Fagiolini A, Frank E, Cherry CR,
Houck PR, Novick DM, Buysse DJ, Kupfer DJ.
Department of Psychiatry University
of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh,
PA 15213, USA.
Clinical indicators for the use of antidepressants
in the treatment of bipolar I depression.
"OBJECTIVES: Current guidelines provide little practical
information on the clinical characteristics of bipolar I patients who are likely
to benefit from the combination of a mood stabilizer and an antidepressant. Rather,
guidelines simply state that an adjunctive antidepressant is recommended in cases
of 'severe' depression. Our objective was to evaluate the clinical and demographic
differences between patients who remitted on a mood stabilizer alone and patients
who subsequently required an adjunctive antidepressant to achieve stabilization.
METHODS: We retrospectively compared the pharmacological treatment strategies
of 39 patients with bipolar I disorder who were in a current depressive episode.
Patients who did not respond to mood stabilizer monotherapy were prescribed an
adjunctive antidepressant. We evaluated the clinical differences at baseline and
week 1, 2 and 3 of treatment between patients stabilizing on a mood stabilizer
alone and patients that did not remit until they subsequently received an adjunctive
antidepressant. RESULTS: Patients who required an adjunctive antidepressant had
significantly higher total Hamilton Depression Rating (HRS-D) scores at week 1,
2 and 3 of treatment, but not at baseline. Patients who remitted on mood stabilizer
monotherapy were more likely to be married, achieved stabilization in less time,
presented with higher Young Mania Rating Scale (YMRS) scores, and experienced
the previous episode of depression more recently than patients who required an
antidepressant. CONCLUSIONS: Our findings suggest that rapid improvement after
achieving a therapeutic dose of a mood stabilizer is clinically significant and
represents a surrogate endpoint in the treatment of bipolar I depression. Larger,
prospective, and controlled studies are needed to verify our results and to identify
additional indicators for a mood stabilizer and antidepressant combination treatment
RS, Mancini DA, McCann S, Srinivasan J, Sagman D, Kennedy SH.
Psychiatry, University of Toronto, Mood and Anxiety Disorders Program, Center
for Addiction and Mental Health, Clarke Site, Ontario, Canada. firstname.lastname@example.org
versus bupropion SR when added to mood stabilizer therapy for the depressive phase
of bipolar disorder: a preliminary single-blind study.
Disord. 2002 Jun;4(3):207-13.
"OBJECTIVE: Antiepileptic drugs (AEDs) are
commonly employed in the treatment of bipolar disorder. The efficacy and tolerability
of topiramate, a novel anticonvulsant, and bupropion SR when added to mood stabilizer
therapy were compared under single-blind conditions (rater-blinded) in patients
meeting DSM-IV criteria for bipolar I/II depression. METHODS: A total of 36 out-patients
with Hamilton Depression Rating Scale (HDRS-17) scores > or = 16 were randomized
to receive escalating doses of either topiramate (50-300 mg/day) or bupropion
SR (100-400 mg/day) for 8 weeks. Data were analyzed on an intent-to-treat basis
using the last observation carried forward method. RESULTS: The percentage of
patients meeting a priori response criteria (> or = 50% decrease from baseline
in mean HDRS-17 total score) was significant for both topiramate (56%) and bupropion
SR (59%) [t(17) = 2.542, p = 0.04 and t(17) = 2.661, p = 0.03, respectively].
Baseline demographic and clinical parameters were comparable between the two treatment
groups. The mean doses of study medication were 176 mg/day (SD = 102 mg/day) for
the topiramate-treated group and 250 mg/day (SD = 133 mg/day) for the bupropion
SR-treated group. A significant and comparable reduction in depressive symptoms
was observed from baseline to endpoint following topiramate and bupropion SR treatment,
according to a > or = 50% reduction in the HDRS-17. Total mean HDRS-17 scores
significantly decreased from baseline to endpoint in both groups (p = 0.001),
however, differences between the topiramate-treated group and the bupropion SR-treated
group were not significant [t(36) = 1.754, p = 0.097]. Both topiramate and bupropion
SR were generally well tolerated. Thirteen patients discontinued the study: 2
because of lack of efficacy, 1 due to withdrawal of consent and 10 following side-effects
(six in the topiramate and four in the bupropion SR-treated group). There were
no cases of affective switch in either arm. Weight loss was experienced by patients
in both groups (mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8
kg in topiramate) [t(17) = 2.325, p = 0.061 and t(17) = 2.481, p = 0.043, respectively].
CONCLUSIONS: These preliminary data suggest that adjunctive topiramate may reduce
depressive symptom severity in acute bipolar depression. The antidepressant efficacy
of this compound requires confirmation via double-blind placebo controlled investigation."
E, Martinez-Aran A, Goikolea JM, Torrent C, Colom F, Benabarre A, Reinares M.
Disorders Program, Barcelona Stanley Foundation Research Center, IDIBAPS, Hospital
Clinic, University of Barcelona, Spain. email@example.com
trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed
patients taking mood stabilizers.
J Clin Psychiatry. 2002
"BACKGROUND: The treatment of depressive episodes occurring
in bipolar patients taking mood stabilizers is an understudied area of research
with outstanding clinical consequences. This study was aimed to assess and compare
the efficacy and safety of 2 different antidepressant drugs, paroxetine and venlafaxine,
in this indication. METHOD: Sixty DSM-IV bipolar patients. each presenting with
a major depressive episode while receiving mood stabilizers, were randomly assigned
to either paroxetine (N = 30) or venlafaxine (N = 30) for 6 weeks in a single-blind
manner. They had to score higher than 17 on the 17-item Hamilton Rating Scale
for Depression (HAM-D-17) and have their mood stabilizer blood levels within the
therapeutic range. Efficacy was measured by the HAM-D. Reports of side effects
were collected at each visit; switch to mania or hypomania was specifically assessed
by the Young Mania Rating Scale at 5 of 7 visits. RESULTS: Significant improvements
in HAM-D scores were observed in both paroxetine- and venlafaxine-treated patients
(Wilcoxon p < .0001). There were no significant differences in either efficacy
or safety measures between the 2 drugs. By intention-to-treat analysis, 43% (N
= 13) of patients taking paroxetine and 48% (N = 14) taking venlafaxine were considered
to be responders. Only 3% (N = 1) of patients switched to hypomania or mania in
the paroxetine group, whereas 13% (N = 4) switched in the venlafaxine group. CONCLUSION:
Paroxetine and venlafaxine are both effective and safe in the treatment of depressive
breakthrough episodes in bipolar disorder. There was a suggestion of a slightly
higher risk for switch to mania or hypomania with venlafaxine." [Abstract]
Department of Psychological Medicine, Dunedin School of Medicine, University
of Otago, Dunedin, New Zealand.
Moclobemide vs. imipramine in bipolar
depression: a multicentre double-blind clinical trial.
Psychiatr Scand. 2001 Aug;104(2):104-9.
"OBJECTIVE: To determine the relative
efficacy, tolerability and risk of precipitating mania of moclobemide and imipramine
in the treatment of bipolar depression. METHOD: A randomized, double-blind, parallel
group, multicentre study of moclobemide (MCB) (450-750 mg daily) and imipramine
(IMI) (150-250 mg daily) in 21 centres in nine countries; 156 patients (65 males,
91 females) aged 18-65 with bipolar depression (17-item Hamilton Depression Rating
Scale (HAMD) score chi16) participated. Clinical status was assessed using standardized
rating scales before treatment and at 1,2,3,4,6 and 8 weeks. The data were analysed
on an intention to treat basis with the last observation carried forward. RESULTS:
In the MCB group, the mean HAMD fell from 23.0 to 13.1, in the IMI group it fell
from 22.5 to 9.5; the mean score on the Montgomery-Asberg Depression Rating Scale
(MADRS) fell from 29.5 to 16.3 on MCB and from 29.2 to 11.6 on IMI. There were
no statistically significant differences between the two groups on any efficacy
measures. Anticholinergic side-effects were three times more common with IMI than
MCB and weight gain was also greater on IMI. Two patients (3.7%) on MCB and six
patients (11%) on IMI were withdrawn because of manic symptoms, with manic symptoms
occurring earlier on IMI, although these differences did not reach statistical
significance. CONCLUSION: No differences in efficacy were detected between MCB
and IMI in the treatment of bipolar depression. The data suggests that MCB is
less likely than IMI to precipitate mania." [Abstract]
H, Saiz-Ruiz J, Costa e Silva JACE, Ansseau M, Herrington R, Vaz-Serra A, Dilling
H, de Risio S.
Service Hospitalo Universitaire de Sante Mentale et de Therapeutique,
Sainte-Anne Hospital, Paris, France.
Efficacy and safety of tianeptine
in the treatment of depressive disorders in comparison with fluoxetine.
Affect Disord. 1999 Dec;56(2-3):109-18.
"BACKGROUND: Depression is treated
by a great variety of antidepressant treatments. SSRIs (such as fluoxetine) are
well known: it is, however, sure that further progress is needed and the search
for antidepressants with other mechanisms of action (such as tianeptine) or different
efficacy is still of interest. METHODS: A multinational study compared tianeptine
with fluoxetine in 387 patients with Depressive Episode, or Recurrent Depressive
Disorder, or Bipolar Affective Disorder (ICD-10), in a double-blind parallel group
design. They were treated for six weeks. RESULTS: At inclusion, no significant
difference between groups was shown. Final MADRS scores were 15.7 and 15.8 with
tianeptine and fluoxetine, respectively (ITT population) (p = 0.944). MADRS responders
were 58% and 56% with tianeptine and fluoxetine, respectively (p = 0.710). No
statistical difference was observed for the other efficacy parameters. Thirty-six
withdrawals occurred in each group, without any difference for the reasons of
discontinuation. There was no major difference between groups for the other safety
parameters. CONCLUSIONS: In this study, both tianeptine and fluoxetine exhibited
a good efficacy and safety." [Abstract]
EH, Mullin JM, Martindale JJ.
Leverndale Hospital, Glasgow, UK.
double-blind multicenter trial comparing sertraline and fluoxetine in outpatients
with major depression.
J Clin Psychiatry. 1995 Jun;56(6):229-37.
Sertraline and fluoxetine have pharmacokinetic and pharmacologic differences,
which may be of clinical relevance. METHOD: A randomized, double-blind, parallel-group
study of 6 weeks' duration comparing the efficacy and safety of sertraline (50-100
mg/day) with those of fluoxetine (20-40 mg/day) was conducted in 286 psychiatric
outpatients with DSM-III-R major depression or bipolar disorder (depressed). Primary
efficacy measurements consisted of the 17-item Hamilton Rating Scale for Depression
(HAM-D) and the Clinical Global Impressions (CGI) scale. Secondary measurements
included the Hamilton Rating Scale for Anxiety (HAM-A), the Raskin Depression
Scale, the Covi Anxiety Scale, and the Leeds Sleep Questionnaire. Additionally,
scores for two items and five factors from the HAM-D were analyzed. RESULTS: Efficacy
was based on 124 evaluable patients in each treatment group. As measured by HAM-D
and CGI-Severity scores, there was a significant (p < .001) improvement from
baseline to each follow-up visit in both treatment groups with no statistically
significant difference between groups. There was also no significant difference
in the proportion of responders in each group. CGI-Improvement responder rates
were 69% for sertraline and 67% for fluoxetine. Results of secondary efficacy
measurements followed the same trend, although from the second week of treatment
there was a numerical advantage (not statistically significant) for sertraline
over fluoxetine in improving anxiety symptoms as measured by the total HAM-A score.
Headache and nausea were the most frequently reported events for both drugs. The
incidence of early patient withdrawals due to treatment-emergent adverse events
was 14% for sertraline and 13% for fluoxetine. The starting dosage (sertraline
50 mg/day, fluoxetine 20 mg/day) was the final dosage in 76% of patients in both
treatment groups. CONCLUSION: Sertraline and fluoxetine were equally effective
and well tolerated in patients with major depression and associated anxiety."
JM, Thase ME, Mallinger AG, Houck P.
Department of Psychiatry, University of
Pittsburgh School of Medicine, PA.
Tranylcypromine versus imipramine
in anergic bipolar depression.
Am J Psychiatry. 1991 Jul;148(7):910-6.
This investigation compared the efficacy of the monoamine oxidase inhibitor (MAOI)
tranylcypromine with that of the tricyclic imipramine in the treatment of anergic
bipolar depressive illness. METHOD: A controlled, double-blind comparison was
used to study 56 outpatients who met operationalized criteria for anergic bipolar
depression. Patients with bipolar I and II depression were equally distributed
between comparison groups. Outcome was measured by the patient-rated Beck Depression
Inventory and the clinician-rated Hamilton Rating Scale for Depression, Raskin
Mania and Depression Scales, Clinical Global Impression Scale, and the Pittsburgh
Reversed Vegetative Symptom Scale. Twenty-eight patients were treated with tranylcypromine
and 28 with imipramine. Seventy-three percent of bipolar depressive patients screened
for the study met criteria for anergic depression, consistent with previous findings
from studies in bipolar illness that stretch back over 100 years. RESULTS: Tranylcypromine
produced statistically significant superior outcome in terms of lower attrition,
greater symptomatic improvement, and higher global response without increased
risk of treatment-emergent hypomania or mania. CONCLUSIONS: The authors propose
that the apparently superior efficacy of tranylcypromine in bipolar depression
is specifically linked to anergia and reversed neurovegetative symptoms. Bipolar
I and bipolar II patients had comparable outcomes, but bipolar I patients had
a significantly greater risk of treatment-emergent mood swings. Although the relatively
poor showing of imipramine warrants close scrutiny, these findings provide further
documentation of the utility of MAOIs in patients presenting with anergia, motor
retardation, hyperphagia, and/or hypersomnia." [Abstract]
A, Bernardi F, Burrai C, Pedditzi M, Del Zompo M.
Department of Neuroscience
Bernard B. Brodie, University of Cagliari, Italy.
study of L-sulpiride versus amitriptyline in lithium-maintained bipolar depressives.
Psychiatr Scand. 1993 Dec;88(6):434-9.
"A double-blind group comparison
study of L-sulpiride and amitriptyline was carried out in 30 bipolar outpatients
on maintenance treatment with lithium suffering from a major depressive recurrence.
L-sulpiride showed equivalent antidepressant activity to amitriptyline at 4 weeks
using the Hamilton Rating Scale for Depression. However, the onset of action was
faster in the L-sulpiride group, showing a significant improvement at 1 week in
both anxiety-somatization and specific depression items, including depressed mood,
feelings of guilt, work & activities and retardation. The incidence of anticholinergic
side effects was significantly higher in the amitriptyline treatment group."
Amsterdam JD, Garcia-Espana F, Fawcett J, Quitkin
FM, Reimherr FW, Rosenbaum JF, Schweizer E, Beasley C.
University of Pennsylvania
Medical Center, Philadelphia, USA.
Efficacy and safety of fluoxetine
in treating bipolar II major depressive episode.
Psychopharmacol. 1998 Dec;18(6):435-40.
"As many as 45% of patients with
major depressive episode also meet DSM-IV criteria for bipolar II (BP II) disorder.
Although some clinicians advocate using a mood stabilizer in treating BP II depression,
antidepressant monotherapy has been less well studied in this disorder. As part
of a prospective, placebo-controlled, relapse-prevention study in 839 patients,
the efficacy and safety of short- and long-term fluoxetine treatment in patients
with BP II major depression compared with patients with unipolar (UP) major depression
was retrospectively examined. Eighty-nine BP II patients (mean age, 41+/-11 years)
were compared with 89 age- and gender-matched UP patients and with 661 unmatched
UP patients (mean age, 39+/-11 years). All received short-term fluoxetine therapy
at 20 mg daily for up to 12 weeks. Complete remission was defined as a final Hamilton
Rating Scale for Depression score < or = 7 by week 9 that was then maintained
for 3 additional weeks. Remitted patients were then randomly assigned to receive
double-blind treatment with one of the following: (1) fluoxetine 20 mg daily for
52 weeks; (2) fluoxetine for 38 weeks, then placebo for 14 weeks; (3) fluoxetine
for 14 weeks, then placebo for 38 weeks; or (4) placebo for 52 weeks. Antidepressant
efficacy was similar in BP and UP patients during short-term therapy. Discontinuation
for lack of efficacy was lower in BP II (5%) than in UP (12%) patients (p = not
significant [NS]), whereas dropouts for adverse events were similar in BP II (11%)
and UP (9%) patients. During long-term relapse-prevention therapy, relapse rates
were similar in BP II and UP patients (p = NS). During short-term fluoxetine therapy,
three BP II (3.8%) versus no matched UP (p = NS) and 0.3% unmatched UP (p = 0.01)
patients had a "manic switch." During long-term fluoxetine therapy,
one (2%) BP II and three (1%) unmatched UP patients (one taking placebo) had a
manic switch (p = NS). In conclusion, fluoxetine may be a safe and effective antidepressant
monotherapy for the short-term treatment of BP II depression with a relatively
low manic switch rate. Fluoxetine may also be effective in relapse-prevention
therapy in patients with BP II disorder." [Abstract]
Shelton RC, Stahl SM
Risperidone and paroxetine given singly and in combination for bipolar depression.
J Clin Psychiatry. 2004 Dec;65(12):1715-9.
BACKGROUND: Bipolar depression is a major clinical problem that remains under-researched. The current study was intended to evaluate the effects of the novel antipsychotic risperidone, the selective serotonin reup-take inhibitor (SSRI) paroxetine, and the combination in patients with bipolar disorder. METHOD: Thirty patients with DSM-IV bipolar (I or II) disorder, depressed phase, who were receiving a stable dose of a mood stabilizer were randomly assigned to 12 weeks of double-blind treatment with risperidone (plus placebo), paroxetine (plus placebo), or the combination of risperidone and paroxetine. Data were gathered from August 1999 to September 2001. RESULTS: All 3 groups experienced significant reductions in depression ratings from baseline to endpoint; there were no significant differences in outcome between groups. There were statistically significant differences in paroxetine dose contrasting paroxetine plus placebo against the combined condition. The switch rate into mania or hypomania was very low, with only 1 patient in the paroxetine plus placebo condition experiencing mild hypomania. CONCLUSION: These results suggest that risperidone, paroxetine, and the combination of risperidone and paroxetine are equally but modestly effective when added to a mood stabilizer in bipolar depression. The paroxetine dose differed between groups, possibly because of drug-drug interactions. Using another SSRI in the combined condition could have produced a more robust effect and should be tested. [Abstract]
CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, Oakes R, Pitts CD.
of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639
Pierce Dr., Suite 4000, Atlanta, GA 30322, USA.
comparison of imipramine and paroxetine in the treatment of bipolar depression.
J Psychiatry. 2001 Jun;158(6):906-12.
"OBJECTIVE: This study compared
the efficacy and safety of paroxetine and imipramine with that of placebo in the
treatment of bipolar depression in adult outpatients stabilized on a regimen of
lithium. METHOD: In a double-blind, placebo-controlled study, 117 outpatients
with DSM-III-R bipolar disorder, depressive phase, were randomly assigned to treatment
with paroxetine (N=35), imipramine (N=39), or placebo (N=43) for 10 weeks. In
addition to lithium monotherapy, patients may have received either carbamazepine
or valproate in combination with lithium for control of manic symptoms. Patients
were stratified on the basis of trough serum lithium levels determined at the
screening visit (high: >0.8 meq/liter; low: </=0.8 meq/liter). Primary efficacy
was assessed by change from baseline in scores on the Hamilton Rating Scale for
Depression and the Clinical Global Impression illness severity scale. RESULTS:
Differences in overall efficacy among the three groups were not statistically
significant. For patients with high serum lithium levels, antidepressant response
at endpoint also did not significantly differ from placebo. However, both paroxetine
and imipramine were superior to placebo for patients with low serum lithium levels.
Compared to imipramine, paroxetine resulted in a lower incidence of adverse events,
most notably emergence of manic symptoms. CONCLUSIONS: Antidepressants may not
be useful adjunctive therapy for bipolar depressed patients with high serum lithium
levels. However, antidepressant therapy may be beneficial for patients who cannot
tolerate high serum lithium levels or who have symptoms that are refractory to
the antidepressant effects of lithium." [Abstract]
e Silva JA, Ruschel SI, Caetano D, Rocha FL, da Silva Lippi JR, Arruda S, Ozun
Jardim Botanico, Rio de Janeiro, Brazil.
study of tianeptine in major depressive episodes.
"The efficacy and safety of tianeptine were compared,
in the course of a multicentre randomised, double-blind, parallel group study,
to those of placebo in the treatment of Major Depressions and Bipolar Disorder,
Depressed with or without melancholia, without psychotic features. After a 1-week
run-in placebo period, 126 depressed out-patients presenting DSM-III-R Major Depression
or Bipolar Disorder, Depressed, with a total MADRS score of at least 25, were
treated for 42 days with either tianeptine (25-50 mg/day) or placebo. Efficacy
assessments were MADRS, CGI, HARS, Zung Depression Self Rating Scale and a VAS.
Better efficacy of tianeptine was shown, and confirmed by covariance analyses,
in final MADRS scores of the intention-to-treat population, of patients treated
for at least 14 days and of completers; also in CGI items 1 and 2, MADRS item
10, and VAS. The results confirmed the efficacy of tianeptine (mean dosage: 37.5
mg/day) in the treatment of Major Depression and Bipolar Disorder, Depressed,
with or without melancholia, compared to placebo. Tianeptine's acceptability did
not differ from that of placebo. For adverse events, a higher incidence of headaches
was found with tianeptine." [Abstract]
Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason
VB, Voss CB, Johnson WE.
Drug therapy in the prevention of recurrences
in unipolar and bipolar affective disorders. Report of the NIMH Collaborative
Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine
Arch Gen Psychiatry. 1984 Nov;41(11):1096-104.
a double-blind, long-term follow-up study, 117 bipolar patients received lithium
carbonate, imipramine hydrochloride, or both and 150 unipolar patients received
lithium carbonate, imipramine, both lithium carbonate and imipramine, or placebo.
With bipolar patients, lithium carbonate and the combination treatment were superior
to imipramine in preventing manic recurrences and were as effective as imipramine
in preventing manic recurrences and were as effective as imipramine in preventing
depressive episodes. The combination treatment provided no advantage over lithium
carbonate alone. With unipolar patients, imipramine and the combination treatment
were more effective than lithium carbonate and placebo in preventing depressive
recurrences. The combination treatment provided no advantage over imipramine alone.
The lithium carbonate-treated group had fewer manic episodes than the other groups.
Treatment outcome, which was evaluated primarily in terms of the occurrence of
major depression or manic episodes, was significantly related to characteristics
of the index episode, ie, the episode that brought the patient into the study."