded
to lithium or other mood-stabilizers. Some people who have
not been able to tolerate any antidepressant because of
switches to mania or increased speed or intensity of
cycling, or because of the development of mixed states,
have been able to tolerate therapeutic doses of anti-
depressants when taking gabapentin.
For most people, gabapentin has minimal side effects.
As gabapentin has only been available for a relatively
short time, it was first marketed in 1990, there is no
information about long term side-effects. As its use with
people with mood disorders started even more recently, it
is not known if people who initially do well on gabapentin
continue to do so after many years of treatment.
The short half-life of gabapentin makes it necessary for it to
be taken in divided doses over the course of the day.
Similar to other drugs that have the ability to reduce depression,
gabapentin can induce mania in some people with bipolar disorder.
It has been hard to demonstrate in controlled studies the
effectiveness of gabapentin as a mood control agent.
There are two major reasons why physicians prescribe and
patients take gabapentin rather than conventional,
better established drugs. They are that not everyone
benefits from treatment with the older, better known
drugs, and that some patients find the side effects of
the established drugs to be unacceptable.
Gabapentin is currently available in about 45 countries.
Here are some abstracts of published reports on the psychiatric uses
of gabapentin:
Please address additions and corrections to:
Ivan K. Goldberg, M.D.
Voice: + 212 876 7800
Email Psydoc@PsyCom.Net
Return to C O N T E N T S
FAQ: Gabapentin for Depression, Mania and Anxiety.
for the treatment of people with seizures.
There are few systematic studies that establish
the safety or efficacy of gabapentin as a treat-
ment for people with mood disorders, anxiety or
tardive dyskinesia. While such studies are in
the progress, what is currently known about
the use of gabapentin for the control of mood and
anxiety disorders and tardive dyskinesia comes
mostly from uncontrolled case reports. The few
double-blind placebo-controlled studies that have
been done to date have not demonstrated that gaba-
pentin is an effective mood stbailizer.
1.What is gabapentin (Neurontin)?
2. When was gabapentin approved for marketing in the USA and
for what indications may it be promoted?
3. Is a generic version of gabapentin available?
4. How does gabapentin differ from other mood stabilizing drugs?
5. What, if anything, uniquely distinguishes gabapentin from
carbamazepine and valproate?
6. People with what sorts of mood and/or anxiety disorders are
candidates for treatment with gabapentin?
7. Is gabapentin useful for the treatment of acute depressed,
manic and mixed states, and can it also be used to prevent future
episodes of mania and/or depression?
8. Are there any laboratory tests that should precede the start
of gabapentin therapy?
9. How is treatment with gabapentin initiated?
10. Are there any special problems prescribing gabapentin for
people taking lithium, carbamazepine (Tegretol), or valproate (Depakote)?
11. What is the usual final dose of gabapentin?
12. How long does it take for gabapentin to 'kick-in?'
13. What are the side-effects of gabapentin?
Adverse Reactions (%)
Adverse Reaction Gabapentin Placebo
Sleepiness 19 9
Dizziness 17 7
Unsteadiness 13 6
Fatigue 11 3
Nystagmus 8 4
Tremor 7 3
Double Vision 6 2
Side-effects are most noticeable the few days after an
increase in dose and then usually fade.
14. Which side-effects are severe enough to force people to
discontinue gabapentin?
15. Does gabapentin have any psychiatric side effects?
16. How does gabapentin interact with prescription and
over-the-counter medications?
17. Is there an interaction between gabapentin and alcohol?
18. Is gabapentin safe for a woman who is about to become
pregnant, pregnant or nursing an infant?
19. Is gabapentin safe for children and adolescents?
20. Can gabapentin be used in elderly people?
21. Do symptoms develop if gabapentin is suddenly discontinued?
22. Is gabapentin toxic if taken in overdose?
23. Can gabapentin be taken along with MAO inhibitors?
24. What does gabapentin cost?
300 mg - $0.67
400 mg - $0.83
600 mg - $1.00
800 mg - $1.00
25. Might gabapentin be effective in people who have failed to
receive benefit from other psychopharmacologic agents?
26. What are the advantages of gabapentin?
27. What are the disadvantages of gabapentin?
28. Why should physicians prescribe, and patients take,
gabapentin, when there are mood regulating medications that have
been available for many years and which have been shown to be
effective in double-blind placebo-controlled studies?
29. Is gabapentin available in countries other than the USA?
30. Are there any published reports on the psychiatric uses of
gabapentin?
1: J Clin Psychiatry. 2006 Mar;67(3):473-7.
A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive
gabapentin for bipolar disorder.
Vieta E, Manuel Goikolea J, Martinez-Aran A, Comes M, Verger K, Masramon X,
Sanchez-Moreno J, Colom F.
Bipolar Disorders Program, Institute of Neuroscience, Hospital Clinic,
University of Barcelona, IDIBAPS, Barcelona, Spain. evieta@clinic.ub.es
OBJECTIVE: To conduct the first randomized, controlled trial assessing the
prophylactic efficacy of gabapentin in bipolar disorder. METHOD: We conducted a
1-year, double-blind, randomized, comparative, placebo-controlled,
parallel-group, multicenter study. As this was a pure prophylactic trial, only
euthymic bipolar I and II patients (DSM-IV) were randomly assigned in a 1:1
ratio to gabapentin (N = 13) or placebo (N = 12) added to the current treatment
(lithium, valproate, carbamazepine, or any combination but not antipsychotics or
antidepressants). Subjects participated in the study for 12 months. The primary
efficacy parameter was the Clinical Global Impressions scale for Bipolar
Illness, Modified (CGI-BP-M), which was assessed at all visits. Other
assessments were the Young Mania Rating Scale (YMRS), Hamilton Rating Scale for
Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), Pittsburgh Sleep
Quality Index (PSQI), and the systematic collection of reported adverse events.
Data were collected from May 1999 to February 2004. RESULTS: The change from
baseline to month 12 in mean CGI-BP-M scores between groups was statistically
significant (p = .0046). Mean score change from baseline to endpoint in the
gabapentin group was -2.1, and the mean score change in the placebo group was
-0.6. No emerging manic or depressive symptoms were seen in either group as
measured with the YMRS, HAM-D, HAM-A, and PSQI. In the PSQI-6 subscale (use of
sleeping medication), the mean score change at month 12 in the gabapentin group
was 0.9, and the mean score change in the placebo group was 0.05 (p = .0267).
Overall, gabapentin was well tolerated. CONCLUSION: This small, randomized
clinical trial comparing the prophylactic efficacy of adjunctive gabapentin to
placebo suggests that, despite lack of acute efficacy, treatment with gabapentin
might provide some benefit on the long-term outcome of bipolar disorder.
2: Actas Esp Psiquiatr. 2006 Jan-Feb;34(1):55-64.
[Use of antiepileptic drugs in bipolar disorder]
[Article in Spanish]
Perez-Ceballos MA, Vega-Gil N, Sanchez MB, Armijo JA.
Servicio de Farmacologia Clinica, Hospital Universitario Marques de Valdecilla,
Universidad de Cantabria, Santander.
OBJECTIVE: Bipolar disorder is a chronic disease difficult to treat that
generates a high degree of incapacity. Although lithium remains the first choice
drug, some patients do not respond and others show adverse reactions. One
alternative to lithium is the use of certain antiepileptic drugs. Data on the
efficacy of old and new antiepileptic drugs in bipolar disorder obtained in
controlled clinical trials are reviewed. DEVELOPMENT: Results in many clinical
trial support the use of some old antiepileptic drugs such as carbamazepine and
sodium valproate in monotherapy in the acute treatment of severe, mixed or mild
manic episodes as well as in the management treatment of bipolar disorder.
Overall, new antiepileptic drugs show a better profile of adverse reactions with
fewer interactions than lithium, but data on their efficacy in bipolar disorder
remain scarce. Oxcarbazepine efficacy in mania is similar to that of the
carbamazepine. Lamotrigine is becoming the best alternative to lithium in
depressive episodes. Topiramate does not appear to be effective in acute
treatment of manic episodes. Levetiracetam seems to produce some benefits, but
controlled, randomized and double blind clinical trials are not yet available.
Data on gabapentin efficacy are controversial. CONCLUSIONS: Although lithium is
still the first choice for the treatment of bipolar disorder, carbamazepine and
valproate are also first choice drugs. Oxcarbazepine and lamotrigine may be a
good option in some patients. Other new antiepileptic drugs may also be
effective in bipolar disorder but more solid evidence of their efficacy is
needed.
3: Ann Pharmacother. 2006 Feb;40(2):276-85. Epub 2006 Jan 10.
Emerging treatments for bipolar disorder: safety and adverse effect profiles.
Marken PA, Pies RW.
Division of Pharmacy Practice, School of Pharmacy, University of
Missouri--Kansas City, Kansas City, MO 64108-2792, USA. markenp@umkc.edu
OBJECTIVE: To provide an overview of the safety and tolerability of newer agents
used to treat bipolar disorder (BPD) and provide clinicians with management
strategies for drug-related toxicity and adverse effects. DATA SOURCES: MEDLINE
was searched through July 2005 for BPD treatment, adverse effects, tolerability,
safety, emerging agents, atypical antipsychotics, new antiepileptic drugs
(AEDs), risperidone, quetiapine, clozapine, ziprasidone, aripiprazole,
lamotrigine, topiramate, gabapentin, oxcarbazepine, and olanzapine. STUDY
SELECTION AND DATA EXTRACTION: Results from randomized controlled trials,
open-label studies, and reviews are described. DATA SYNTHESIS: Emerging agents
recently approved for BPD include atypical antipsychotics and new AEDs. Safety
and tolerability are as important as efficacy because poor adherence in BPD
worsens outcome; metabolic and other comorbidities pose specific challenges; and
manic patients often require combination therapy, which increases adverse
effects. Most atypical antipsychotics cause fewer extrapyramidal symptoms than
conventional antipsychotics, but may cause more weight gain and metabolic
complications. The newer AEDs generally cause less weight gain than the older
agents, and some even promote weight loss. Several newer AEDs used in BPD also
offer the advantages of fewer drug interactions and less need for therapeutic
drug monitoring compared with older AEDs. CONCLUSIONS: Pending the results of
ongoing controlled studies, several emerging agents may be useful additions to
the therapeutic arsenal for BPD.
4: Harefuah. 2005 Nov;144(11):810-5, 821.
[The treatment of mood stabilizers in children and adolescents suffering from
bipolar affective disorder]
[Article in Hebrew]
Green T, Shoval G, Weizman A.
Geha Mental Health Center, Petah Tikva.
Bipolar disorder is defined as a mood disorder. It is characterized by
alteration in mood, from elation and/or irritability to depression. The
prevalence of this disorder in children and adolescents is 1%, and it disrupts
the lives of children and adolescents. The treatment of bipolar disorder
includes mood stabilizers. In contrast to the extensive literature in adult
bipolar disorder, controlled studies of lithium and anticonvulsants in the
management of mood disorders in childhood are scarce. This review summarizes
recent clinical pharmacologic studies of mood stabilizers, including lithium and
anticonvulsants in the management of bipolar disorder in children and
adolescents who suffer from this syndrome. In addition, the authors review new
anticonvulsants such as lamotrigine, gabapentin and topiramate as mood
stabilizers.
5: Bipolar Disord. 2005 Aug;7(4):307-25.
Safety and tolerability of emerging pharmacological treatments for bipolar
disorder.
Dunner DL.
Center for Anxiety and Depression, and Department of Psychiatry and Behavioral
Sciences, University of Washington School of Medicine, Seattle, WA 98105, USA.
ddunner@u.washington.edu
OBJECTIVES: Over the past few years numerous new agents have been examined for
their efficacy in bipolar disorder (BPD). New antiepileptic agents and atypical
antipsychotics currently form the bulk of these emerging agents. As the
armamentarium for treating BPD increases, it allows for the possibility of
choosing drugs on the basis of their tolerability as well as their efficacy,
rather than on efficacy alone. METHODS: Efficacy data for newer antiepileptic
drugs (lamotrigine, topiramate, gabapentin, oxcarbazepine) and atypical
antipsychotics (olanzapine, clozapine, risperidone, quetiapine, ziprasidone,
aripiprazole) are briefly reviewed. The article focuses on relative safety and
tolerability of these agents. RESULTS: In general, most of these newer agents
have better side effect and tolerability profiles than older agents commonly
used to treat BPD (lithium, valproate, carbamazepine); however, these must be
weighed against efficacy demonstrated to date in randomized, controlled trials.
Cognitive impairment is a concern with topiramate, weight gain and risk of
diabetes with some of the atypical antipsychotic agents, and rash with
lamotrigine. CONCLUSIONS: Side effects of newer emerging agents for the
treatment of BPD can be effectively managed and the risks reduced by instituting
practical strategies early in management.
6: Expert Rev Neurother. 2005 Jan;5(1):63-8.
Bipolar mixed states and their treatment.
Vieta E.
Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS,
Villarroel 170/Rossello 140, 08036, Barcelona, Spain. evieta@clinic.ub.es
Bipolar mixed states remain a nosologic dilemma, diagnostic challenge and
neglected area of therapeutic research. While the outcome of mixed states is
generally poorer than that of pure manic and depressive episodes, little is
known about how to treat such a condition. The aim of this report is to
investigate the results of clinical trials, including mixed bipolar patients, in
order to provide some hints on the efficacy of the different compounds on this
specific subpopulation. As a result of this research, it becomes clear that only
dysphoric mania has been reasonably addressed in clinical trials, and
unfortunately very little is known about the treatment of other mixed states.
There is some indirect evidence that mixed mania may be more responsive to
anticonvulsants than to lithium. Divalproate, and to a lesser extent
carbamazepine, may be used either in monotherapy or as adjuncts to lithium. Use
of other anticonvulsants, such as gabapentin, lamotrigine, levetiracetam,
oxcarbazepine, tiagabine, topiramate or zonisamide is not yet supported by
controlled data. The use of antidepressants is largely discouraged, as they may
worsen this condition. On the other hand, atypical antipsychotics may be
effective and safe either in monotherapy or in combination with lithium or
valproate. Further research is urgently needed in this neglected area of
psychiatry.
7: Acta Psychiatr Scand Suppl. 2005;(426):21-8.
Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder.
Muzina DJ, Elhaj O, Gajwani P, Gao K, Calabrese JR.
Department of Psychiatry and Psychology, Cleveland Clinic Foundation, Cleveland
Clinic Lerner College of Medicine, Case University, OH, USA. muzinad@ccf.org
OBJECTIVE: To review the clinical trials literature on the use of antiepileptic
drugs (AED) as mood stabilizers and to suggest an evidence-based approach when
utilizing these agents in bipolar disorder. METHOD: The literature is reviewed
and subdivided into the following sections: carbamazepine and oxcarbazepine,
valproate, lamotrigine, gabapentin and other AED, and discussion. RESULTS: Data
exist to support the use of carbamazepine and valproate - and to a lesser
extent, oxcarbazepine - in the management of acute manic episodes associated
with bipolar I disorder. Lamotrigine, gabapentin, and other AED have not
demonstrated consistent anti-manic effects. Clinical trials data favor
lamotrigine over all other AED in the treatment of acute bipolar I depression
and in rapid cycling bipolar disorder (particularly type II), although the
absence of an active comparator in these lamotrigine trials must be noted.
Lamotrigine, carbamazepine, and valproate all have evidence supporting their
roles as potential long-term mood stabilizers to prevent bipolar relapse, with
lamotrigine having a stronger effect in the prevention of depression.
CONCLUSION: The AED are a heterogeneous group of medications with differential
spectrum of efficacy in the treatment of bipolar disorder.
8: Rev Bras Psiquiatr. 2004 Oct;26 Suppl 3:37-43. Epub 2004 Dec 7.
[Anticonvulsants and antipsychotics in the treatment of bipolar disorder]
[Article in Portuguese]
Moreno RA, Moreno DH, Soares MB, Ratzke R.
GRUDA, Instituto de Psiquiatria, Hospital de Clinicas, Faculdade de Medicina,
Universidade de Sao Paulo. rmoreno@sti.com.br
Bipolar disorder is a complex medical condition, and up to the date there is no
single treatment with proven efficacy in the control of all aspects of the
illness. The available literature on the use of anticonvulsants (valproate,
carbamazepine, oxcarbazepine, lamotrigine, gabapentin, topiramate, clonazepam)
and atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine,
ziprasidone, and aripiprazole) for acute and prophylactic treatment of bipolar
disorder was reviewed. There is a large amount of evidence that lithium is
efficacious in the prophylaxis of episodes and better for acute mania than for
depressive episodes. Other data show that carbamazepine and valproate are
effective in acute manic episodes. Lamotrigine has been shown to reduce cycling
and effective in depressive episodes. Based on the available data, olanzapine
was found to be the most appropriate atypical antipsychotic agent for the
treatment of manic bipolar patients, although there are also studies suggesting
the efficacy of risperidone, aripiprazole and clozapine. The preliminary data
evaluating the efficacy of quetiapine and ziprasidone in bipolar disorder are
still very limited. There is no consistent information supporting the
prophylactic use of newer antipsychotics.
9: Drugs. 2004;64(19):2199-220.
Antiepileptic drugs in the treatment of anxiety disorders: role in therapy.
Van Ameringen M, Mancini C, Pipe B, Bennett M.
Department of Psychiatry and Behavioural Neurosciences, McMaster University,
Hamilton, Ontario, Canada. vanamer@mcmaster.ca
Pharmacotherapy for anxiety disorders is an active area of research. A variety
of drug groups have been shown to be effective in treating many of the anxiety
disorders, with selective serotonin reuptake inhibitors (SSRIs) being considered
first-line agents for virtually all anxiety disorders. There is a clinical need
for alternative drug treatments, as many patients do not achieve a complete
response and experience significant adverse effects. The successful use of
antiepileptic drugs in mood disorders has led clinicians and researchers to
investigate their potential efficacy in other psychiatric disorders,
particularly in anxiety disorders. There have been a number of investigations
conducted in the form of case reports, case series and open-label trials,
suggesting the potential usefulness of antiepileptic drug treatment in a variety
of anxiety disorders. More reliable evidence for the use of antiepileptic drugs
in anxiety disorders can be gleaned from recent placebo-controlled trials. Thus
far, the strongest placebo-controlled evidence has demonstrated the efficacy of
pregabalin in treating social phobia and generalised anxiety disorder, while
smaller or less robust controlled trials have suggested the potential efficacy
of gabapentin in social phobia, lamotrigine in post-traumatic stress disorder,
and valproic acid in panic disorder. Antiepileptic drugs may have a place in the
treatment of anxiety disorders; however, further investigation is warranted to
determine in what circumstances they should be used as monotherapy or as
augmenting agents in individuals who are partially or non-responsive to
conventional therapy.
10: CNS Spectr. 2004 Sep;9(9 Suppl 9):11-8.
Rethinking the treatment paradigm for bipolar depression: the importance of
long-term management.
Baldassano CF, Ballas CA, O'Reardon JP.
Department of Psychiatry, University of Pennsylvania Medical Center,
Philadelphia, PA 19104, USA. cfb@mail.med.upenn.edu
The need for long-term management of bipolar disorder is evident. Bipolar
patients spend more time depressed than manic; however, few agents used for
maintenance therapy of bipolar disorder have demonstrated good efficacy in
delaying relapse into depression. This article provides a comprehensive review
of open-label and randomized, controlled studies examining prophylactic efficacy
in bipolar disorder, especially bipolar depression. Lithium, considered the gold
standard for bipolar disorder maintenance therapy may be more effective in
delaying manic relapse than in delaying depressive relapse. Evidence for the
efficacy of divalproex and carbamazepine in delaying depressive relapse is yet
to be fully elucidated. Lamotrigine has demonstrated efficacy in delaying time
to depressive relapse. Unpublished studies show olanzapine's efficacy in
preventing manic recurrence, while its efficacy in preventing depressive
recurrence is yet to be proven. As patients with bipolar disorder are prone to
experiencing depressive episodes, more attention needs to be focused on
preventing depressive relapse. To date, three agents--lithium, lamotrigine, and
olanzapine--have been shown to have prophylactic benefits in treating this
highly recurrent disorder.
11: Acta Psychiatr Scand Suppl. 2004;(422):18-33.
New medication treatment options for bipolar disorders.
Ketter TA, Wang PW, Nowakowska C, Marsh WK.
Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, California, USA. tketter@stanford.edu
OBJECTIVE: To assess new treatment options for bipolar disorders. METHOD:
Controlled studies of new treatments for bipolar disorders were identified by
computerized searches and reviews of scientific meeting proceedings, and were
compiled by drug category. RESULTS: Two main categories of medications, newer
anticonvulsants and newer antipsychotics, are yielding emerging new treatment
options for bipolar disorders. Newer anticonvulsants have diverse psychotropic
profiles, and although not generally effective for acute mania, may have utility
for other aspects of bipolar disorders (e.g. lamotrigine for maintenance or
acute bipolar depression), or for comorbid conditions (e.g. gabapentin for
anxiety or pain, topiramate for obesity, bulimia, alcohol dependence, or
migraine, and zonisamide for obesity). In contrast, newer antipsychotics
generally appear effective for acute mania, and some may ultimately prove
effective in acute depression (e.g. olanzapine combined with fluoxetine,
quetiapine) and maintenance (e.g. olanzapine). CONCLUSION: Emerging research is
yielding new treatment options for bipolar disorders and comorbid conditions.
12: J Clin Psychiatry. 2004;65 Suppl 10:28-35.
Newer anticonvulsants in the treatment of bipolar disorder.
Yatham LN.
Division of Mood Disorders, University of British Columbia, Vancouver, British
Columbia, Canada. yatham@internchange.ubc.ca
The anticonvulsants valproate and carbamazepine have efficacy in treating acute
mania, but their efficacy in treating acute bipolar depression and preventing
mood episodes remains uncertain. Despite this, and given their utility and
widespread use, both are widely accepted as standard treatments for bipolar
disorder. All the newer anticonvulsants that have become available during the
last decade have been or are being assessed to determine their efficacy in the
treatment of various phases of bipolar disorder. Among the newer
anticonvulsants, some appear to have efficacy in treating core bipolar symptoms,
while others have efficacy in treating psychiatric comorbidity such as substance
abuse or an anxiety disorder. Lamotrigine is the most widely studied and is
effective in treating and preventing bipolar depression, and it is the only
anticonvulsant approved by the U.S. Food and Drug Administration as a
maintenance treatment for bipolar disorder. Other newer anticonvulsants,
levetiracetam, oxcarbazepine, phenytoin, and zonisamide offer promise, but
further studies are required before they can be recommended for routine use to
treat bipolar disorder. Gabapentin and topiramate do not appear to have efficacy
in treating acute mania, but their utility in bipolar depression and prevention
of mood episodes has not been studied in double-blind trials. Pregabalin has
utility in treating generalized anxiety disorder, but it has not been studied in
bipolar disorder. Given the success of lamotrigine in treating bipolar disorder,
further double-blind controlled trials of the newer anticonvulsants in treating
bipolar disorder are warranted. This article summarizes current evidence from
trials of anticonvulsants in bipolar disorder and makes recommendations for
their clinical use.
13: Int Clin Psychopharmacol. 2004 May;19(3):113-24.
A review of acute treatments for bipolar depression.
Silverstone PH, Silverstone T.
Departments of Psychiatry and Neuroscience, University of Alberta, Edmonton,
Alberta, Canada. peter.silverstone@ualberta.ca
Bipolar patients generally spend much more time in the depressed phase of their
illness than the manic phase, and there are many more bipolar type II and
bipolar spectrum disorder patients than there are bipolar type I. Additionally,
there is a significant risk of suicide in bipolar patients when depressed. The
treatment of the depressed phase of bipolar disorder is therefore a matter of
some priority. Here, we review current evidence supporting the use of five
groups of treatments: anti-depressants; lithium; anti-convulsants (valproate,
and carbamazepine, lamotrigine, gabapentin); anti-psychotics; and other
treatments (electroconvulsive therapy, benzodiazepines, sleep-deprivation, and
dopamine agonists). From this review, it is apparent that the literature
regarding the treatment of bipolar depression is significantly limited in
several key areas. Nonetheless, from the evidence currently available, the
treatments with the best evidence for efficacy are selective serotonin reuptake
inhibitors (SSRIs) and lamotrigine. There is also some evidence in favour of
bupropion and moclobemide. Although lithium and olanzapine monotherapies can
also be beneficial, they appear less efficacious than antidepressants. One of
the major concerns about treatment with antidepressants has been the risk of
precipitating a switch into mania. However, recent studies suggest that, if a
mood stabilizer and antidepressant are given concurrently, then the risk of
switching is minimized. There is also recent evidence for an independent
antidepressant action for at least one atypical antipsychotic. Therefore, the
conclusion from this review, in contrast to previous suggestions, is that a
combination of an atypical antipsychotic and either an SSRI or lamotrigine may
provide a useful first-line treatment for depressed bipolar disorder patients.
Further research is clearly required to examine this approach and compare it
with other possible treatment options.
14: CNS Spectr. 2003 Dec;8(12):930-2, 941-7.
New anticonvulsant medication uses in bipolar disorder.
Wang PW, Ketter TA, Becker OV, Nowakowska C.
Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Palo Alto, California, USA. wangp0@stanford.edu
Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy
in classic bipolar disorders whereas divalproex sodium and carbamazepine may
have broader spectrum efficacy that includes non-classic bipolar disorder. In
the last 10 years, a series of anticonvulsants have been approved for marketing
in the United States. Gabapentin has indirect g-aminobuytric acid-ergic actions,
is generally well tolerated, and appears to have anxiolytic, analgesic, and
hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally
well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000
patients). Lamotrigine is indicated for maintenance treatment in bipolar
disorder. Emerging evidence suggests lamotrigine may have utility in bipolar
disorder patients with depression and treatment-refractory rapid cycling, as
well as analgesic effects. Topiramate and zonisamide may allow both weight loss,
while topiramate may have specific efficacy in bulimia, binge eating disorder,
and alcohol dependence. Two small studies found oxcarbazepine had similar
efficacy to lithium and haloperidol in acute mania. Phenytoin, an older
anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer
anticonvulsant, may be worth exploring and has minimal drug-drug interactions.
None of these newer agents has been shown effective in a large placebo
controlled trial for acute mania. Although the clinical profiles of these newer
anticonvulsants do not appear to overlap markedly with divalproex and
carbamazepine (except perhaps for oxcarbazepine), these novel agents may still
offer important new options in relieving a variety of specific target symptoms
in patients with bipolar disorder.
15: Expert Opin Drug Saf. 2004 Jan;3(1):1-8.
Behavioural effects of the newer antiepileptic drugs: an update.
Besag FM.
Specialist Medical Department, Twinwoods Health Resource Centre, Milton Road,
Bedford, Bedfordshire MK41 6AT, UK. FBesag@aol.com
The negative and positive effects of the nine newer antiepileptic drugs that
have received a product licence in the UK or in the US are reviewed. The
importance of avoiding misinterpretation of the data because of confounding
factors such as alternative psychosis, the release phenomenon or drug
interactions is emphasised. Vigabatrin has been associated with both psychosis
and depression. Due to the concentric visual field defects that may occur with
vigabatrin, its use is now limited, although it remains the drug of choice for
infantile spasms. Lamotrigine seems to be largely associated with improvement
rather than deterioration of mood and behaviour. It may have a role in treating
affective disorder. Gabapentin probably has relatively little effect on
behaviour but may exacerbate behavioural problems in some children with
pre-existing difficulties. Topiramate may precipitate both psychosis and
depression, but these are less likely to occur if the currently recommended
lower starting doses, escalation rates and target doses are used. The data for
tiagabine are limited, but there is no clear evidence for psychosis or
depression being caused by this drug. Oxcarbazepine may be of value in treating
mood disorder, but the information is very limited. There are few reports of
behavioural disturbances with levetiracetam, but the data suggest that there is
no significant increase in psychosis or depression. There are some reports of
psychosis and other behavioural disturbances with felbamate, but the use of this
drug is limited by the serious adverse effects of hepatotoxicity and aplastic
anaemia. There is some evidence for psychosis with zonisamide, but there is also
a suggestion that this drug may be of benefit in treating psychiatric disorders.
Careful individual assessment of each patient should enable the clinician to
determine whether the medication or some other factor is responsible for any
behavioural disturbance.
16: J Manag Care Pharm. 2003 Nov-Dec;9(6):559-68.
Examination of the evidence for off-label use of gabapentin.
Mack A.
PharmD, Clinical Pharmafy Coordinator, Three Rivers Administrative Services,
Monroeville, PA 15146, USA. amack@trhp.com
OBJECTIVES: (1) Describe the relevance of off-label use of gabapentin to managed
care pharmacy; (2) summarize recent FDA warnings and media reports related to
off-label gabapentin use; (3) review medical information pertaining to the
off-label use of gabapentin; (4) outline alternatives to off-label use of
gabapentin in an evidence-based fashion, where literature exists to support such
alternatives; and (5) encourage key clinicians and decision makers in managed
care pharmacy to develop and support programs that restrict the use of
gabapentin to specific evidence-based situations. SUMMARY: Gabapentin is
approved by the U.S. Food and Drug Administration (FDA) for adjunctive therapy
in treatment of partial seizures and postherpetic neuralgia. Various off-label
(unapproved) uses have been reported, and the use of gabapentin for off-label
purposes has reportedly exceeded use for FDAapproved indications. Pharmaceutical
marketing practices and physician dissatisfaction with currently available
pharmacological treatment options may be key factors that contribute to this
prescribing trend. Recently, the media has focused on these issues, noting that
many cases of reported safety and effectiveness of gabapentin for off-label use
may have been fabricated. A thorough review of the medical and pharmacy
literature related to off-label use of gabapentin was performed, and a summary
of the literature for the following conditions is presented: bipolar disorder,
peripheral neuropathy, diabetic neuropathy, complex regional pain syndrome,
attention deficit disorder, restless legs syndrome, trigeminal neuralgia,
periodic limb movement disorder of sleep, migraine headaches, and alcohol
withdrawal syndrome. A common theme in the medical literature for gabapentin is
the prevalence of open-label studies and a lack of randomized controlled
clinical trials for all but a small number of indications. CONCLUSIONS: In the
majority of circumstances where it has reported potential for.off-label. use,
gabapentin is not the optimal treatment. The off-label use of gabapentin for
indications not approved by the FDA should be reserved for cases where there is
solid research support (e.g., diabetic neuropathy and prophylaxis of frequent
migraine headaches). Managed care pharmacists should develop programs to
restrict the use of gabapentin to these specific evidence-based situations, and
key decision makers in managed care practice should feel confident in supporting
these use restrictions for gabapentin.
17: J Pain Palliat Care Pharmacother. 2002;16(4):19-37.
Newer anticonvulsant drugs in neuropathic pain and bipolar disorder.
Chandramouli J.
Department of Pharmacy Services, University Hospitals and Clinics, Salt Lake
City, UT 84132, USA. jane.chandramouli@hsc.utah.edu
Older anticonvulsants have been used to manage both chronic pain and bipolar
disorders. As the armamentarium of anticonvulsants increases, the role of the
newer agents for pain or mood disorders is uncertain. This paper summarizes the
clinical data available with gabapentin, lamotrigine, oxcarbazepine, tiagabine
and topiramate for bipolar disorder and lamotrigine, oxcarbazepine, tiagabine
and topiramate for neuropathic pain.
18: Int J Neuropsychopharmacol. 2003 Dec;6(4):427-42.
The evidence-based pharmacological treatment of social anxiety disorder.
Blanco C, Raza MS, Schneier FR, Liebowitz MR.
Department of Psychiatry of Columbia College of Physicians and Surgeons and the
New York State Psychiatric Institute, New York, NY, USA. cb255@columbia.edu
Social anxiety disorder (SAD) is a highly prevalent and often disabling
disorder. This paper reviews the pharmacological treatment of SAD based on
published placebo-controlled studies and published meta-analyses. It addresses
three specific questions: What is the first-line treatment of SAD? How long
should treatment last? What should be the management of treatment-resistant
cases? Based on their efficacy for SAD and common comorbid disorders,
tolerability, and safety, SSRIs should be considered as the first-line treatment
for most patients. Less information is available regarding the optimal length of
treatment, although individuals who discontinue treatment after 12-20 wk appear
more likely to relapse than those who continue on medication. Even less
empirical evidence is available to support strategies for treatment-resistant
cases. Clinical experience suggests that SSRI non-responders may benefit from
augmentation with benzodiazepines or gabapentin, or from switching to MAOIs,
RIMAs, benzodiazepines or gabapentin. Cognitive-behavioural therapy may also be
a helpful adjunct or alternative.
19: Ann Clin Psychiatry. 2003 Jun;15(2):95-108.
The diverse roles of anticonvulsants in bipolar disorders.
Ketter TA, Wang PW, Becker OV, Nowakowska C, Yang YS.
Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, California 94305-5723, USA.
Anticonvulsant drugs (ACs) have diverse antiseizure, psychotropic, and
biochemical effects. Carbamazepine and valproate have mood-stabilizing actions,
benzodiazepines and gabapentin have anxiolytic actions, lamotrigine is useful in
rapid cycling and acute treatment and prophylaxis of bipolar depression, and
topiramate and zonisamide can yield weight loss. Limited controlled data suggest
the carbamazepine keto derivative oxcarbazepine has antimanic effects. A
categorical approach to the diverse roles of ACs in bipolar disorders is
proposed, using broad categories of ACs, on the basis of their predominant
psychotropic profiles. Thus, some ACs have "sedating" profiles that may include
sedation, cognitive difficulties, fatigue, weight gain, and possibly antimanic
and/or anxiolytic effects. In contrast, some newer ACs have "activating"
profiles that may include improved energy, weight loss, and possibly
antidepressant and even anxiogenic effects. Still other newer ACs have novel
"mixed" profiles, combining sedation and weight loss. A categorical-mechanistic
extension of this approach is also presented, with hypotheses that "sedating"
profiles might be related to prominent potentiation of gamma-aminobutyric acid
(GABA) inhibitory neurotransmission, "activating" profiles could be related to
prominent attenuation of glutamate excitatory neurotransmission, and for "mixed"
profiles, sedation and weight loss might be related to concurrent GABAergic and
antiglutamatergic actions, respectively. The categorical approach may have
utility as an aid to clinicians in reinforcing the heterogeneity ACs, and
recalling psychotropic profiles of individual ACs, but is limited as it fails to
address the etiology of the heterogeneity of AC psychotropic effects. The
categorical-mechanistic extension strives to address this issue, but requires
systematic clinical investigation of more precise relationships between
psychotropic profiles and discrete mechanisms of action to assess its merits.
20: Depress Anxiety. 2003;18(1):29-40.
Pharmacological treatment of social anxiety disorder: a meta-analysis.
Blanco C, Schneier FR, Schmidt A, Blanco-Jerez CR, Marshall RD, Sanchez-Lacay A,
Liebowitz MR.
Department of Psychiatry of Columbia College of Physicians and Surgeons, Madrid,
Spain. cb255@columbia.edu
Placebo-controlled trials have evaluated the efficacy of several medications in
the treatment of social anxiety disorder but information regarding their
relative efficacy is lacking. We compared the efficacy of medications
systematically studied for the treatment of social anxiety disorder using
meta-analytic techniques. The methodology included a database search of articles
published between January 1980 and June 2001 and manual searches of
bibliographies in published manuscripts. Trials were included if they reported
outcome data on the Liebowitz Social Anxiety Scale (LSAS) or a categorical
measure of responder status. Data were extracted independently by two authors.
The Q statistic was used to assess homogeneity across trials. All analyses were
conducted using intent-to-treat data. There was substantial heterogeneity across
trials. The medications with largest effect sizes were phenelzine [effect size,
1.02; 95% Confidence Interval (CI), 0.52-1.52], clonazepam (effect size, 0.97;
95% CI, 0.49-1.45), gabapentin (effect size, 0.78; 95% CI, 0.29-1.27),
brofaromine (effect size, 0.66; 95% CI, 0.38-0.94), and the selective serotonin
reuptake inhibitors (SSRIs; effect size, 0.65; 95% CI, 0.50-0.81). There were no
statistically significant differences between medications or medication groups.
However, formal methods of interim monitoring adapted for meta-analyses
suggested strongest evidence of efficacy for SSRIs and brofaromine. Several
medications are efficacious for the treatment of social anxiety disorder. The
stability of the SSRI effect size estimate in conjunction with other evidence
for safety and tolerability and their ability to treat comorbid conditions
supports the use of SSRIs as the first-line treatment. Direct comparisons of
SSRIs vs. other promising medications deserve consideration. Copyright 2003
Wiley-Liss, Inc.
21: J Psychopharmacol. 2003 Jun;17(2):184-8.
Effects of gabapentin on anxiety induced by simulated public speaking.
de-Paris F, Sant'Anna MK, Vianna MR, Barichello T, Busnello JV, Kapczinski F,
Quevedo J, Izquierdo I.
Centro de Memoria, Departamento de Bioquimica, Instituto de Ciencias Basicas da
Saude, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.
The effects of gabapentin, 400 mg and 800 mg, on anxiety induced by simulated
public speaking (SPS) were investigated. Thirty-two normal male volunteers (aged
17-30 years) had their anxiety and mood evaluated by self-scales [Visual
Analogue Mood Scale (VAMS) and Profile of Mood State (POMS)] during the SPS
procedure. Physiological measures (heart rate and blood pressure) were taken.
Treatment with gabapentin at 800 mg attenuated the anxiety of subjects that had
a decrease on the VAMS item calm-excite. In addition, volunteers that received
gabapentin at 400 mg and 800 mg showed a decrease in the hostility score in
POMS. Our results suggest, in agreement with other studies, an anxiolytic
potential to gabapentin.
22: J Affect Disord. 2003 Jun;75(1):83-91.
The clinical use of gabapentin in bipolar spectrum disorders.
Carta MG, Hardoy MC, Hardoy MJ, Grunze H, Carpiniello B.
Division of Psychiatry, Department of Public Health, University of Cagliari, Via
Liguria 13, 09127 Cagliari, Italy. mgcarta@tiscali.it
BACKGROUND: with increasing awareness of lithium's limitations, several new
anticonvulsants had been tested for their mood stabilisation during recent
years. Among the innovative third generation mood stabilizing anticonvulsants,
gabapentin (GBP) seems to have a broad spectrum of efficacy, although no certain
data are available as to its efficacy and use in clinical practice. Accordingly,
an extensive review on this subject has been carried out. METHODS: A
computer-generated search of the biomedical literature and abstract books of the
more important scientific psychiatric congresses until June 2000 was undertaken
to identify all pertinent case reports, case series and studies of GBP as
monotherapy or adjunctive therapy in mood disorders. We identified 40 open-label
studies on the use of GBP in at least 600 patients with bipolar disorder (BP),
manic, depressed, or mixed episodes and unipolar depression and four controlled
studies. RESULTS: The 40 open-label studies and two of the controlled trials
suggested that GBP may have a role as adjunctive agent in the treatment of
patients with bipolar disorders particularly when complicated by co-morbid
anxiety disorder or substance abuse. GBP is usually very well tolerated and has
no pharmacological interference with other mood stabilisers. However, in the
other two double-blind studies GBP has not been found to be efficacious in the
treatment of refractory mania or refractory bipolar depression. CONCLUSIONS:
Although failing to show clear antimanic efficacy in randomized trials,
gabapentin still remains a clinically useful agent when it comes to combination
treatment in refractory and co-morbid patients.
23: Bipolar Disord. 2003 Jun;5(3):203-16.
Alternatives to lithium and divalproex in the maintenance treatment of bipolar
disorder.
Gnanadesikan M, Freeman MP, Gelenberg AJ.
Department of Psychiatry, University of Arizona, Tuscon 85724, USA.
OBJECTIVES: The role of lithium carbonate in the maintenance treatment of
bipolar disorder is well established. Unfortunately, many patients fail to
respond adequately to this agent or are unable to tolerate its adverse effects.
Divalproex has become a commonly used alternative to lithium, but it also is
ineffective or poorly tolerated in many patients. This article attempts to
review the available data on maintenance therapy in bipolar disorder with a
variety of anticonvulsants and antipsychotics (both conventional and novel),
with reference to relevant studies in acute mania and bipolar depression as
well. METHODS: Evidence on maintenance therapy and relevant acute-phase data
were collected using MEDLINE database searches. RESULTS: Data on maintenance
therapy with agents other than lithium and divalproex are sparse, and often
derived from open, uncontrolled studies. Implications and flaws of available
data are discussed. CONCLUSIONS: Other than lithium, there are few robust
double-blind data to support the use of a variety of agents in the maintenance
phase. However, uncontrolled data suggest that a number of agents merit further
study.
24: Actas Esp Psiquiatr. 2003 May-Jun;31(3):149-55.
[Up-date in the treatment of rapid cycling and other refractory bipolar
disorders]
[Article in Spanish]
Fernandez Perez I, de Frutos MJ, Lujan E, Ortiz del Romero J.
Hospital Psiquiatrico de Madrid, Madrid, Spain. prinfresa@hotmail.com
INTRODUCTION: Up-date in the treatment of rapid cycling and other resistant
bipolar disorders. METHODS: A Medline research of the literature was performed
in several databases as Pub-Med, Cochrane and Embasse, from 1998 to December
2001. We have also reviewed bibliography supplied by different laboratories and
several monographies. RESULTS: 30 articles were selected: 11 reviews, 17
openlabeled studies and 2 articles on general recommendations. From the 17
open-labaled studies, 10 were on topiramate (25 to 400 mg/day) as a coadjuvant
of another stabilizer. Improvement ranged from 40 to 70%; 4 adding gabapentin to
the previous treatment, at the dosage of 60 to 5,600 mg/day, 27 and 92% showed
improvement; 1 with mexiletine (200 to 1,200 mg/day) in which 46% were full
responders, 15% partial responders and 38 % had no response, 100% response in
manic or mixed and 38 % in depressed patients; and 2 with lamotrigine (50 to 500
mg/day) in which 52 to 80 % showed improvement. With risperidone at the dosage
of 2-3 mg/day as coadjuvant, improvement was seen in 62 %. Olanzapine had direct
short-term antimanic effects, with 49 % improvement in single drug therapy and
57 % as coadjuvant. CONCLUSIONS: More double-blind studies are necessary to
assess efficacy in monotherapy or as coadjuvants, in short-term or even in
monotherapy, and to compare the different treatments with each other as well as
with the conventional treatment. The authors agree in pointing out the efficacy
of gabapentin and topiramate associated to another stabilizer, and also of
lamotrigine in depressed phases.
25: J Clin Psychopharmacol. 2003 Apr;23(2):182-92.
Antidepressant properties of anticonvulsant drugs for bipolar disorder.
Ernst CL, Goldberg JF.
Department of Psychiatry, Cambridge Hospital, Cambridge, Massachusetts, USA.
A growing number of anticonvulsant drugs are receiving attention as possible
mood stabilizers. This attention is based mainly on the assumption that the
antimanic efficacy of anticonvulsants makes them suitable as mood stabilizers.
However, their antidepressant properties have received less scrutiny. In this
review, current evidence concerning the acute and prophylactic efficacy of
divalproex, carbamazepine, gabapentin, lamotrigine, and topiramate in bipolar
depression is evaluated. Clinical outcome data are considered, together with
limitations of existing studies and the concept of unmet clinical needs.
Findings in placebo-controlled trials suggest an acute and prophylactic
antidepressant effect with lamotrigine monotherapy and more modest
antidepressant benefits with other agents administered as monotherapies. Results
of published studies are considered with respect to the conceptualization of
mood stabilization as arising from antimanic and antidepressant efficacy in
bipolar disorder.
26: J Affect Disord. 2002 Dec;72 Suppl 1:S15-21.
Relevance of new and newly rediscovered anticonvulsants for atypical forms of
bipolar disorder.
Grunze H, Walden J.
Department of Psychiatry, LMU, Nussbaumstr. 7, D-80336 Munich, Germany.
grunze@psy.med.uni-muenchen.de
The so-called atypical forms of bipolar disorder are not a rarity, but instead
are rather the rule. Particularly in specialized settings such as the bipolar
disorder clinic, the majority of patients are characterized by atypical
manifestations (). Mixed states, psychotic mania and a rapid cycling course of
bipolar disorder are a challenge both to pharmacological and non-pharmacological
treatment. The benefit of classical mood stabilizers such as lithium and
carbamazepine is limited in monotherapy, although valproate has a broader
spectrum of activity in atypical bipolar disorders and is often used in
combination with other agents. Thus, new treatment alternatives are needed
urgently for optimizing the treatment of atypical bipolar disorder. During the
last decade, several new antiepileptic drugs have been released, e.g.
lamotrigine, gabapentin, tiagabine, topiramate and levetiracetam. Others have
been available for some time, but only recently have become the focus of bipolar
disorder research; for example, phenytoin, and especially, oxcarbazepine. This
review will consider our current knowledge of the benefit of these new and newly
rediscovered anticonvulsants in treating bipolar disorders, with a special focus
on their value in treating atypical manifestations.
27: Bipolar Disord. 2002 Oct;4(5):296-301.
Gabapentin augmentation therapy in bipolar depression.
Wang PW, Santosa C, Schumacher M, Winsberg ME, Strong C, Ketter TA.
Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, CA 94305-5723, USA. wangp0@stanford.edu
BACKGROUND: Gabapentin (GBP) may be useful in bipolar disorders, including as
adjunctive therapy for bipolar depression, although controlled studies suggest
inefficacy as primary treatment for mania or treatment-resistant rapid cycling.
METHODS: We performed a 12-week trial of open GBP (mean dose 1725 mg/day) added
to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women,
mean age 38.4 years) depressed (28-item Hamilton Depression Rating Scale (HDRS)
> 18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness
duration was 18.6 years, current depressive episode duration was 18.0 weeks.
Prospective 28-item HDRS, Young Mania Rating Scale (YMRS) and Clinical Global
Impression-Severity (CGI-S) ratings were obtained. RESULTS: Overall, HDRS
ratings decreased 53% from 32.5 +/- 7.7 at baseline to 16.5 +/- 12.8 at week 12
(p < 0.0001). Twelve of 22 (55%) patients had moderate to marked improvement
(HDRS decrease = 50%) with HDRS decreasing 78% from 27.9 +/- 6.2 to 6.2 +/- 4.5
(p < 0.0001). Eight of 22 (36%) patients remitted (HDRS > or = 8). In
non-responders, HDRS decreased from 38.0 +/- 5.4 to 28.9 +/- 6.7 (p = 0.005).
Ten of 13 (77%) mild to moderately depressed (baseline HDRS > 18 and <35)
patients responded, while only two of nine patients (22%) with severe depression
(HDRS > or = 35) responded (p < 0.03). Both groups, however, had similar,
statistically significant HDRS decreases. GBP was well tolerated. CONCLUSION:
Open adjunctive GBP was effective and well tolerated in patients with mild to
moderate bipolar depression. This open pilot study must be viewed with caution,
and randomized controlled studies are warranted.
28: Epilepsy Res. 2002 Jun;50(1-2):195-202.
Antiepileptic drugs in psychiatry-focus on randomized controlled trial.
Muzina DJ, El-Sayegh S, Calabrese JR.
Department of Psychiatry and Psychology, Cleveland Clinic Foundation, 9500
Euclid Avenue, Cleveland, OH 44195, USA. muzinad@ccf.org
It is now clear that the class of antiepileptic drugs (AED) constitute a
heterogeneous grouping of medications with diverse medical applications. In
particular, the spectrum of psychiatric uses of these medications has grown
substantially. Valproate and carbamazepine are commonly used in the treatment of
bipolar mania, lamotrigine in bipolar depression, and gabapentin in various
anxiety disorders. Only divalproex sodium and carbamazepine have received
regulatory approval in various countries around the world. This article will
review the double-blind, placebo-controlled literature regarding the safety and
spectrum of efficacy associated with the use of the above drugs in mood and
anxiety disorders.
29: J Clin Psychiatry. 2002 Apr;63(4):275-83.
Third generation anticonvulsants in bipolar disorder: a review of efficacy and
summary of clinical recommendations.
Yatham LN, Kusumakar V, Calabrese JR, Rao R, Scarrow G, Kroeker G.
Department of Psychiatry, University of British Columbia, Vancouver, Canada.
yatham@interchange.ubc.ca
BACKGROUND: To review the literature on efficacy of third generation
anticonvulsants for treatment of bipolar disorder and provide clinical
recommendations. METHOD: Open and controlled studies, case reports, and case
series on the efficacy of lamotrigine, gabapentin, topiramate, tiagabine, and
zonisamide were located through electronic searches of several databases, by
manual search of proceedings of international meetings, and through contacting
authors of recent reports. RESULTS: Lamotrigine is the best studied
anticonvulsant and has efficacy in acute bipolar depression and in longer term
treatment of bipolar depression as well as rapid-cycling bipolar II disorder but
not in acute mania. Open reports suggest usefulness of gabapentin as an adjunct
in bipolar disorder, but double-blind trials failed to confirm efficacy in acute
mania and treatment-resistant rapid-cycling bipolar disorder. Topiramate is
reported to be effective in acute mania and rapid-cycling bipolar disorder in
several open studies, but methodological problems in a double-blind study led to
a failed study in acute mania. However, topiramate may lead to weight loss in
some patients. Zonisamide deserves further investigation, but tiagabine does not
appear to be useful in acute mania. CONCLUSION: Lamotrigine clearly fills an
unmet need in treating bipolar depression and rapid-cycling bipolar disorder.
Other third generation anticonvulsants with the exception of tiagabine offer
promise but require confirmation of their efficacy from double-blind studies.
30: J Affect Disord. 2002 Feb;68(1):1-23.
The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and
treatment issues.
Freeman MP, Freeman SA, McElroy SL.
University of Cincinnati College of Medicine, Biological Psychiatry Program,
Department of Psychiatry, P.O. Box 670559, 231 Bethesda Avenue, Cincinnati, OH
45267-0559, USA. marlenef@email.arizona.edu
BACKGROUND: Although symptoms of anxiety as well as anxiety disorders commonly
occur in patients with bipolar disorder, the pathophysiologic, theoretical, and
clinical significance of their co-occurrence has not been well studied. METHODS:
The epidemiological and clinical studies that have assessed the overlap of
bipolar and anxiety disorders are reviewed, with focus on panic disorder and
obsessive-compulsive disorder (OCD), and to a lesser extent, social phobia and
post-traumatic stress disorder. Potential neural mechanism and treatment
response data are also reviewed. RESULTS: A growing number of epidemiological
studies have found that bipolar disorder significantly co-occurs with anxiety
disorders at rates that are higher than those in the general population.
Clinical studies have also demonstrated high comorbidity between bipolar
disorder and panic disorder, OCD, social phobia, and post-traumatic stress
disorder. Psychobiological mechanisms that may account for these high
comorbidity rates likely involve a complicated interplay among various
neurotransmitter systems, particularly norepinephrine, dopamine,
gamma-aminobutyric acid (GABA), and serotonin. The second-messenger system
constituent, inositol, may also be involved. Little controlled data are
available regarding the treatment of bipolar disorder complicated by an anxiety
disorder. However, adequate mood stabilization should be achieved before
antidepressants are used to treat residual anxiety symptoms so as to minimize
antidepressant-induced mania or cycling. Moreover, preliminary data suggesting
that certain antimanic agents may have anxiolytic properties (e.g. valproate and
possibly antipsychotics), and that some anxiolytics may not induce mania (e.g.
gabapentin and benzodiazepines other than alprazolam) indicate that these agents
may be particularly useful for anxious bipolar patients. CONCLUSIONS: Comorbid
anxiety symptoms and disorders must be considered when diagnosing and treating
patients with bipolar disorder. Conversely, patients presenting with anxiety
disorders must be assessed for comorbid mood disorders, including bipolar
disorder. Pathophysiological, theoretical, and clinical implications of the
overlap of bipolar and anxiety disorders are discussed.
31: Biol Psychiatry. 2002 Jan 1;51(1):109-20.
Pharmacotherapy of social anxiety disorder.
Blanco C, Antia SX, Liebowitz MR.
Department of Psychiatry, Columbia College of Physicians and Surgeons, 1051
Riverside Drive, New York, NY 10032, USA.
Over the last few years, a number of medications have demonstrated their
efficacy in the acute treatment of social anxiety disorder. At present,
selective serotonin reuptake inhibitors probably constitute the first line
treatment, based on their safety, tolerability, and efficacy in the treatment of
social anxiety disorder and common comorbid conditions. Data from single trials
suggest that clonazepam, bromazepam, and gabapentin may have efficacy similar to
the serotonin reuptake inhibitors, but further studies are needed to confirm
these findings. The monoamine oxidase inhibitor phenelzine appears to be at
least as efficacious as these other agents, but should be reserved for cases
that fail to respond to these safer medications. Among the reversible inhibitors
of monoamine oxidase A, brofaromine may also be an effective drug, while
moclobemide appears to be less potent.Future research directions should include
delineating ways to achieve remission (as opposed to response); developing
strategies for augmenting partial responders and treating nonresponders to first
line approaches; studying the long-term response to medication and prevention of
relapse when medication is discontinued; clarifying ways to integrate
psychosocial and pharmacological treatment approaches; developing predictors of
which patients do best with which treatments; and the treatment of social
anxiety disorder in children and adolescents.
32: Harv Rev Psychiatry. 2001 Sep-Oct;9(5):209-22.
Antiepileptic drugs for the acute and maintenance treatment of bipolar disorder.
De Leon OA.
Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612,
USA.
Both traditional and newer antiepileptic drugs have been considered for the
acute and maintenance treatment of bipolar disorder. Although the psychotropic
actions of these compounds have long been recognized, their specific
mood-stabilizing properties have become evident only relatively recently.
Carbamazepine and valproate are the antiepileptics most thoroughly studied for
the treatment of bipolar disorder, but trials of the newer compounds such as
lamotrigine, gabapentin, topiramate, and tiagabine have also begun to emerge.
This article reviews the published research (including controlled trials,
outcome reports, case series, and anecdotal observations) relevant to the
efficacy of these agents in the acute and maintenance treatment of bipolar
disorder. It also reviews the available information regarding clinical
predictors of response. Despite considerable interest in these drugs, data are
still limited. Comparison of clinical responses to the various mood stabilizers
and determination of their mechanisms of action could help to improve treatment
for bipolar disorder.
33: Expert Opin Investig Drugs. 2001 Apr;10(4):661-71.
Erratum in:
Expert Opin Investig Drugs 2001 Jul;10(7):following 1205.
Novel treatments for bipolar disorder.
Bowden CL.
University of Texas Health Science Center at San Antonio, Department of
Psychiatry (Mail Code 7792), 7703 Floyd Curl Drive, San Antonio, Texas
78229-3900, USA. bowdenc@uthscsa.edu
Treatments other than lithium have recently emerged as equally important in the
management of bipolar disorder. The spectrum of efficacy of newer treatments
differs from lithium and among the novel drug treatments valproate, generally
used as the better tolerated divalproex form, principally benefits manic
symptomatology both acutely and in prophylaxis. Atypical antipsychotic drugs
have demonstrated efficacy in reducing acute manic symptoms. No controlled
evidence of efficacy in prophylaxis has been published. Lamotrigine has
demonstrated efficacy in both acute bipolar depression and maintenance efficacy
in rapid cycling bipolar patients, especially those patients with bipolar II
disorder, which is principally manifested as depression. Randomised,
double-blind, placebo- controlled studies provide good evidence that regimens of
risperidone or olanzapine in combination with lithium or valproate provide
greater improvement in acute mania than the mood stabilisers alone. Similarly,
valproate combined with antipsychotics provided greater improvement in mania
than antipsychotic medication alone and resulted in lower dosage of the
antipsychotic medication. A positive but unclear placebo-controlled study of
omega-3 fatty acids added to lithium in bipolar disorder needs confirmation in
standard clinical trial paradigms. Several other drugs that were reported as
beneficial in various facets of bipolar disorder in open trials have not
differed from placebo when studied in randomised, placebo-controlled trials.
34: Ann Clin Psychiatry. 1999 Dec;11(4):217-22.
Gabapentin as an adjunct to standard mood stabilizers in outpatients with mixed
bipolar symptomatology.
Sokolski KN, Green C, Maris DE, DeMet EM.
Mental Health Care Group, Veterans Affairs Medical Center, Long Beach,
California 90822, USA.
Gabapentin is a new adjunctive medication to antiseizure therapies. Anecdotal
evidence suggests that it may also help to alleviate mood symptoms in patients
with bipolar illness. An open-label study examined the effects of adjunctive
gabapentin in bipolar patients with mixed symptoms who had previously
demonstrated only partial treatment responses. Mood ratings and side-effect
profiles were followed weekly in 10 patients for 1 month. Decreases in Hamilton
depression (P < 0.05) and Bech mania ratings (P < 0.01) were evident in the
first week of treatment and were sustained. Potent early improvements were noted
in early, middle, and late insomnia. The results suggest that gabapentin may be
of benefit to bipolar patients who only partially respond to other mood
stabilizers. A favorable side-effect profile and rapid action make this drug an
attractive choice as an adjunctive therapy.
35: Am J Health Syst Pharm. 1999 Oct 1;56(19):1939-44.
Gabapentin and lamotrigine in bipolar disorder.
Botts SR, Raskind J.
College of Pharmacy and Allied Health Professions, St. John's University,
Jamaica, NY 11439, USA. Botts@lij.edu
The utility of gabapentin and lamotrigine for the treatment of bipolar disorder
is reviewed. Bipolar disorder is characterized by extreme mood fluctuations,
including mania, hypomania, depression, and mixed episodes. Extrapolation of
postulated mechanisms of anticonvulsant activity in bipolar disorder has led to
the use of the newer anticonvulsants gabapentin and lamotrigine for therapy.
Both agents appear promising on the basis of limited (often anecdotal) evidence.
They may prove effective in patients with difficult cases of bipolar disorder,
such as patients with rapid cycling, mixed episodes, and illness refractory to
other treatments. Lamotrigine may offer a much-needed treatment alternative for
bipolar depression and could be found effective for acute mania, but the need
for slow dosage adjustment and the risk of rash may limit overall clinical
utility. Gabapentin may offer significant advantages for acute mania: The dosage
can be adjusted rapidly, adverse effects are generally minimal, the therapeutic
index is high, there is no required laboratory monitoring, and there is minimal
potential for interactions with other psychotropics. Until the results of
randomized controlled trials are known, however, these two agents should be
reserved for patients with bipolar disorder unresponsive to traditional
therapies and for patients who cannot tolerate traditional agents. Preliminary
evidence indicates that gabapentin and lamotrigine may be useful for the
treatment of bipolar disorder.
36: Pharmacotherapy. 1999 May;19(5):565-72.
Gabapentin: a review of published experience in the treatment of bipolar
disorder and other psychiatric conditions.
Letterman L, Markowitz JS.
Department of Pharmacy Practice, Medical University of South Carolina,
Charleston 29425, USA.
Successful therapy with valproate and carbamazepine in patients with psychiatric
disorders led to investigation of other anticonvulsants for similar indications.
Gabapentin is a relatively new anticonvulsant being investigated for potential
use in the treatment of bipolar disorder (BD), anxiety disorders, behavioral
dyscontrol, and substance use disorders. Its favorable side effect profile,
absence of the need for therapeutic drug monitoring, and minimal drug
interactions give gabapentin a potential role in these indications. Computer
searches of the biomedical literature were undertaken to identify all pertinent
case reports, case series, and studies of the drug as monotherapy or adjunctive
therapy for BD; 10 reports were retrieved. In the treatment of various anxiety
disorders, one study, one case report, and one case series were identified. At
least one case series described gabapentin therapy for alcohol withdrawal and
one case report of the drug for agitation associated with dementia. Published,
well-designed studies evaluating the agent's effectiveness as monotherapy for BD
are lacking. Its benefit as an adjunctive treatment with other mood stabilizers
is also unestablished. Data regarding its efficacy in the treatment of anxiety
disorders or manifestations of substance abuse are limited. These areas may
deserve further investigation.
37: Neuropsychobiology. 1998 Oct;38(3):192-7.
Lamotrigine and gabapentin. Alternative in the treatment of bipolar disorder.
Ferrier IN.
University Department of Psychiatry, University of Newcastle upon Tyne, Royal
Victoria Infirmary, Newcastle upon Tyne, UK. margaret.simpson@ncl.ac.uk
The anticonvulsants carbamazepine and sodium valproate have efficacy in
hypomania, bipolar depression and in the prophylaxis of bipolar disorder. This
paper reviews published evidence on the effects of the new anticonvulsants
gabapentin and lamotrigine in bipolar disorder. The conclusion is that there is
good evidence from open studies to indicate that randomised double-blind trials
of these compounds should be carried out. The pharmacology of these
anticonvulsants is reviewed and putative predictors of good response identified.
38: Am J Psychiatry. 1998 Jan;155(1):12-21.
Mood stabilizer combinations: a review of safety and efficacy.
Freeman MP, Stoll AL.
Psychopharmacology Unit, Division of Psychiatry, Brigham and Women's Hospital,
Boston, MA 02115, USA. mpfreeman@bics.bwh.harvard.edu
OBJECTIVE: Polypharmacy is common in the treatment of refractory bipolar
disorder. The purpose of this article is to review the safety and efficacy of
mood stabilizers in combinations. METHOD: A manual and computer (MEDLINE) search
was performed for combinations of the most commonly used mood-stabilizing
agents. RESULTS: The authors review safety and efficacy data on the more
frequently encountered combinations of established and putative mood
stabilizers. CONCLUSIONS: There have been few controlled studies of the use of
combinations of mood stabilizers. The interactions of such combinations are
sometimes complex, often very useful, and potentially dangerous. One general
rule that may reduce the risks of toxic drug interactions is to add medication
to the patient's current regimen in modest doses and increase the dose slowly.
The safest and most efficacious mood stabilizer combinations appear to be the
mixtures of anticonvulsants and lithium, particularly valproate plus lithium.
Once the mechanisms of the mood stabilizers are identified, it is possible that
a more rational approach to combination therapy will emerge, based on synergism
at the sites of action.
39: Ann Clin Psychiatry. 1997 Jun;9(2):99-103.
A pilot trial of adjunctive gabapentin in the treatment of bipolar disorder.
McElroy SL, Soutullo CA, Keck PE Jr, Kmetz GF.
Department of Psychiatry, University of Cincinnati College of Medicine, Ohio
45267-0559, USA.
Several antiepileptic drugs (AEDs) have documented efficacy in the manic phase
of bipolar disorder. To investigate the efficacy, tolerability, and safety of
the new AED, gabapentin, in mania, we treated nine consecutive outpatients with
bipolar I or II disorder by DSM-IV criteria who were experiencing hypomanic,
manic, or mixed states inadequately responsive to standard mood stabilizers with
open-label, adjunctive gabapentin. Response of manic symptoms was assessed
monthly as none, minimal, moderate, or marked. Of the nine patients, seven
displayed a moderate or marked reduction in manic symptoms by 1 month after
addition of gabapentin, and an additional patient displayed moderate improvement
after 3 months. Of these eight patients, six displayed continued antimanic
responses for follow-up periods ranging from 1 to 7 months. Side effects were
most commonly neurological, mild, and transient. Adjunctive gabapentin may have
antimanic and mood-stabilizing effects in some patients with bipolar disorder
and is generally well tolerated. Controlled studies of gabapentin in bipolar
disorder appear to be warranted.
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