Posted by Jay_Bravest_Face on September 1, 2009, at 2:47:49
In reply to getting articles as a patient, not an institution, posted by iforgotmypassword on August 31, 2009, at 19:33:52
How does this look?--it's from PDF format....I can send you just the PDF.----
Brief report
Effect of aripiprazole on self-reported anhedonia in
bipolar depressed patients
Marianna Mazza a,⁎, Maria Rosaria Squillacioti a,
Riccardo Daniele Pecora b, Luigi Janiri a, Pietro Bria a
a Institute of Psychiatry and Psychology, Bipolar Disorders Unit, Catholic University of Sacred Heart, Rome, Italy
b Polo Ospedaliero SS. Trinità, Sora, ASL Frosinone, Italy
Received 27 February 2008; received in revised form 20 April 2008; accepted 2 May 20081. Introduction
Aripiprazole is a second generation antipsychotic that
exhibits high receptor affinity for dopamine D2 and D3
receptors and shows moderate affinity for dopamine D4
receptors. It acts as a partial agonist at the presynaptic
dopamine autoreceptors and postsynaptic D2 receptors
(Aihara et al., 2004).Aripiprazole monotherapy is approved by the FDA
for the acute treatment of bipolar mania/mixed states
and maintenance for individuals with a recent manic or
mixed episode and for treatment of depression when
used along with antidepressants (McIntyre et al., 2007).
Some recent open-label studies in small samples
indicate beneficial effects of adjunctive therapy or
monotherapy with aripirazole in treatment of bipolar
depression (Sokolski, 2007; Keck et al., 2007). Some
other studies suggest that aripiprazole was associated
with beneficial effects on mood in some patients with
bipolar depression, but also had a high discontinuation
rate, primarily due to side effects such as akathisia
(McElroy et al., 2007; Kemp et al., 2007).
Available online at www.sciencedirect.com
Psychiatry Research 165 (2009) 193196
www.elsevier.com/locate/psychres
⁎ Corresponding author. Institute of Psychiatry and Psychology,
Catholic University of Sacred Heart of Rome, Via Ugo De Carolis, 48
00136 Roma, Italy. Tel.: +39 06 35348285; fax: +39 06 35501909.
E-mail addresses: mariannamazza@hotmail.com,
marianna.mazza@rm.unicatt.it (M. Mazza).
0165-1781/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.psychres.2008.05.003Relatively little information is available about the
frequency and severity of anhedonia in patients with
bipolar disorder (Etain et al., 2007; Serretti and Olgiati,
2004). Anhedonia is a condition in which the capacity to
experience pleasure is totally or partially lost, frequently
occurring in mood disorders, as a negative symptom in
schizophrenia, and in substance use disorders. Anhedonia
can be assessed and quantified as a subjectively experienced
phenomenon using the Snaith-Hamilton Pleasure
Scale (SHAPS), a brief assessment scale for estimation of
the degree to which a person is able to experience pleasure
or the anticipation of a pleasurable experience. The
SHAPS covers four domains of hedonic experience:
interest/pastimes, social interaction, sensory experience,
and food/drink (Snaith et al., 1995).
The aim of this open-label trial was to assess the
frequency and severity of depression and anhedonia
during treatment with aripiprazole in bipolar patients
under conditions of routine clinical practice.
2. Patients and methods
In this prospective, observational, 16-week open study,
we included patients if they: 1) were between 18 and
65 years of age; 2) had a DSM-IV (American Psychiatric
Association, 1994) diagnosis of bipolar disorder type I; 3)
had clinically significant depressive symptoms without
prominent manic symptoms, defined as having two consecutive
total MontgomeryÅsberg Depression Scale
(MADRS) (Montgomery and Åsberg, 1979) scores≥14
and two total Young Mania Rating Scale (YMRS) (Young
et al., 1978) scores≤12; 4) were either inadequately
responsive to or poorly tolerant of adequate treatment
with at least one mood stabilizer; 5) did not meet current
DSM-IV criteria for a substance dependence disorder;
6) had no unstable general medical conditions; 7) had no
clinically significant prestudy physical examination,
laboratory, electrocardiogram, or urinalysis abnormalities.
Pregnant or breast-feeding women were excluded from
the study. Persons with a history of neuroleptic malignant
syndrome or allergy or hypersensitivity to aripiprazole
were excluded from the study.
Adequate mood stabilizer treatment was broadly
defined as at least 2 weeks of treatment with a minimum
blood level or daily dose as indicated for the following:
lithium, 0.7 mEq/L; divalproex, 50 mcg/ml; lamotrigine,
200 mg/day; carbamazepine, 600 mg/day; oxcarbazepine,
900 mg/day; levetiracetam, 1000 mg/day; olanzapine,
5 mg/day; risperidone, 2 mg/day; quetiapine,
600 mg/day; and clozapine, 50 mg/day (McElroy et al.,
2007). Patients were excluded from participation if they
were receiving an antidepressant medication. Patients
were also excluded if they were receiving carbamazepine
because of potential pharmacokinetic interactions
with aripiprazole. The Institutional Review Board
approved the protocol, and all patients provided written
informed consent to receive treatment with aripiprazole.
After a 3- to 30-day screening period to assess patient
eligibility, patients were begun on aripiprazole as monotherapy.
The initial dose of aripiprazole was 5 to 10 mg/
day, usually given at night, and typically increased by 5 to
10 mg/day every 7 days according to patient response and
side effects. Aripirazole could be increased to a maximum
dose of 30 mg/day. Benzodiazepines (up to 2 mg/day of
lorazepam equivalents) were permitted for insomnia.
The primary outcome measures were theMADRS total
score and the self-rating SHAPS (range 014, higher
values representing more severe anhedonia; cut-off score
for anhedonia≥3) (Snaith et al., 1995). Additional
assessments included the YMRS score, response, and
remission. Response was defined as≥50% reduction in the
MADRS total score at the final assessment from baseline.
Remissionwas defined as aMADRStotal score≤12 at the
final assessment.
Baseline demographic and clinical features of the
patient population were calculated using the appropriate
descriptive functions, using means for continuous variables
and frequencies for categorical variables. Visual
and statistical examination of the measures met criteria
for a normal distribution, and statistical analysis relied
on parametric measures. Group differences were analysed
using Chi-square tests. The upper limit for significance
was Pb0.05. Correlations were analysed
using the Spearman correlation coefficient (rs) (twotailed,
pairwise exclusion of missing data) where the
upper level of significance was set at Pb0.05) (Table 1).
Table 1
Demographic and clinical features of 50 outpatients with bipolar
disorders receiving aripiprazole
Bipolar diagnosis, n (%)
Bipolar I 50 (100%)
Females, n (%) 25 (30%)
Caucasians, n (%) 45 (94%)
Age (years), mean (S.D.) 44.6 (11.7)
Weight (kg), mean (S.D.) 78.3 (15.6)
BMI, mean (S.D.) 29.7 (5.3)
Scale Baseline 16-weeks P
MADRS, mean (S.D.) 27.6 (5.7) 18 (3.7) b0.0001
SHAPS, mean (S.D.) 6.8 (4.55) 2.83 (2.9) b0.001
YMRS, mean (S.D.) 4.8 (2.2) 4.6 (1.9) b0.87
BMI = body mass index, weight in kg/height in m2; MADRS =
MontgomeryÅsberg Scale for Depression; SHAPS = Snaith
Hamilton Pleasure Scale; YMRS = Young Mania Rating Scale.3. Results
All patients completed the 16-week trial. Patients
showed a significant decrease in mean MADRS total
score (−9.6, t=−4.48, Pb0.0001). Patients did not show
a change in mean YMRS total score (−0.15, t=−0.12,
Pb0.87). Thirty-three (66%) patients met response
criteria (≥50% decrease in baseline MADRS total score
at last evaluation) and seventeen (34%) patients met
remission criteria (MADRS total score≤12 at last
evaluation) (Table 1).
The mean dose of aripiprazole at last evaluation was
14.9 (±7.6) mg/day. Patients received a mean endpoint
aripiprazole dose of 12.5 mg/day.
Our sample of patients showed statistically insignificant
weight gain (0.9±2.64 kg) over the 16-week trial.
Aripiprazole was well tolerated by all patients:
only eight (16%) patients experienced side effects.
The most common side effects were akathisia and
headache.
3.1. Anhedonia
Anhedonia was present in 26 (52%) of all bipolar
patients. From baseline to 16 weeks, SHAPS scores
decreased from 2.80 to 0.83 on the average. After
16 weeks of treatment, anhedonia was present in 10
(20%) patients (χ2 =33.3, df=1, Pb0.001). Anhedonia
(SHAPS) and depression (MADRS) scores were
significantly correlated (r=0.50, Pb0.001), while no
significative correlation was found between anhedonia
(SHAPS) and mania (YMRS) scores.
When individual MADRS items were considered,
scores on Inability to feel, one of the core symptoms of
depression, which is very similar to the dimension of
anhedonia, were significantly reduced at week-16
evaluation in comparison with baseline (Pb0.01). Other
MADRS items forwhich therewas statistically significant
improvement over baseline were Apparent sadness,
Reported sadness, Concentration difficulties and
Lassitude (Pb0.05) (Table 2).
4. Discussion
In this 16-week open-label trial, the frequency and
severity of depression and anhedonia were studied during
treatment with aripiprazole in bipolar patients under conditions
of routine clinical practice. Depression and
anhedonia were significantly reduced during treatment
with aripiprazole.
All patients completed the SHAPSquestionnaire, a selfreport
instrument for the detection of anhedonia. The rate
of anhedonia provides an indication of the excellent applicability
in this population. Because 52% of the patients
were anhedonic, our data show that anhedonia represents a
frequent symptom in patients suffering from bipolar
disorder type I.
Aripiprazole has a number of possible mechanisms
of action that may be important in the treatment of
depressive symptoms such as anhedonia. Such mechanisms
include the action of aripiprazole serotonin (5-HT)
receptors as a 5-HT1A partial receptor agonist, a 5-HT2C
partial receptor agonist and a 5-HT2A receptor antagonist.
Aripiprazole also acts as a dopamine D2 partial
receptor agonist, and has a possible action at adrenergic
receptors. Furthermore, aripiprazole may have possible
neuroprotective effects (Pae et al., 2008). These functional
characteristics suggest that not only the dopaminergic
system, but also the serotoninergic system
are involved in the therapeutic effect of aripiprazole,
and produce effective decrements in negative symptoms
(Kessler, 2007). From this perspective, anhedonia
can be interpreted as the equivalent in unipolar depression
and bipolar depression patients of negative
symptoms in schizophrenia patients and aripiprazole
seems to have antidepressant and anti-anhedonic
properties.
Our sample of patients showed statistically insignificant
weight gain over the 16-week trial, confirming a
favourable metabolic profile of aripiprazole (McIntyre
et al., 2007), while only 16% of patients experienced
side effects (mostly akathisia and headache), showing a
good tolerability, in contrast with some previous studies
(McElroy et al., 2007; Kemp et al., 2007).
The interpretations of our results are limited by
important methodologic shortcomings. First of all, this
Table 2
Means (standard deviation) for individual items constituting the
Montgomery-Åsberg Depression Rating Scale (MADRS)
Item Baseline
evaluation
16-week treatment
evaluation
Apparent sadness 3.96 (0.33) 2.94 (0.51) ⁎
Reported sadness 4.16 (0.51) 3.52 (0.71) ⁎
Inner tension 3.54 (0.62) 2.99 (0.66)
Reduced sleep 2.28 (1.35) 1.99 (1.64)
Reduced appetite 1.68 (1.04) 1.57 (0.49)
Concentration difficulties 2.25 (1.06) 1.77 (1.36) ⁎
Lassitude 2.05 (0.66) 1.44 (0.22) ⁎
Inability to feel 4.11 (1.42) 3.16 (0.25) ⁎⁎
Pessimistic thoughts 3.01 (0.57) 2.80 (0.34)
Suicidal thoughts 0.99 (0.22) 0.78 (0.51)
⁎ Significantly improved compared with baseline, Pb0.05.
⁎⁎ Significantly improved compared with baseline, Pb0.01.was a small, nonrandomized, open-label study. Thus, the
possibility that the observed favourable response of bipolar
depressive symptoms to aripiprazole therapy was
instead due to clinician or patient bias, placebo response,
or spontaneous improvement cannot be excluded. In
addition, self-report instruments like the SHAPS are
generally of low reliability compared with scales administered
by clinicians. Nevertheless, scores on MADRS
subscales seem to be in line with the SHAPS scores.
Specificity of the effects of aripiprazole on depression
and anhedonia needs to be further evaluated in doubleblind,
controlled trials. However, the goal of this pilot
study was merely to show the course of anhedonia
in bipolar patients during aripiprazole treatment under
routine conditions.
5. Conclusion
In conclusion, this study demonstrates that anhedonia
is a frequent symptom in patients with bipolar disorder
type I and that it can be reliably assessed with the selfrated
SHAPS. In this sample of patients, aripiprazole
showed a good tolerability and efficacy in the treatment
of depressive symptoms, in particular anhedonic symptoms.
Because of the frequency and clinical relevance
of depression and anhedonia in bipolar patients, further
studies of the efficacy and effectiveness of this novel
antipsychotic in bipolar disorder, depression and anhedonia
are warranted.References
Aihara, K., Shimada, J.,Miwa, T., Tottori, K., Burris, K.D., Yocca, F.D.,
Horie,M., Kikuchi, T., 2004. The novel antipsychotic aripiprazole is
a partial agonist at short and long isoforms of D2 receptors linked to
the regulation of adenylyl cyclase activity and prolactin release. Brain
Research 1003 (12), 917.
American Psychiatric Association, 1994. Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. APA, Washington, DC.
Etain, B., Roy, I., Henry, C., Rousseva, A., Schurhoff, F., Leboyer, M.,
Bellivier, F., 2007. No evidence for physical anhedonia as a candidate
symptom or an endophenotype in bipolar affective disorder. Bipolar
Disorders 9 (7), 706712.
Keck, P.E., Calabrese, J.R.,McIntyre, R.S.,McQuade,R.D., Carson,W.H.,
Eudicone, J.M., Carlson, B.X., Marcus, R.N., Sanchez, R., for the
Aripiprazole Study Group, 2007. Aripiprazole monotherapy for
maintenance therapy in bipolar I disorder: a 100-week, double-blind
study versus placebo. Journal of Clinical Psychiatry 68, 14801491.
Kemp, D.E., Gilmer, W.S., Fleck, L., Straus, J.L., D*g*, P.L., Karaffa,
M., 2007. Aripiprazole augmentation in treatment-resistant bipolar
depression: early response and development of akathisia. Progress in
Neuro-Psychopharmacology & Biological Psychiatry 31, 574577.
Kessler, R.M., 2007. Aripiprazole: what is the role of dopamine D2
receptor partial agonism? American Journal of Psychiatry 164 (9),
13101312.
McElroy, S.L., Suppes, T., Frye, M.A., Altshuler, L.L., Stanford, K.,
Martens, B., Leverich, G.S., Post, R.M., Keck Jr., P.E., 2007.
Open-label aripiprazole in the treatment of acute bipolar depression:
a prospective pilot trial. Journal of Affective Disorders 101
(13), 275281.
McIntyre, R.S., Soczynska, J.K., Woldeyohannes, H.O., Miranda, A.,
Konarski, J.Z., 2007. Aripiprazole: pharmacology and evidence in
bipolar disorder. Expert Opinion on Pharmacotherapy 8 (7),
10011009.
Montgomery, S.A., Åsberg, M., 1979. A new depression scale
designed to be sensitive to change. British Journal of Psychiatry
134, 382389.
Pae, C.U., Serretti, A., Patkar, A.A., Masand, P.S., 2008. Aripiprazole
in the treatment of depressive and anxiety disorders: a review of
current evidence. CNS Drugs 22 (5), 367388.
Serretti, A., Olgiati, P., 2004. Dimensions of major psychoses: a
confirmatory factor analysis of six competing models. Psychiatry
Research 127 (12), 101109.
Snaith, R.P., Hamilton, M., Morley, S., Humayan, A., Hargreaves, D.,
Trigwell, P., 1995. A scale for the assessment of hedonic tone: the
SnaithHamilton Pleasure Scale. British Journal of Psychiatry 167
(1), 99103.
Sokolski, K.N., 2007. Adjunctive aripiprazole in bipolar I depression.
Annals of Pharmacotherapy 41 (1), 3540.
Young, R.C., Biggs, J.T., Ziegler, V.E., Meyer, D.A., 1978. A rating
scale for mania: reliability, validity and sensitivity. British Journal
of Psychiatry 133, 429435
poster:Jay_Bravest_Face
thread:915130
URL: http://www.dr-bob.org/babble/20090826/msgs/915197.html