Journal of Affective Disorders 173 (2015) 211–215
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Cognitive tolerability following successful long term treatment of major depression and anxiety disorders with SSRi antidepressants Dina Popovic a,n, Eduard Vieta a, Michele Fornaro b, Giulio Perugi c a Bipolar Disorders Program, Department of Psychiatry and Psychology, Hospital Clínic, IDIBAPS, CIBERSAM, University of Barcelona, 170 Villarroel st., 08036 Barcelona, Catalonia, Spain b Harvard School of Public Health, Boston, MA, USA c Clinica Psichiatrica, Dipartmento di Medicina Sperimentale, University of Pisa, Via Roma 67, Pisa, Italy
art ic l e i nf o
a b s t r a c t
Article history: Received 22 July 2014 Received in revised form 6 November 2014 Accepted 6 November 2014 Available online 15 November 2014
Background: The present study aims to evaluate cognitive tolerability profile of SSRIs in long-term treatment. The secondary aim is to explore differences of side effects profile between patients with major depression (MD) and anxiety disorders (AD). Methods: Sixty-seven consecutive patients, successfully treated with SSRIs in monotherapy for at least six months for MD or AD, were assessed for side effects, with a special focus on cognition. Results: Over 20% of MD and AD patients in long term treatment with SSRIs reported cognitive symptoms including fatigue, inattentiveness, lack of concentration, memory impairment and apathy. Recall memory impairment, attention deficit and somnolence were most frequently rated as moderate or severe. There were no significant differences in SSRI cognitive side effects profile between MD and AD patients. Limitations: Subjective measure of cognitive functioning, limited sample size, lack of a control group. Conclusions: A large proportion of depressed and anxious patients treated successfully with SSRIs for over six months reported cognitive, affective, motivational symptoms. These symptoms are likely to represent SSRI side effects rather than residual depressive symptomatology. & 2014 Elsevier B.V. All rights reserved.
Keywords: SSRI Antidepressant Cognitive side effects Tolerability Long-term
1. Introduction Selective serotonin reuptake inhibitors (SSRIs) represent the gold standard of treatment for a wide spectrum of mood, anxiety and behavioural disorders (De las Cuevas and Sanz, 2006). SSRIs represent an important progress in terms of safety and tolerability when compared to previously used agents. The great manageability of these compounds has permitted the access to specific medication to a wide range of patients previously untreated or exposed to unspecific and/or non-effective treatments. Their broader diffusion has permitted to extend the treatment of depression to non-specialist psychiatric environments. In the last decades an elevated number of patients was treated with SSRIs for extended periods of time and limits to the efficacy and tolerability of these drugs have been reported ever more often. Despite considerable improvements in toxicity and acute side-effect profile when compared to tricyclic antidepressants and monoamine oxidase inhibitors, SSRIs are still associated with significant long-
n
Corresponding author. Tel.: 0034932275400x3130; fax: +34 932 275 795. E-mail address: [email protected] (D. Popovic).
http://dx.doi.org/10.1016/j.jad.2014.11.008 0165-0327/& 2014 Elsevier B.V. All rights reserved.
term side effects that affect treatment adherence and quality of life (Baldwin, 2006). Around 50–60% of patients diagnosed with major depressive disorder (MDD) treated with SSRIs reaches a response (Papakostas et al., 2008; Brent et al., 2008), although many of these responders experience residual depressive symptoms (McClintock et al., 2011). Long-term outcome is even less favorable and underexplored. Cognitive symptoms of patients with psychiatric disorders contribute substantially to the burden of illness (Papakostas, 2014; Vieta, 2014). Individuals with MDD who present cognitive symptoms following antidepressant treatment have worse functional outcomes, are less likely to remit and tend to have more relapses (Papakostas, 2014). Cognitive impairment, in fact, may be considered a measure of allostatic load (Vieta et al., 2013). Although antidepressants are suggested to improve cognitive function to some degree in patients with MDD (Keefe et al., 2014), there is a lack of adequate and well-controlled studies to investigate this issue (McIntyre et al., 2014). Furthermore, in the current scientific literature there is an evident paucity of studies aiming to evaluate side effects emerging during long-term treatment with SSRIs (Cassano and Fava, 2004), in particular studies evaluating patients treated for over six months and/or in
212
D. Popovic et al. / Journal of Affective Disorders 173 (2015) 211–215
monotherapy. Even most of the studies on short-term side effect profile did not routinely assess cognitive side effects. The aim of the present study was to evaluate the tolerability profile of various SSRIs used in long-term treatment of MD and anxiety disorders (AD), with a particular focus on cognitive side effects. The secondary aim was to detect eventual differences of side effect profile among patients affected by MDD and patients with AD.
2. Methods 2.1. Study sample The study sample was composed of 67 consecutive patients treated at the outpatient clinic of Pisa University Hospital between March 2008 and May 2009. Eligible patients were aged Z18, treated with a SSRI in monotherapy for at least six months, were able to give informed consent and fill out self-administered questionnaires. Exclusion criteria included concurrent nontreated or impactful physical pathologies, organic mental disorders, chronic psychoses or schizophrenia, assumption of other psychiatric medication; including continuous use of benzodiazepines, not providing informed consent. The study protocol was approved by the local Ethic Committee. Patients received no payment for participation in this study. 2.2. Study scales Participants were evaluated by a trained psychiatrist (DP and MF) by the means of Diagnostic, Clinical and Therapeutic Checklist (DCTC) developed by our group. Participants were then provided with a questionnaire pack consisting of several self-rated scales, including Harvard Department of Psychiatry/NDSD (HANDS) scale, The Epworth Sleepiness Scale (ESS), the Brief Fatigue Inventory (BFI), the MGH Cognitive and Physical Functioning Questionnaire (CPFQ) and a study-specific questionnaire developed by Fava et al. (2006). DCTC is a semi-structured interview exploring diagnostic criteria for the current and lifetime diagnosis according to DSMIV TR Axis I disorders; psychiatric and physical comorbidities and psychopharmacological treatments are also explored. DCTC also includes the assessment of the illness severity and patients’ psychosocial functioning, by the means of CGI (Clinical Global Impression) and GAF (Global Assessment of Functioning) scales. CGI evaluates the illness severity according to clinician’s experience, while GAF represents global evaluation of individual’s psychosocial functioning.
HANDS scale consists of 10 questions evaluating depressive symptoms. The scale predicts the likelihood of an individual suffering from any depressive disorder, with a cut-off total score of nine points or higher indicating the presence of MDD (Baer et al., 2000). The ESS and BFI are self-rated scales measuring excessive sleepiness and fatigue, respectively. An ESS score of eight or greater indicates pathologic sleepiness. For BFI, in accordance with other similar studies (Fava et al.,2006), we have considered cut-off of four for each item (40 total score) to identify patients with moderate to severe fatigue. The MGH CPFQ consists of seven questions evaluating subject’s cognitive and physical well-being. Answers are graded on a sixpoint scale, ranging from “greater than normal” (a score of 1) to “totally absent” (a score of 6). The study-specific questionnaire lists the prescribed antidepressant and potential cognitive side effects patients could present. Side effect occurrence is rated from “not at all” to “a lot”. In order to compare among different SSRIs we have calculated the “equivalent paroxetine dose” as following: 30 mg Paroxetine¼20 mg Escitalopram¼30 mg Citalopram¼30 mg Fluoxetine¼140 mg Sertraline. (Baldessarini, 2013). 2.3. Statistical analysis Descriptive analyses were utilized for the definition of the frequencies. Patients were divided in two groups on the basis of the presence of current or lifetime major depression (MD group) and anxiety disorder without current or lifetime comorbid major depression (AD group). Continuous variables were compared by Student’s t-tests and ANOVA and categorical variables by Chisquare and Fisher’s exact test when appropriated (α-value, two tailed). Multivariate analysis (MANCOVA) and logistic regression were performed. Mean differences in some quantitative variables were assessed by the Mann-Whitney test for two independent groups, when appropriate. Significance was set at p o0.05 (two tailed). Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, 18.0 version for Windows).
3. Results Sixty-seven patients (mean age 43.8 715.04, males n ¼31, 46.3%) were included in the study, 37 (55.2%) with a current or lifetime history of MDD and 30 (44.8%) affected by AD without comorbid MDD. Mean SSRIs dose corresponded to 19 712.66 mg of paroxetine equivalent. Patients were affected by following
Table 1 Demographic and clinical characteristics of “Major depression” vs. “Anxiety disorders” groups.
Age (years)n Equivalent dose (mg Paroxetine) Time spent in treatment (months) HANDS tot GAF ESS tot BFI tot Medication Paroxetine Citalopram Escitalopram Fluoxetine Sertraline
Major depression (n ¼37)
Anxiety disorders (n¼ 30)
Mean
SD
Mean
SD
47.27 16.54 38.00 2.11 78.06 2.74 14.72 n 20 4 2 3 8
16.06 9.648 45.883 3.003 12.147 3.657 19.393 % 54.1 10.8 5.4 8.1 21.6
39.53 22.03 31.67 1.47 76.67 2.04 8.29 n 16 3 5 2 4
12.667 15.233 45.110 2.945 18.815 2.919 12.211 % 53.3 10.0 16.7 6.7 13.3
F
Sig.
4.626 3.223 0.320 0.767 0.131 0.654 2.354 χ² 0,003 0.12 2.246 0.50 0.777
0.035 0.077 0.573 0.384 0.719 0.422 0.130 p 0.953 0.914 0.134 0.823 0.379
D. Popovic et al. / Journal of Affective Disorders 173 (2015) 211–215
phenomenological overlap between side effects and residual symptoms of depression. Thus, symptoms such as fatigue, cognitive impairment, apathy, irritability, and sleep and appetite changes may represent features of depression as well as antidepressant side effects (Kelly et al., 2008). Because of the possible overlap between symptoms of depression and SSRIs side effects, patients were split in two groups-MD and AD- according to the presence or absence of depression as main or comorbid diagnosis. The two groups presented similar demographic characteristics, except for the mean age. Both groups met criteria for treatment response according to the HANDS, CGI and GAF total scores, without significant differences among groups. Psychosocial impairment as self-evaluated by the means of Harvard Department of Psychiatry study-specific questionnaire was reported in a low percentage of patients (working difficulties and interpersonal difficulties in 7.7%, social impairment in 3.1% of patients). The most frequent cognitive complaints were inattentiveness, forgetfulness, mental slowing, apathy and word-finding difficulty, reported in 15 to 25% of patients. One patient out of four or five reported lack of concentration, memory impairment and apathy. There were no significant differences between the two groups regarding cognitive complaints profile. This finding supports the hypothesis that cognitive symptoms are not simply a result of 35 31.4
30 26.9
Proportion of patients,%
disorders: MDD (n ¼35, 52.2%), panic disorder (n¼12, 17.9%), obsessive compulsive disorder (n ¼11, 16.4%), panic disorder with agoraphobia (n ¼7, 10.4%), social phobia (n ¼2, 3%), generalized anxiety disorder (n¼ 2, 3%) and bulimia nervosa (n ¼1, 1.5%). The two groups presented similar demographic and clinical characteristics (Please see Table 1), except for the mean age being higher in the MD group (47.27 716.06 versus 39.537 12. 67). Both groups met criteria for response according to the HANDS (score o 9). The most frequent cognitive side-effects, as emerging from MGH-CPFQ questionnaire, were fatigue (n ¼21, 31.3%), inattentiveness (n ¼18, 26.9%) and recall memory impairment (n¼14, 20.9%) (Please see Table 2) No significant differences were detected between the two groups (Wilks Lambda 0.854, Sig. 0.208). The symptoms most frequently rated as moderate to severe, as depicted in Fig. 1, were fatigue (n ¼8, 12%), apathy, inattentiveness and memory impairment (n ¼4, 6%). The most frequent side effects, as reported on the studyspecific questionnaire developed by Fava et al., (7) were concentration impairment (n ¼16, 25%), memory impairment (n ¼14, 21.9%), apathy (n ¼13, 20.4%) and fatigue (n ¼13, 20.4%) (Please see Table 3). There were no differences between groups (Wilks Lambda 0.939, Sig.0.824). The most common side effects reported in the MD group were fatigue (n ¼8, 23%), reduced concentration (n ¼8, 23%), apathy (n ¼7, 20.6%) and memory impairment (n ¼7, 20.6%). The most often reported side effects in the AD group were concentration impairment (n ¼8, 26.7%), memory impairment (n¼ 7, 23.3%) and somnolence (n ¼7, 24.1%). The symptoms most frequently rated as moderate to severe were recall memory impairment (n¼7, 11%), attention deficit (n¼ 6, 9.4%) and somnolence (n ¼5, 7.9%) (Fig. 2). When evaluating sleepiness based on the ESS scores, there were no significant differences among the two groups, and both groups received a main score lower than 8. Fatigue severity, as assessed by BFI was classified as “mild” in both groups (Table 1).
213
25 20.9
16.4
17.19
16.4 14.9
15 11.9
12
14.9 11.9
10.4
10
4. Discussion
6
6
6 4.5
5
3 1.5
3
ss Fa tig In ue at te nt iv en Fo es rg s W et or hf dul fin ne di ss ng di ffi cu M en lty ta ls lo w in g
ne
ee pi
A
pa th y
0
Sl
To the best of our knowledge this is the first study assessing side effects, in particular cognitive complaints, in patients treated with SSRIs in monotherapy for over six months. This study was conduced in “real-world setting”, which may account for higher incidence of SSRI related side effects than usually reported in clinical trials (Bolling and Kohlenberg, 2004). Among the long-term SSRI side effects a key role is played by cognitive side effects such as impairment of memory, concentration and attention as well as motivational and affective response to external stimuli and/or events (Bolling and Kohlenberg, 2004; Hu et al., 2004; Fava et al., 2006). The correct evaluation of antidepressant side effects is often challenging given the
20.9
19.4
20
Any impairment
Mild impairment
Moderate to severe
Fig. 1. Proportion of patients with cognitive and physical impairment (Study Specific Questionnaire, MGH-CPFQ).
Table 2 MGH-CPFQ in “Major depression” vs. “Anxiety disorders” groups.
Reduced Motivation Reduced Wakefulness Reduced energy Reduced focus Reduced recall Memory Word-finding Difficulty Mental slowing
Major depression (N¼ 37)
Anxiety disorder (N¼30)
Total (N¼ 67)
n
%
n
%
n
%
8 9 12 11 9 9 6
21.6 24.3 32.4 29.7 24.3 24.3 16.2
3 2 9 7 5 2 6
10 6.7 30 23.3 16.7 6.7 20
11 11 21 18 14 11 12
16.4 16.4 31.4 26.9 20.9 16.4 17.9
χ²
p
1.631 3.764 0.46 0.345 0.588 3.764 0.161
0.202 0.052 0.831 0.557 0.443 0.052 0.688
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D. Popovic et al. / Journal of Affective Disorders 173 (2015) 211–215
Table 3 Harvard department of psychiatry study-specific questionnaire CPFQ in “Major depression” vs. “Anxiety disorders” groups. Variable
Apathy Somnolence Fatigue Reduced concentration Reduced memory Word- finding difficulty Mental slowing Work/study difficulties Economic impairment Worsening of psychiatric disorder Reduced self-esteem Social impairment Interpersonal difficulties
Major depression (N¼37)
Anxiety disorder (N¼ 30)
Total (N¼ 67)
n
%
n
%
n
%
7 5 8 8 7 6 4 4 3 0 2 2 4
22.6 14.7 23.5 23.5 20.6 17.6 11.8 11.4 8.6 0 5.7 5.7 11.4
6 7 5 8 7 4 4 1 0 1 2 0 1
18.2 24.1 16.7 26.7 23.3 13.3 13.3 3.3 0 3.3 6.7 0 3.3
13 12 13 16 14 10 8 5 3 1 4 2 5
20.4 19.0 20.3 25.0 21.9 15.6 12.5 7.7 4.6 1.5 6.2 3.1 7.7
25
Proportion of patients,%
21.9 20.4
20.4
20
19 15.7
15.6
15
14.1
14.1 12.5 11.1
11 10.9 9.4
10
0.003 0.903 0.464 0.084 0.70 0.225 0.036 1.491 2.696 1.185 0.025 1.769 1.491
0.953 0.342 0.496 0.772 0.791 0.635 0.850 0.222 0.101 0.276 0.873 0.184 0.222
10.9 9.4
7.9 6.3
p
the patients. The profile of the cognitive symptomatology is similar and present in both depressive and anxious patients, suggesting that these symptoms are side effects of SSRIs, rather than residual depressive symptoms. Considering that our study population is characterized by good response to monotherapy, it is likely that the above mentioned symptomatology is even more relevant in patients with partial response and treated with drug combinations. The consequence and the impact of iatrogenic cognitive symptoms on subjective well-being and social functioning deserve further exploration.
30
25
χ²
6.3
Role of funding source This is a investigator-initiated study. Dr. Popovic’s work is supported by a Sara Borrell post-doctoral grant CD13/ 00149, provided by Carlos III Institute, Spanish Ministry of Science and Innovation.
6.3
5 1.6
Any impairment
al l di ffi cu lty M en ta lA cu ity
ec R
W or dfin di ng
Fo cu s
gy er En
M ot iv at io W n ak ef ul ne ss
0
Mild impairment
Moderate to severe
Fig. 2. Proportion of patients with cognitive and physical impairment (Harvard Department of Psychiatry Cognitive and Physical Functioning Questionnaire CPFQ).
residual depressive symptomatology in subgroups of patients. The abovementioned hypothesis is further supported by evidence indicating that antidepressants influence cognitive and emotional processing functions even in healthy subjects (Serretti et al., 2010). The main limitation of our study is that we have not included objective measures of cognitive function. Moreover, due to the limited sample size, both type I and type II errors are possible. Finally, the study lacks a healthy control group. In fact, while keeping in mind that various psychiatric disorders, as well as different drug treatments can produce impairment in general attention and concentration and in measures of psychological and motor performance, in our opinion the comparison between patients with depression and anxiety spectrum disorders can serve to overcome the absence of a placebo comparator. In conclusion, about one quarter of our depressive or anxious patients successfully treated with SSRIs for at least six months, presented cognitive, affective, motivational complaints. These symptoms were reported as moderate to severe in around 10% of
Conflict of interest Dr. Popovic has served as speaker for Bristol-Myers Squibb, Merck Sharp & Dohme and Janssen-Cilag. Dr. Fornaro declares no conflicts of interest. Prof. Perugi has acted as consultant of Astra Zeneca, Eli Lilly, Lundbeck; received grant/research support from Eli lilly; is on the speaker/advisory board of Sanofi Aventis, Bristol Myers Squibb, Astra Zeneca, Eli Lilly, Jannsen-Cilag, Lundbeck. Prof. Vieta has received research support from or served as consultant, adviser, or speaker for Alexza, Almirall, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest Research Institute, 7th Framework Program of the European Union, Geodon Richter, GlaxoSmithKline, Janssen-Cilag, Jazz, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Solvay, Schering-Plough, Shire, Spanish Ministry of Science and Innovation, Stanley Medical Research Institute, Takeda, Teva, United Biosource Corporation and Wyeth.
Acknowledgements Dr. Popovic’s work is supported by a Sara Borrell post-doctoral grant CD13/ 00149, provided by Carlos III Institute, Spanish Ministry of Science and Innovation.
References De las Cuevas, C., Sanz, E.J., 2006. Safety of selective serotonin reuptake inhibitors in pregnancy. Curr. Drug Saf. 1 (1), 17–24. Papakostas, G.I., Nelson, J.C., Kasper, S., et al., 2008. A meta-analysis of clinical trials comparing reboxetine, a norepinephrine reuptake inhibitor, with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. Eur. Neuropsychopharm. 18 (2), 122–127. Brent, D., Emslie, G., Clarke, G., et al., 2008. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA 299 (8), 901–913. McClintock, S.M., Husain, M.M., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Trivedi, M.H., Cook, I., Morris, D., Warden, D., Rush, A.J., 2011. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J. Clin. Psychopharm. 31 (2), 180–186.
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Baldwin, D.S., 2006. The importance of long-term tolerability in achieving recovery. Int. J. Psychiat. Clin. Prac 10 (Suppl 1), 31–37. Papakostas, G.I., 2014. Cognitive symptoms in patients with major depressive disorder and their implications for clinical practice. J. Clin. Psychiat. 75 (1), 8–14. Vieta, E., 2014. The bipolar maze: a roadmap through translational psychopathology. Acta Psychiat. Scand. 129 (5), 323–327. Vieta, E., Popovic, D., Rosa, A.R., et al., 2013. The clinical implications of cognitive impairment and allostatic load in bipolar disorder. Eur. Psychiat. 28, 21–29. Keefe, R.S.E., McClintock, S.M., Roth, R.M., Doraiswamy, P.M., Tiger, S., Madhoo, M., 2014. Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review. J. Clin. Psych.Psych. 75 (8), 864–876. McIntyre, R.S., Lophaven, S., Olsen, C.K., 2014. A randomized, double-blind, placebocontrolled study of vortioxetine on cognitive function in depressed adults. Int. J. Neuropsychopharm. 30, 1–11. Cassano, P., Fava, M., 2004. Tolerability issues during long-term treatment with antidepressants. Ann. Clin. Psychiat 16 (1), 15–25. Baer, L., Jacobs, D.G., Meszler-Reizes, J., et al., 2000. Development of a brief screening instrument: the hands. Psychother. Psyc. 69 (1), 35–41.
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Baldessarini, R.J., 2013. Chemotherapy in Psychiatry. Pharmacologic Basis of Treatments for Major Mental Illness, third ed. Springer, p. 183. Bolling, M.Y., Kohlenberg, R.J., 2004. Reasons for quitting serotonin reuptake inhibitor therapy: paradoxical psychological side effects and patient satisfaction. Psychother Psyc. 73, 380–385. Hu, X.H., Bull, S.A., Hunkeler, E.M., et al., 2004. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J. Clin. Psychiat. 65, 959–965. Fava, M., Graves, L.M., Benazzi, F., et al., 2006. A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment. J. Clin. Psychiatr. 67 (11), 1754–1759. Kelly, K., Posternak, M., Alpert, J.E., 2008. Toward achieving optimal response: understanding and managing antidepressant side effects. Dialogues. Clin. Neurosci. 10 (4), 409–418. Serretti, A., Calati, R., Goracci, A., Di Simplicio, M., Castrogiovanni, P., De Ronchi, D., 2010. Antidepressants in healthy subjects: what are the psychotropic/psychological effects? Eur. Neuropsychopharm 20 (7), 433–453.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Cognitive tolerability following successful long term treatment of major depression and anxiety disorders with SSRi antidepressants Dina Popovic a,n, Eduard Vieta a, Michele Fornaro b, Giulio Perugi c a Bipolar Disorders Program, Department of Psychiatry and Psychology, Hospital Clínic, IDIBAPS, CIBERSAM, University of Barcelona, 170 Villarroel st., 08036 Barcelona, Catalonia, Spain b Harvard School of Public Health, Boston, MA, USA c Clinica Psichiatrica, Dipartmento di Medicina Sperimentale, University of Pisa, Via Roma 67, Pisa, Italy
art ic l e i nf o
a b s t r a c t
Article history: Received 22 July 2014 Received in revised form 6 November 2014 Accepted 6 November 2014 Available online 15 November 2014
Background: The present study aims to evaluate cognitive tolerability profile of SSRIs in long-term treatment. The secondary aim is to explore differences of side effects profile between patients with major depression (MD) and anxiety disorders (AD). Methods: Sixty-seven consecutive patients, successfully treated with SSRIs in monotherapy for at least six months for MD or AD, were assessed for side effects, with a special focus on cognition. Results: Over 20% of MD and AD patients in long term treatment with SSRIs reported cognitive symptoms including fatigue, inattentiveness, lack of concentration, memory impairment and apathy. Recall memory impairment, attention deficit and somnolence were most frequently rated as moderate or severe. There were no significant differences in SSRI cognitive side effects profile between MD and AD patients. Limitations: Subjective measure of cognitive functioning, limited sample size, lack of a control group. Conclusions: A large proportion of depressed and anxious patients treated successfully with SSRIs for over six months reported cognitive, affective, motivational symptoms. These symptoms are likely to represent SSRI side effects rather than residual depressive symptomatology. & 2014 Elsevier B.V. All rights reserved.
Keywords: SSRI Antidepressant Cognitive side effects Tolerability Long-term
1. Introduction Selective serotonin reuptake inhibitors (SSRIs) represent the gold standard of treatment for a wide spectrum of mood, anxiety and behavioural disorders (De las Cuevas and Sanz, 2006). SSRIs represent an important progress in terms of safety and tolerability when compared to previously used agents. The great manageability of these compounds has permitted the access to specific medication to a wide range of patients previously untreated or exposed to unspecific and/or non-effective treatments. Their broader diffusion has permitted to extend the treatment of depression to non-specialist psychiatric environments. In the last decades an elevated number of patients was treated with SSRIs for extended periods of time and limits to the efficacy and tolerability of these drugs have been reported ever more often. Despite considerable improvements in toxicity and acute side-effect profile when compared to tricyclic antidepressants and monoamine oxidase inhibitors, SSRIs are still associated with significant long-
n
Corresponding author. Tel.: 0034932275400x3130; fax: +34 932 275 795. E-mail address: [email protected] (D. Popovic).
http://dx.doi.org/10.1016/j.jad.2014.11.008 0165-0327/& 2014 Elsevier B.V. All rights reserved.
term side effects that affect treatment adherence and quality of life (Baldwin, 2006). Around 50–60% of patients diagnosed with major depressive disorder (MDD) treated with SSRIs reaches a response (Papakostas et al., 2008; Brent et al., 2008), although many of these responders experience residual depressive symptoms (McClintock et al., 2011). Long-term outcome is even less favorable and underexplored. Cognitive symptoms of patients with psychiatric disorders contribute substantially to the burden of illness (Papakostas, 2014; Vieta, 2014). Individuals with MDD who present cognitive symptoms following antidepressant treatment have worse functional outcomes, are less likely to remit and tend to have more relapses (Papakostas, 2014). Cognitive impairment, in fact, may be considered a measure of allostatic load (Vieta et al., 2013). Although antidepressants are suggested to improve cognitive function to some degree in patients with MDD (Keefe et al., 2014), there is a lack of adequate and well-controlled studies to investigate this issue (McIntyre et al., 2014). Furthermore, in the current scientific literature there is an evident paucity of studies aiming to evaluate side effects emerging during long-term treatment with SSRIs (Cassano and Fava, 2004), in particular studies evaluating patients treated for over six months and/or in
212
D. Popovic et al. / Journal of Affective Disorders 173 (2015) 211–215
monotherapy. Even most of the studies on short-term side effect profile did not routinely assess cognitive side effects. The aim of the present study was to evaluate the tolerability profile of various SSRIs used in long-term treatment of MD and anxiety disorders (AD), with a particular focus on cognitive side effects. The secondary aim was to detect eventual differences of side effect profile among patients affected by MDD and patients with AD.
2. Methods 2.1. Study sample The study sample was composed of 67 consecutive patients treated at the outpatient clinic of Pisa University Hospital between March 2008 and May 2009. Eligible patients were aged Z18, treated with a SSRI in monotherapy for at least six months, were able to give informed consent and fill out self-administered questionnaires. Exclusion criteria included concurrent nontreated or impactful physical pathologies, organic mental disorders, chronic psychoses or schizophrenia, assumption of other psychiatric medication; including continuous use of benzodiazepines, not providing informed consent. The study protocol was approved by the local Ethic Committee. Patients received no payment for participation in this study. 2.2. Study scales Participants were evaluated by a trained psychiatrist (DP and MF) by the means of Diagnostic, Clinical and Therapeutic Checklist (DCTC) developed by our group. Participants were then provided with a questionnaire pack consisting of several self-rated scales, including Harvard Department of Psychiatry/NDSD (HANDS) scale, The Epworth Sleepiness Scale (ESS), the Brief Fatigue Inventory (BFI), the MGH Cognitive and Physical Functioning Questionnaire (CPFQ) and a study-specific questionnaire developed by Fava et al. (2006). DCTC is a semi-structured interview exploring diagnostic criteria for the current and lifetime diagnosis according to DSMIV TR Axis I disorders; psychiatric and physical comorbidities and psychopharmacological treatments are also explored. DCTC also includes the assessment of the illness severity and patients’ psychosocial functioning, by the means of CGI (Clinical Global Impression) and GAF (Global Assessment of Functioning) scales. CGI evaluates the illness severity according to clinician’s experience, while GAF represents global evaluation of individual’s psychosocial functioning.
HANDS scale consists of 10 questions evaluating depressive symptoms. The scale predicts the likelihood of an individual suffering from any depressive disorder, with a cut-off total score of nine points or higher indicating the presence of MDD (Baer et al., 2000). The ESS and BFI are self-rated scales measuring excessive sleepiness and fatigue, respectively. An ESS score of eight or greater indicates pathologic sleepiness. For BFI, in accordance with other similar studies (Fava et al.,2006), we have considered cut-off of four for each item (40 total score) to identify patients with moderate to severe fatigue. The MGH CPFQ consists of seven questions evaluating subject’s cognitive and physical well-being. Answers are graded on a sixpoint scale, ranging from “greater than normal” (a score of 1) to “totally absent” (a score of 6). The study-specific questionnaire lists the prescribed antidepressant and potential cognitive side effects patients could present. Side effect occurrence is rated from “not at all” to “a lot”. In order to compare among different SSRIs we have calculated the “equivalent paroxetine dose” as following: 30 mg Paroxetine¼20 mg Escitalopram¼30 mg Citalopram¼30 mg Fluoxetine¼140 mg Sertraline. (Baldessarini, 2013). 2.3. Statistical analysis Descriptive analyses were utilized for the definition of the frequencies. Patients were divided in two groups on the basis of the presence of current or lifetime major depression (MD group) and anxiety disorder without current or lifetime comorbid major depression (AD group). Continuous variables were compared by Student’s t-tests and ANOVA and categorical variables by Chisquare and Fisher’s exact test when appropriated (α-value, two tailed). Multivariate analysis (MANCOVA) and logistic regression were performed. Mean differences in some quantitative variables were assessed by the Mann-Whitney test for two independent groups, when appropriate. Significance was set at p o0.05 (two tailed). Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, 18.0 version for Windows).
3. Results Sixty-seven patients (mean age 43.8 715.04, males n ¼31, 46.3%) were included in the study, 37 (55.2%) with a current or lifetime history of MDD and 30 (44.8%) affected by AD without comorbid MDD. Mean SSRIs dose corresponded to 19 712.66 mg of paroxetine equivalent. Patients were affected by following
Table 1 Demographic and clinical characteristics of “Major depression” vs. “Anxiety disorders” groups.
Age (years)n Equivalent dose (mg Paroxetine) Time spent in treatment (months) HANDS tot GAF ESS tot BFI tot Medication Paroxetine Citalopram Escitalopram Fluoxetine Sertraline
Major depression (n ¼37)
Anxiety disorders (n¼ 30)
Mean
SD
Mean
SD
47.27 16.54 38.00 2.11 78.06 2.74 14.72 n 20 4 2 3 8
16.06 9.648 45.883 3.003 12.147 3.657 19.393 % 54.1 10.8 5.4 8.1 21.6
39.53 22.03 31.67 1.47 76.67 2.04 8.29 n 16 3 5 2 4
12.667 15.233 45.110 2.945 18.815 2.919 12.211 % 53.3 10.0 16.7 6.7 13.3
F
Sig.
4.626 3.223 0.320 0.767 0.131 0.654 2.354 χ² 0,003 0.12 2.246 0.50 0.777
0.035 0.077 0.573 0.384 0.719 0.422 0.130 p 0.953 0.914 0.134 0.823 0.379
D. Popovic et al. / Journal of Affective Disorders 173 (2015) 211–215
phenomenological overlap between side effects and residual symptoms of depression. Thus, symptoms such as fatigue, cognitive impairment, apathy, irritability, and sleep and appetite changes may represent features of depression as well as antidepressant side effects (Kelly et al., 2008). Because of the possible overlap between symptoms of depression and SSRIs side effects, patients were split in two groups-MD and AD- according to the presence or absence of depression as main or comorbid diagnosis. The two groups presented similar demographic characteristics, except for the mean age. Both groups met criteria for treatment response according to the HANDS, CGI and GAF total scores, without significant differences among groups. Psychosocial impairment as self-evaluated by the means of Harvard Department of Psychiatry study-specific questionnaire was reported in a low percentage of patients (working difficulties and interpersonal difficulties in 7.7%, social impairment in 3.1% of patients). The most frequent cognitive complaints were inattentiveness, forgetfulness, mental slowing, apathy and word-finding difficulty, reported in 15 to 25% of patients. One patient out of four or five reported lack of concentration, memory impairment and apathy. There were no significant differences between the two groups regarding cognitive complaints profile. This finding supports the hypothesis that cognitive symptoms are not simply a result of 35 31.4
30 26.9
Proportion of patients,%
disorders: MDD (n ¼35, 52.2%), panic disorder (n¼12, 17.9%), obsessive compulsive disorder (n ¼11, 16.4%), panic disorder with agoraphobia (n ¼7, 10.4%), social phobia (n ¼2, 3%), generalized anxiety disorder (n¼ 2, 3%) and bulimia nervosa (n ¼1, 1.5%). The two groups presented similar demographic and clinical characteristics (Please see Table 1), except for the mean age being higher in the MD group (47.27 716.06 versus 39.537 12. 67). Both groups met criteria for response according to the HANDS (score o 9). The most frequent cognitive side-effects, as emerging from MGH-CPFQ questionnaire, were fatigue (n ¼21, 31.3%), inattentiveness (n ¼18, 26.9%) and recall memory impairment (n¼14, 20.9%) (Please see Table 2) No significant differences were detected between the two groups (Wilks Lambda 0.854, Sig. 0.208). The symptoms most frequently rated as moderate to severe, as depicted in Fig. 1, were fatigue (n ¼8, 12%), apathy, inattentiveness and memory impairment (n ¼4, 6%). The most frequent side effects, as reported on the studyspecific questionnaire developed by Fava et al., (7) were concentration impairment (n ¼16, 25%), memory impairment (n ¼14, 21.9%), apathy (n ¼13, 20.4%) and fatigue (n ¼13, 20.4%) (Please see Table 3). There were no differences between groups (Wilks Lambda 0.939, Sig.0.824). The most common side effects reported in the MD group were fatigue (n ¼8, 23%), reduced concentration (n ¼8, 23%), apathy (n ¼7, 20.6%) and memory impairment (n ¼7, 20.6%). The most often reported side effects in the AD group were concentration impairment (n ¼8, 26.7%), memory impairment (n¼ 7, 23.3%) and somnolence (n ¼7, 24.1%). The symptoms most frequently rated as moderate to severe were recall memory impairment (n¼7, 11%), attention deficit (n¼ 6, 9.4%) and somnolence (n ¼5, 7.9%) (Fig. 2). When evaluating sleepiness based on the ESS scores, there were no significant differences among the two groups, and both groups received a main score lower than 8. Fatigue severity, as assessed by BFI was classified as “mild” in both groups (Table 1).
213
25 20.9
16.4
17.19
16.4 14.9
15 11.9
12
14.9 11.9
10.4
10
4. Discussion
6
6
6 4.5
5
3 1.5
3
ss Fa tig In ue at te nt iv en Fo es rg s W et or hf dul fin ne di ss ng di ffi cu M en lty ta ls lo w in g
ne
ee pi
A
pa th y
0
Sl
To the best of our knowledge this is the first study assessing side effects, in particular cognitive complaints, in patients treated with SSRIs in monotherapy for over six months. This study was conduced in “real-world setting”, which may account for higher incidence of SSRI related side effects than usually reported in clinical trials (Bolling and Kohlenberg, 2004). Among the long-term SSRI side effects a key role is played by cognitive side effects such as impairment of memory, concentration and attention as well as motivational and affective response to external stimuli and/or events (Bolling and Kohlenberg, 2004; Hu et al., 2004; Fava et al., 2006). The correct evaluation of antidepressant side effects is often challenging given the
20.9
19.4
20
Any impairment
Mild impairment
Moderate to severe
Fig. 1. Proportion of patients with cognitive and physical impairment (Study Specific Questionnaire, MGH-CPFQ).
Table 2 MGH-CPFQ in “Major depression” vs. “Anxiety disorders” groups.
Reduced Motivation Reduced Wakefulness Reduced energy Reduced focus Reduced recall Memory Word-finding Difficulty Mental slowing
Major depression (N¼ 37)
Anxiety disorder (N¼30)
Total (N¼ 67)
n
%
n
%
n
%
8 9 12 11 9 9 6
21.6 24.3 32.4 29.7 24.3 24.3 16.2
3 2 9 7 5 2 6
10 6.7 30 23.3 16.7 6.7 20
11 11 21 18 14 11 12
16.4 16.4 31.4 26.9 20.9 16.4 17.9
χ²
p
1.631 3.764 0.46 0.345 0.588 3.764 0.161
0.202 0.052 0.831 0.557 0.443 0.052 0.688
214
D. Popovic et al. / Journal of Affective Disorders 173 (2015) 211–215
Table 3 Harvard department of psychiatry study-specific questionnaire CPFQ in “Major depression” vs. “Anxiety disorders” groups. Variable
Apathy Somnolence Fatigue Reduced concentration Reduced memory Word- finding difficulty Mental slowing Work/study difficulties Economic impairment Worsening of psychiatric disorder Reduced self-esteem Social impairment Interpersonal difficulties
Major depression (N¼37)
Anxiety disorder (N¼ 30)
Total (N¼ 67)
n
%
n
%
n
%
7 5 8 8 7 6 4 4 3 0 2 2 4
22.6 14.7 23.5 23.5 20.6 17.6 11.8 11.4 8.6 0 5.7 5.7 11.4
6 7 5 8 7 4 4 1 0 1 2 0 1
18.2 24.1 16.7 26.7 23.3 13.3 13.3 3.3 0 3.3 6.7 0 3.3
13 12 13 16 14 10 8 5 3 1 4 2 5
20.4 19.0 20.3 25.0 21.9 15.6 12.5 7.7 4.6 1.5 6.2 3.1 7.7
25
Proportion of patients,%
21.9 20.4
20.4
20
19 15.7
15.6
15
14.1
14.1 12.5 11.1
11 10.9 9.4
10
0.003 0.903 0.464 0.084 0.70 0.225 0.036 1.491 2.696 1.185 0.025 1.769 1.491
0.953 0.342 0.496 0.772 0.791 0.635 0.850 0.222 0.101 0.276 0.873 0.184 0.222
10.9 9.4
7.9 6.3
p
the patients. The profile of the cognitive symptomatology is similar and present in both depressive and anxious patients, suggesting that these symptoms are side effects of SSRIs, rather than residual depressive symptoms. Considering that our study population is characterized by good response to monotherapy, it is likely that the above mentioned symptomatology is even more relevant in patients with partial response and treated with drug combinations. The consequence and the impact of iatrogenic cognitive symptoms on subjective well-being and social functioning deserve further exploration.
30
25
χ²
6.3
Role of funding source This is a investigator-initiated study. Dr. Popovic’s work is supported by a Sara Borrell post-doctoral grant CD13/ 00149, provided by Carlos III Institute, Spanish Ministry of Science and Innovation.
6.3
5 1.6
Any impairment
al l di ffi cu lty M en ta lA cu ity
ec R
W or dfin di ng
Fo cu s
gy er En
M ot iv at io W n ak ef ul ne ss
0
Mild impairment
Moderate to severe
Fig. 2. Proportion of patients with cognitive and physical impairment (Harvard Department of Psychiatry Cognitive and Physical Functioning Questionnaire CPFQ).
residual depressive symptomatology in subgroups of patients. The abovementioned hypothesis is further supported by evidence indicating that antidepressants influence cognitive and emotional processing functions even in healthy subjects (Serretti et al., 2010). The main limitation of our study is that we have not included objective measures of cognitive function. Moreover, due to the limited sample size, both type I and type II errors are possible. Finally, the study lacks a healthy control group. In fact, while keeping in mind that various psychiatric disorders, as well as different drug treatments can produce impairment in general attention and concentration and in measures of psychological and motor performance, in our opinion the comparison between patients with depression and anxiety spectrum disorders can serve to overcome the absence of a placebo comparator. In conclusion, about one quarter of our depressive or anxious patients successfully treated with SSRIs for at least six months, presented cognitive, affective, motivational complaints. These symptoms were reported as moderate to severe in around 10% of
Conflict of interest Dr. Popovic has served as speaker for Bristol-Myers Squibb, Merck Sharp & Dohme and Janssen-Cilag. Dr. Fornaro declares no conflicts of interest. Prof. Perugi has acted as consultant of Astra Zeneca, Eli Lilly, Lundbeck; received grant/research support from Eli lilly; is on the speaker/advisory board of Sanofi Aventis, Bristol Myers Squibb, Astra Zeneca, Eli Lilly, Jannsen-Cilag, Lundbeck. Prof. Vieta has received research support from or served as consultant, adviser, or speaker for Alexza, Almirall, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest Research Institute, 7th Framework Program of the European Union, Geodon Richter, GlaxoSmithKline, Janssen-Cilag, Jazz, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Solvay, Schering-Plough, Shire, Spanish Ministry of Science and Innovation, Stanley Medical Research Institute, Takeda, Teva, United Biosource Corporation and Wyeth.
Acknowledgements Dr. Popovic’s work is supported by a Sara Borrell post-doctoral grant CD13/ 00149, provided by Carlos III Institute, Spanish Ministry of Science and Innovation.
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