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Antidepressant efficacy of olanzapine as monotherapy in major depressive disorder, without psychosis: A pilot study
Psychiatry Research: Neuroimaging 146 (2006) 149 – 155 www.elsevier.com/locate/psychresns
Antidepressant efficacy of olanzapine as monotherapy in major depressive disorder, without psychosis: A pilot studyB Jose Mathewsa, Keith S. Garciaa, Mark A. Mintuna,b, Yvette I. Shelinea,b,* a
Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 S. Euclid, St. Louis, MO 63110, USA b Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA Received 12 January 2005; received in revised form 19 July 2005; accepted 7 August 2005
Abstract In this pilot study we assessed the efficacy of olanzapine as monotherapy in the treatment of major depressive disorder, without psychosis. We also demonstrated the in vivo 5-HT2A receptor occupancy of olanzapine using positron emission tomography. An open-label prospective 6-week study design with 14 patients who met the inclusion and exclusion criteria for the study were enrolled from the general community of the St. Louis metropolitan area. All patients met DSM-IV criteria for major depressive disorder without psychosis, had a Hamilton Depression Rating Scale (HAMD17) score N 18 and were between the ages of 18 and 65. The primary measure of efficacy was the change in HAMD 17 total score from baseline to endpoint. The data were collected between 1998 and 2004. There was a significant reduction in the HAMD17 scores from baseline to endpoint. Half the patients (n = 6) showed z50% reduction in their HAMD17 scores. This study points to the potential of olanzapine as a therapeutic agent for the treatment of major depressive disorder without psychosis. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Antidepressants; 5-HT2A receptors; Neuroimaging; Positron emission tomography
1. Introduction There is evidence from schizophrenia trials that olanzapine has significant effects on mood. A recent review of the published literature on the efficacy of atypical antipsychotic agents in the treatment of depression, hostility, and suicidality in patients with schizophrenia B Disclosure: Dr. Mathews is on the speaker’s bureau of Janssen and Bristol-Myers Squibb. Dr. Garcia is on the speaker’s bureau of Pfizer and GlaxoSmithKline. Dr. Sheline is on the scientific advisory board of Bristol-Myers Squibb. Dr. Mintun has no conflict of interest disclosure. * Corresponding author. Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 S. Euclid, St. Louis, MO 63110, USA. Tel.: +1 314 362 8422; fax: +1 314 362 7599. E-mail address: [email protected] (Y.I. Sheline).
suggested that olanzapine may have an antidepressant effect and may reduce suicidality in patients with schizophrenia (Keck et al., 2000). There is also evidence for its use as an augmentation agent for the treatment of treatment-resistant major depression (Ghaemi et al., 2000; Shelton et al., 2001; Parker, 2002). Olanzapine has also been shown to be effective in the treatment of psychotic depression in open label studies and case reports (Nelson et al., 2001; Schatzberg, 2003). In the pivotal study comparing the efficacy of olanzapine and an olanzapine–fluoxetine combination in the treatment of bipolar I depression, the olanzapine alone group showed statistically significant improvement in depressive symptoms versus the placebo group (Tohen et al., 2003). These studies hint at a possible antidepressant action of olanzapine, although
0925-4927/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2005.08.003
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the question of whether olanzapine has any antidepressant effect in patients with unipolar major depression remains unanswered. There is also a dearth of literature looking at the efficacy of olanzapine in the treatment of unipolar depression as the sole agent in patients without psychosis. This pilot study tries to address the possibility of olanzapine as a monotherapy for unipolar major depression. The pharmacokinetic profile of olanzapine shows potent 5-HT2A receptor antagonism (Zhang and Bymaster, 1999); which may account for its antidepressant effects. Abnormalities in the 5-HT2A receptor have been reported in patients with depression and are likely indicative of altered serotonergic function (Mann et al., 1986; Arango et al., 1992). Selective antagonism of the 5-HT2A receptor with EMD 281014 showed significant increases in swimming and decreased immobility in the forced swim test paradigm in rats with congenital learned helplessness, an animal model for depression (Patel et al., 2004). Clinical studies have shown significant antidepressant properties for drugs such as mirtazapine (De Boer et al., 1995), nefazadone (Meyer et al., 1999) and trazadone (Fiorella et al., 1995) that have prominent 5-HT2A receptor antagonism. This pilot study looks at the efficacy of olanzapine as monotherapy for the treatment of major depressive disorder without psychosis to test the hypothesis that olanzapine has antidepressant efficacy for the treatment of unipolar major depressive disorder. Positron emission tomography (PET) is a powerful tool to study in vivo human brain receptor occupancy. The radio-ligand [18F]altanserin is a high affinity, selective agent for imaging 5-HT2A receptors (Lemaire et al., 1991) with reliable and established effects in in vivo human brain imaging (Mintun et al., 2004). A quantitative receptor binding study was done using [18F]altanserin to demonstrate in vivo 5-HT2A receptor occupancy of olanzapine at a clinically relevant dose, and it may be this property of olanzapine that contributes to antidepressant efficacy. 2. Methods 2.1. Study design Fourteen patients who met the inclusion and exclusion criteria for the study were enrolled after giving informed consent. The study was designed as an openlabel, prospective, 6-week trial with the primary objective of assessing the efficacy of olanzapine as an antidepressant medication in patients with major depressive disorder. All patients had a washout period of
at least five antidepressant half-lives rather than a fixed time interval. This was felt to be a better way to control for antidepressant medication such as fluoxetine, with a long half-life and the longest half-life medication was used to establish a washout period when a patient was on multiple medications. Patients were started on olanzapine 2.5 mg and titrated up according to clinical response, with a maximal daily dose of 20 mg. Adjunctive use of lorazepam was permitted up to 1 mg/day for treatment of insomnia, although it was not used in any of the patients in this study. No other psychotropic medication use was permitted during the course of study. A quantitative 5HT2A receptor binding study was done using positron emission tomography and [18F]altanserin to measure regional 5-HT2A receptor binding in the brain. Regions of interest were determined as previously described (Sheline et al., 2002) using ANALYZE software to trace boundaries and apply these regions (see Fig. 4) to individual datasets in Talairach atlas coordinates. The PET image data were collected and processed from one patient using imaging methods described in Mintun et al. (2004). 2.2. Patients All patients were between the ages of 18 and 65. They met DSM-IV criteria for unipolar major depressive disorder with a score on the 17-item version of the Hamilton Rating Scale for Depression (HAMD17) (Hamilton, 1960) of z 18. Participants were recruited from the general community of the St. Louis metropolitan area through advertisements and the Volunteer for Health program at the Barnes Jewish Hospital. The demographic characteristics are listed in Table 1. Diagnoses were confirmed by a psychiatrist through structured clinical interview. Exclusion criteria included a previous trial of olanzapine, diagnosis of schizophrenia, diagnosis of bipolar disorder, acute co-morbid medical Table 1 Demographic data Demographics N = 14
Mean
S.D.
Age (years) Gender (m, f)
47.4 5, 9
14.1
Race Caucasian African American American Indian/Alaskan Indian Unknown
10 2 1 1
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illness, active substance abuse within 3 months of study entry, Parkinson’s disease, myasthenia gravis, history of seizures, active hepatitis B, jaundice or participants considered at high risk for suicide. Before participation, all patients provided written informed consent. The Institutional Review Board at Washington University School of Medicine approved the study. 2.3. Assessments Patients had a baseline clinical visit and visits at weeks 1, 2, 3, 4, 5 and 6. The primary measure of efficacy was change in the total score on the HAMD-17 from baseline to endpoint (Fig. 1). A secondary efficacy analysis was done for the anxiety/somatization subscale (items 10, 11, 12, 13, 15, 17) (Detke et al., 2004; Brannan et al., 2005) and the Maier subscale (items 1, 2, 7, 8, 9, 10) (Maier and Philipp, 1985), both of which are subscales of the HAMD17 that examines the anxiety components and the core depressive symptoms, respectively. Rates of response were assessed and defined as at least a 50% improvement in HAMD17 scores. Remission rate, defined as an HAMD17 score of b 8, was also assessed. Adverse events were recorded on each clinical visit using the side effects check list. Severity of extrapyramidal symptoms (EPS) was evaluated by means of the Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976; Schooler and Kane, 1982) and the Simpson–Angus scale (Simpson and Angus, 1970), which were administered on each clinical visit. A thorough medical history was obtained in a standardized manner at the beginning of the study and the available medical records including laboratory tests were screened at the baseline visit. Vital signs were recorded at each visit.
Fig. 2. Change in total HAMD17 score, anxiety/somatization subscale and Maier subscale.
2.4. Data analysis All study participants with at least one post-baseline assessment were included in the primary efficacy population and the data were analyzed using a last-observation-carried-forward analysis. Changes from baseline in HAMD17 total scores, the anxiety/somatization subscale and the Maier subscale were analyzed by paired t-test. Last-observation-carried-forward and observed-case (completer) data are reported. Change from baseline in the EPS and AIMS scores are also reported, and they were analyzed by paired t-test. All t-tests are two-tailed. Commonly reported side effects are reported as a percentage of patients experiencing them at any time during the study. 3. Results Of the 14 patients enrolled in this study, 12 patients had at least one post-baseline evaluation. Eight of these patients finished the study. The mean dose of olanzapine was 7.5 mg (S.D. 3.16) and median dose was 10 mg with a range of 2.5 to 10 mg. 3.1. Efficacy
Fig. 1. A representation of the change in subjects’ Hamilton Depression scores from baseline to endpoint.
There were significant reductions in the HAMD17 total score, anxiety/somatization subscale and the Maier subscale from baseline to endpoint (Fig. 2). The pretreatment and post-treatment means with standard deviations (SD), t statistics and degrees of freedom (df) were as follows: HAMD17 total score—baseline: 23.33 (4.65); endpoint: 12.75 (7.99), paired t-test, t = 6.05, df = 11,
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Fig. 3. Average magnetic resonance image (A). Slice from a co-registered PET scan of [18F]altanserin (B). PET scan image after the administration of olanzapine showing 5-HT2A receptor competitive antagonism of olanzapine (C).
P b 0.001. Half of the patients (n = 6) showed z 50% reduction in their HAMD17 scores. Remission of symptoms with a HAMD17 score of b 8 was achieved in a third of the patients (n = 4). Anxiety/Somatization— baseline: 7.16 (1.19); endpoint: 3.91 (2.50), paired ttest, t = 4.45, df = 11), P b 0.00. Maier subscale—baseline: 12.75 (0.61); endpoint: 7.50 (1.03), paired t-test, t = 5.90, df = 11, P b 0.001. Reductions in HAMD17 scores in both total and subgroup analysis were seen in both the study completer group (n = 8) and the group that did not finish the study (n = 4). However, the reduction in the HAMD17 score did not reach statistical significance (paired t-test, df = 3, P N 0.1) in the non-completer group. The study completer group showed significant reductions as follows:
HAMD17 total score—pre-treatment: 22.75 (1.73); post-treatment: 10.62 (2.18), paired t-test, t = 6.90 df = 7, P b 0.001. Anxiety/somatization—pre-treatment: 7.12 (1.24); post-treatment: 3.00 (1.30), paired t-test, t = 6.45, df = 7, P b 0.001. Maier—pre-treatment: 12.75 (2.25); post-treatment: 6.75 (3.24), paired t-test, t = 6.35, df = 7, P b 0.001. The anxiety/somatization symptom scale reduction of z 50% from baseline to endpoint was noted in 66% of patients (n = 8). 3.2. PET study The imaging data show in vivo 5-HT2A receptor binding of olanzapine (Fig. 3). This binding was noted in all of the observed areas (see Fig. 4) as
1.8 [18F]Altanserin Regional Binding Potential
Pre-Treatment 1.6
During Treatment
1.4 1.2 1 0.8 0.6 0.4 0.2
ta
lP
ie
ua
ar
bg Su
ra te La
en
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R us yr G
FC
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ip cc O
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ita
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0
Fig. 4. Before treatment with olanzapine and the competitive antagonism of 5-HT2A receptors with the treatment effects of olanzapine are depicted above.
J. Mathews et al. / Psychiatry Research: Neuroimaging 146 (2006) 149–155 Table 2 Percentage of side effects reported in all visits Side effects
All visits (% of occurrence)
Concentration decrease Dry mouth Agitation Light headedness Somnolence Pharyngitis Headaches Myalgia Asthenia Diarrhea Dyspepsia Dizziness Incoordination Tremor Sweating Nausea Constipation Abnormal vision
57.1 42.9 42.9 42.9 42.9 42.9 35.7 35.7 28.6 28.6 28.6 28.6 28.6 28.6 28.6 21.4 21.4 7.1
evidenced by the reduction of the [18F]altanserin binding potential after the administration of olanzapine. 3.3. Adverse events Adverse events that were reported by the patient once they were on olanzapine were considered treatment emergent, and all such adverse events reported by more than 10% of the patients are listed in Table 2. Mean changes in and emergence of extrapyramidal symptoms were low and did not reach statistical significance. The AIMS baseline and endpoint means with the standard deviations and t-statistics are as follows: baseline 0.41(S.D. 0.79) endpoint: 0.16 (S.D. 0.38), paired t-test, t = 1.91 (df: 11), P N 0.08. The Simpson– Angus baseline and endpoint statistics were as follows: baseline 10.25 (S.D. 0.45); endpoint 10.16 (S.D. 0.38), paired t-test, t = 0.56, P N 0.58. 4. Discussion This is the first pilot study to examine the efficacy of olanzapine as monotherapy in unipolar major depression, without psychotic features, to our knowledge. Our study shows statistically significant efficacy in the reduction of depressive symptoms in patients with major depressive disorder without psychotic features. The reduction in HAMD17 scores was significant for both the total score and the anxiety/somatization and Maier subscales. Half of the patients showed a response that was defined as a z 50% reduction in the HAMD17 scores. This number increases to two thirds of patients
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showing a response in the subscale cluster of anxiety/ somatization symptoms. Remission, defined as a HAMD17 score less than 8, was achieved in a third of the patients. Olanzapine was generally well tolerated with no significant treatment-emergent extrapyramidal side effects. The PET study was done using quantitative methods that allow accurate measurement of receptor binding. Eight regions of interest (ROIs) were created to include four limbic/paralimbic regions (hippocampus, subgenual prefrontal cortex, anterior cingulate and gyrus rectus) and four additional nonlimbic ROIs (occipital cortex, dorsal lateral pre-frontal cortex, lateral temporal cortex and lateral parietal cortex). Olanzapine showed significant 5-HT2A receptor binding in all of the regions. Fig. 3, which is a co-registered magnetic resonance image, clearly demonstrates significantly reduced [18F]altanserin binding after the administration of olanzapine, thus demonstrating the in vivo 5-HT2A receptor binding of olanzapine which competitively displaced [18F]altanserin from the 5-HT2A receptors. Although no formal personality assessment was completed, as it was not a goal of this study, the patients who showed remarkable improvements in their symptoms had a history of impulsiveness with difficulties at work, relationships and histories of substance abuse. These patients also had significant anxiety, insomnia and agitation as the presenting symptoms. A greater improvement in these symptom clusters with two thirds of the patients showing a response in the anxiety/somatization subscale is in line with studies of olanzapine in the treatment of borderline personality disorder, which is characterized by impulsive behavior in various social and interpersonal domains (Schulz et al., 1999; Bogenschutz and Nurnberg, 2004). The following case vignette illustrates the type of patient that showed significant improvement. Patient A: 38 years old Caucasian male with recurrent Major Depressive Disorder. Patient had a history of alcohol abuse and nicotine dependence but has been abstinent since 1980 and 1988, respectively. He had a history of treatment with fluoxetine, imipramine and amitriptyline but was on no antidepressant medications before the start of the study. He presented with significant psychic and somatic anxiety symptoms, depressed mood and insomnia. His HAMD17 score was 22. Patient was titrated to a dose of 10 mg of olanzapine by the third week of the study. He had significant improvement in his mood, sleep and anxiety symptoms. Furthermore, he no longer felt that life was not worth living and noted more positive thinking. The adverse effects that he experienced that were different from the
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screening exam are: dyspepsia, constipation, dizziness, and pharyngitis. Subjective tolerance of olanzapine was high. There were no treatment-emergent extrapyramidal adverse effects as measured by AIMS and Simpson–Angus Scale. The HAMD17 score improved from 22 to 11. There are caveats to the interpretation of this study. This was an open label pilot study with a small sample size suggestive of a possible antidepressant efficacy for olanzapine. Larger randomized controlled trials will be required to provide the definitive answer to whether olanzapine is an effective antidepressant; however, there is a paucity of controlled data at this time. The use of inclusion and exclusion criteria may select a sample that is not truly representative of our clinical population with the usual co-morbid illnesses, as is the case with all controlled trials; a future large simple trial with co-morbidities will enhance generalizability. An experienced psychiatrist interviewed the patient and ruled out the presence of any psychotic symptoms at the time of the initiation of the study or any history of psychosis; however, use of an instrument such as the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) would have been preferable. Although all patients had a washout period of at least five halflives, an exact record of this washout duration was not kept. Information about the duration of the current episode other than the patient’s meeting DSM-IV criteria for major depressive disorder, the number of failed medication trials and the number of lifetime episodes was not recorded. The exact mechanism of the antidepressant action of olanzapine is unknown as is the case with all the antidepressant medications. Antagonism of the 5-HT2A receptor may play an important part as there are other antidepressants such as mirtazapine (De Boer et al., 1995), nefazadone (Meyer et al., 1999) and trazadone (Fiorella et al., 1995) that have 5-HT2A receptor antagonist properties. With these limitations in mind, this study does point to the potential of olanzapine as a therapeutic agent for the treatment of major depressive disorder without psychosis. Future placebo-controlled, randomized trials will be needed to further explore the antidepressant efficacy of olanzapine in unipolar major depressive disorder without psychosis. Acknowledgments The research reported was supported in part by a research grant from Eli Lily and by a K24 research grant MH65421 from the National Institute for Mental Health (NIMH), both awarded to YIS.
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J. Mathews et al. / Psychiatry Research: Neuroimaging 146 (2006) 149–155 Overall, J.E., Gorham, D.R., 1962. The Brief Psychiatric Rating Scale. Psychological Reports 10, 799 – 812. Parker, G., 2002. Olanzapine augmentation in the treatment of melancholia: the trajectory of improvement in rapid responders. International Clinical Psychopharmacology 17, 87 – 89. Patel, J.G., Bartoszyk, G.D., Edwards, E., Ashby, C.R. Jr., 2004. The highly selective 5-hydroxytryptamine (5-HT)2A receptor antagonist, EMD 281014, significantly increases swimming and decreases immobility in male congenital learned helpless rats in the forced swim test. Synapse 52, 73 – 75. Schatzberg, A.F., 2003. New approaches to managing psychotic depression. Journal of Clinical Psychiatry 64, 19 – 23. Schooler, N.R., Kane, J.M., 1982. Research diagnoses for tardive dyskinesia. Archives of General Psychiatry 39, 486 – 487. Schulz, S.C., Camlin, K.L., Berry, S.A., Jesberger, J.A., 1999. Olanzapine safety and efficacy in patients with borderline personality disorder and comorbid dysthymia. Biological Psychiatry 46, 1429 – 1435. Sheline, Y.I., Mintun, M.A., Moerlein, S.M., Snyder, A.Z., 2002. Greater loss of 5-HT2A receptors in midlife than in late life. American Journal of Psychiatry 159, 430 – 435.
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Shelton, R.C., Tollefson, G.D., Tohen, M., Stahl, S., Gannon, K.S., Jacobs, T.G., Buras, W.R., Bymaster, F.P., Zhang, W., Spencer, K.A., Feldman, P.D., Meltzer, H.Y., 2001. A novel augmentation strategy for treating resistant major depression. American Journal of Psychiatry 158, 155 – 156. Simpson, G.M., Angus, J.W.S., 1970. A rating scale for extrapyramidal side effects. Acta Psychiatrica Scandinavica. Supplementum 212, S11 – S19. Tohen, M., Vieta, E., Calabrese, J., Ketter, T.A., Sachs, G., Bowden, C., Mitchell, P.B., Centorrino, F., Risser, R., Baker, R.W., Evans, A.R., Beymer, K., Dube, S., Tollefson, G.D., Breier, A., 2003. Efficacy of olanzapine and olanzapine–fluoxetine combination in the treatment of bipolar I depression. Archives of General Psychiatry 60, 1079 – 1088. Zhang, W., Bymaster, F.P., 1999. The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT2A and muscarinic receptors. Psychopharmacology 141 (3), 267 – 278.
Antidepressant efficacy of olanzapine as monotherapy in major depressive disorder, without psychosis: A pilot studyB Jose Mathewsa, Keith S. Garciaa, Mark A. Mintuna,b, Yvette I. Shelinea,b,* a
Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 S. Euclid, St. Louis, MO 63110, USA b Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA Received 12 January 2005; received in revised form 19 July 2005; accepted 7 August 2005
Abstract In this pilot study we assessed the efficacy of olanzapine as monotherapy in the treatment of major depressive disorder, without psychosis. We also demonstrated the in vivo 5-HT2A receptor occupancy of olanzapine using positron emission tomography. An open-label prospective 6-week study design with 14 patients who met the inclusion and exclusion criteria for the study were enrolled from the general community of the St. Louis metropolitan area. All patients met DSM-IV criteria for major depressive disorder without psychosis, had a Hamilton Depression Rating Scale (HAMD17) score N 18 and were between the ages of 18 and 65. The primary measure of efficacy was the change in HAMD 17 total score from baseline to endpoint. The data were collected between 1998 and 2004. There was a significant reduction in the HAMD17 scores from baseline to endpoint. Half the patients (n = 6) showed z50% reduction in their HAMD17 scores. This study points to the potential of olanzapine as a therapeutic agent for the treatment of major depressive disorder without psychosis. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Antidepressants; 5-HT2A receptors; Neuroimaging; Positron emission tomography
1. Introduction There is evidence from schizophrenia trials that olanzapine has significant effects on mood. A recent review of the published literature on the efficacy of atypical antipsychotic agents in the treatment of depression, hostility, and suicidality in patients with schizophrenia B Disclosure: Dr. Mathews is on the speaker’s bureau of Janssen and Bristol-Myers Squibb. Dr. Garcia is on the speaker’s bureau of Pfizer and GlaxoSmithKline. Dr. Sheline is on the scientific advisory board of Bristol-Myers Squibb. Dr. Mintun has no conflict of interest disclosure. * Corresponding author. Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 S. Euclid, St. Louis, MO 63110, USA. Tel.: +1 314 362 8422; fax: +1 314 362 7599. E-mail address: [email protected] (Y.I. Sheline).
suggested that olanzapine may have an antidepressant effect and may reduce suicidality in patients with schizophrenia (Keck et al., 2000). There is also evidence for its use as an augmentation agent for the treatment of treatment-resistant major depression (Ghaemi et al., 2000; Shelton et al., 2001; Parker, 2002). Olanzapine has also been shown to be effective in the treatment of psychotic depression in open label studies and case reports (Nelson et al., 2001; Schatzberg, 2003). In the pivotal study comparing the efficacy of olanzapine and an olanzapine–fluoxetine combination in the treatment of bipolar I depression, the olanzapine alone group showed statistically significant improvement in depressive symptoms versus the placebo group (Tohen et al., 2003). These studies hint at a possible antidepressant action of olanzapine, although
0925-4927/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.pscychresns.2005.08.003
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the question of whether olanzapine has any antidepressant effect in patients with unipolar major depression remains unanswered. There is also a dearth of literature looking at the efficacy of olanzapine in the treatment of unipolar depression as the sole agent in patients without psychosis. This pilot study tries to address the possibility of olanzapine as a monotherapy for unipolar major depression. The pharmacokinetic profile of olanzapine shows potent 5-HT2A receptor antagonism (Zhang and Bymaster, 1999); which may account for its antidepressant effects. Abnormalities in the 5-HT2A receptor have been reported in patients with depression and are likely indicative of altered serotonergic function (Mann et al., 1986; Arango et al., 1992). Selective antagonism of the 5-HT2A receptor with EMD 281014 showed significant increases in swimming and decreased immobility in the forced swim test paradigm in rats with congenital learned helplessness, an animal model for depression (Patel et al., 2004). Clinical studies have shown significant antidepressant properties for drugs such as mirtazapine (De Boer et al., 1995), nefazadone (Meyer et al., 1999) and trazadone (Fiorella et al., 1995) that have prominent 5-HT2A receptor antagonism. This pilot study looks at the efficacy of olanzapine as monotherapy for the treatment of major depressive disorder without psychosis to test the hypothesis that olanzapine has antidepressant efficacy for the treatment of unipolar major depressive disorder. Positron emission tomography (PET) is a powerful tool to study in vivo human brain receptor occupancy. The radio-ligand [18F]altanserin is a high affinity, selective agent for imaging 5-HT2A receptors (Lemaire et al., 1991) with reliable and established effects in in vivo human brain imaging (Mintun et al., 2004). A quantitative receptor binding study was done using [18F]altanserin to demonstrate in vivo 5-HT2A receptor occupancy of olanzapine at a clinically relevant dose, and it may be this property of olanzapine that contributes to antidepressant efficacy. 2. Methods 2.1. Study design Fourteen patients who met the inclusion and exclusion criteria for the study were enrolled after giving informed consent. The study was designed as an openlabel, prospective, 6-week trial with the primary objective of assessing the efficacy of olanzapine as an antidepressant medication in patients with major depressive disorder. All patients had a washout period of
at least five antidepressant half-lives rather than a fixed time interval. This was felt to be a better way to control for antidepressant medication such as fluoxetine, with a long half-life and the longest half-life medication was used to establish a washout period when a patient was on multiple medications. Patients were started on olanzapine 2.5 mg and titrated up according to clinical response, with a maximal daily dose of 20 mg. Adjunctive use of lorazepam was permitted up to 1 mg/day for treatment of insomnia, although it was not used in any of the patients in this study. No other psychotropic medication use was permitted during the course of study. A quantitative 5HT2A receptor binding study was done using positron emission tomography and [18F]altanserin to measure regional 5-HT2A receptor binding in the brain. Regions of interest were determined as previously described (Sheline et al., 2002) using ANALYZE software to trace boundaries and apply these regions (see Fig. 4) to individual datasets in Talairach atlas coordinates. The PET image data were collected and processed from one patient using imaging methods described in Mintun et al. (2004). 2.2. Patients All patients were between the ages of 18 and 65. They met DSM-IV criteria for unipolar major depressive disorder with a score on the 17-item version of the Hamilton Rating Scale for Depression (HAMD17) (Hamilton, 1960) of z 18. Participants were recruited from the general community of the St. Louis metropolitan area through advertisements and the Volunteer for Health program at the Barnes Jewish Hospital. The demographic characteristics are listed in Table 1. Diagnoses were confirmed by a psychiatrist through structured clinical interview. Exclusion criteria included a previous trial of olanzapine, diagnosis of schizophrenia, diagnosis of bipolar disorder, acute co-morbid medical Table 1 Demographic data Demographics N = 14
Mean
S.D.
Age (years) Gender (m, f)
47.4 5, 9
14.1
Race Caucasian African American American Indian/Alaskan Indian Unknown
10 2 1 1
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illness, active substance abuse within 3 months of study entry, Parkinson’s disease, myasthenia gravis, history of seizures, active hepatitis B, jaundice or participants considered at high risk for suicide. Before participation, all patients provided written informed consent. The Institutional Review Board at Washington University School of Medicine approved the study. 2.3. Assessments Patients had a baseline clinical visit and visits at weeks 1, 2, 3, 4, 5 and 6. The primary measure of efficacy was change in the total score on the HAMD-17 from baseline to endpoint (Fig. 1). A secondary efficacy analysis was done for the anxiety/somatization subscale (items 10, 11, 12, 13, 15, 17) (Detke et al., 2004; Brannan et al., 2005) and the Maier subscale (items 1, 2, 7, 8, 9, 10) (Maier and Philipp, 1985), both of which are subscales of the HAMD17 that examines the anxiety components and the core depressive symptoms, respectively. Rates of response were assessed and defined as at least a 50% improvement in HAMD17 scores. Remission rate, defined as an HAMD17 score of b 8, was also assessed. Adverse events were recorded on each clinical visit using the side effects check list. Severity of extrapyramidal symptoms (EPS) was evaluated by means of the Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976; Schooler and Kane, 1982) and the Simpson–Angus scale (Simpson and Angus, 1970), which were administered on each clinical visit. A thorough medical history was obtained in a standardized manner at the beginning of the study and the available medical records including laboratory tests were screened at the baseline visit. Vital signs were recorded at each visit.
Fig. 2. Change in total HAMD17 score, anxiety/somatization subscale and Maier subscale.
2.4. Data analysis All study participants with at least one post-baseline assessment were included in the primary efficacy population and the data were analyzed using a last-observation-carried-forward analysis. Changes from baseline in HAMD17 total scores, the anxiety/somatization subscale and the Maier subscale were analyzed by paired t-test. Last-observation-carried-forward and observed-case (completer) data are reported. Change from baseline in the EPS and AIMS scores are also reported, and they were analyzed by paired t-test. All t-tests are two-tailed. Commonly reported side effects are reported as a percentage of patients experiencing them at any time during the study. 3. Results Of the 14 patients enrolled in this study, 12 patients had at least one post-baseline evaluation. Eight of these patients finished the study. The mean dose of olanzapine was 7.5 mg (S.D. 3.16) and median dose was 10 mg with a range of 2.5 to 10 mg. 3.1. Efficacy
Fig. 1. A representation of the change in subjects’ Hamilton Depression scores from baseline to endpoint.
There were significant reductions in the HAMD17 total score, anxiety/somatization subscale and the Maier subscale from baseline to endpoint (Fig. 2). The pretreatment and post-treatment means with standard deviations (SD), t statistics and degrees of freedom (df) were as follows: HAMD17 total score—baseline: 23.33 (4.65); endpoint: 12.75 (7.99), paired t-test, t = 6.05, df = 11,
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Fig. 3. Average magnetic resonance image (A). Slice from a co-registered PET scan of [18F]altanserin (B). PET scan image after the administration of olanzapine showing 5-HT2A receptor competitive antagonism of olanzapine (C).
P b 0.001. Half of the patients (n = 6) showed z 50% reduction in their HAMD17 scores. Remission of symptoms with a HAMD17 score of b 8 was achieved in a third of the patients (n = 4). Anxiety/Somatization— baseline: 7.16 (1.19); endpoint: 3.91 (2.50), paired ttest, t = 4.45, df = 11), P b 0.00. Maier subscale—baseline: 12.75 (0.61); endpoint: 7.50 (1.03), paired t-test, t = 5.90, df = 11, P b 0.001. Reductions in HAMD17 scores in both total and subgroup analysis were seen in both the study completer group (n = 8) and the group that did not finish the study (n = 4). However, the reduction in the HAMD17 score did not reach statistical significance (paired t-test, df = 3, P N 0.1) in the non-completer group. The study completer group showed significant reductions as follows:
HAMD17 total score—pre-treatment: 22.75 (1.73); post-treatment: 10.62 (2.18), paired t-test, t = 6.90 df = 7, P b 0.001. Anxiety/somatization—pre-treatment: 7.12 (1.24); post-treatment: 3.00 (1.30), paired t-test, t = 6.45, df = 7, P b 0.001. Maier—pre-treatment: 12.75 (2.25); post-treatment: 6.75 (3.24), paired t-test, t = 6.35, df = 7, P b 0.001. The anxiety/somatization symptom scale reduction of z 50% from baseline to endpoint was noted in 66% of patients (n = 8). 3.2. PET study The imaging data show in vivo 5-HT2A receptor binding of olanzapine (Fig. 3). This binding was noted in all of the observed areas (see Fig. 4) as
1.8 [18F]Altanserin Regional Binding Potential
Pre-Treatment 1.6
During Treatment
1.4 1.2 1 0.8 0.6 0.4 0.2
ta
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ie
ua
ar
bg Su
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Fig. 4. Before treatment with olanzapine and the competitive antagonism of 5-HT2A receptors with the treatment effects of olanzapine are depicted above.
J. Mathews et al. / Psychiatry Research: Neuroimaging 146 (2006) 149–155 Table 2 Percentage of side effects reported in all visits Side effects
All visits (% of occurrence)
Concentration decrease Dry mouth Agitation Light headedness Somnolence Pharyngitis Headaches Myalgia Asthenia Diarrhea Dyspepsia Dizziness Incoordination Tremor Sweating Nausea Constipation Abnormal vision
57.1 42.9 42.9 42.9 42.9 42.9 35.7 35.7 28.6 28.6 28.6 28.6 28.6 28.6 28.6 21.4 21.4 7.1
evidenced by the reduction of the [18F]altanserin binding potential after the administration of olanzapine. 3.3. Adverse events Adverse events that were reported by the patient once they were on olanzapine were considered treatment emergent, and all such adverse events reported by more than 10% of the patients are listed in Table 2. Mean changes in and emergence of extrapyramidal symptoms were low and did not reach statistical significance. The AIMS baseline and endpoint means with the standard deviations and t-statistics are as follows: baseline 0.41(S.D. 0.79) endpoint: 0.16 (S.D. 0.38), paired t-test, t = 1.91 (df: 11), P N 0.08. The Simpson– Angus baseline and endpoint statistics were as follows: baseline 10.25 (S.D. 0.45); endpoint 10.16 (S.D. 0.38), paired t-test, t = 0.56, P N 0.58. 4. Discussion This is the first pilot study to examine the efficacy of olanzapine as monotherapy in unipolar major depression, without psychotic features, to our knowledge. Our study shows statistically significant efficacy in the reduction of depressive symptoms in patients with major depressive disorder without psychotic features. The reduction in HAMD17 scores was significant for both the total score and the anxiety/somatization and Maier subscales. Half of the patients showed a response that was defined as a z 50% reduction in the HAMD17 scores. This number increases to two thirds of patients
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showing a response in the subscale cluster of anxiety/ somatization symptoms. Remission, defined as a HAMD17 score less than 8, was achieved in a third of the patients. Olanzapine was generally well tolerated with no significant treatment-emergent extrapyramidal side effects. The PET study was done using quantitative methods that allow accurate measurement of receptor binding. Eight regions of interest (ROIs) were created to include four limbic/paralimbic regions (hippocampus, subgenual prefrontal cortex, anterior cingulate and gyrus rectus) and four additional nonlimbic ROIs (occipital cortex, dorsal lateral pre-frontal cortex, lateral temporal cortex and lateral parietal cortex). Olanzapine showed significant 5-HT2A receptor binding in all of the regions. Fig. 3, which is a co-registered magnetic resonance image, clearly demonstrates significantly reduced [18F]altanserin binding after the administration of olanzapine, thus demonstrating the in vivo 5-HT2A receptor binding of olanzapine which competitively displaced [18F]altanserin from the 5-HT2A receptors. Although no formal personality assessment was completed, as it was not a goal of this study, the patients who showed remarkable improvements in their symptoms had a history of impulsiveness with difficulties at work, relationships and histories of substance abuse. These patients also had significant anxiety, insomnia and agitation as the presenting symptoms. A greater improvement in these symptom clusters with two thirds of the patients showing a response in the anxiety/somatization subscale is in line with studies of olanzapine in the treatment of borderline personality disorder, which is characterized by impulsive behavior in various social and interpersonal domains (Schulz et al., 1999; Bogenschutz and Nurnberg, 2004). The following case vignette illustrates the type of patient that showed significant improvement. Patient A: 38 years old Caucasian male with recurrent Major Depressive Disorder. Patient had a history of alcohol abuse and nicotine dependence but has been abstinent since 1980 and 1988, respectively. He had a history of treatment with fluoxetine, imipramine and amitriptyline but was on no antidepressant medications before the start of the study. He presented with significant psychic and somatic anxiety symptoms, depressed mood and insomnia. His HAMD17 score was 22. Patient was titrated to a dose of 10 mg of olanzapine by the third week of the study. He had significant improvement in his mood, sleep and anxiety symptoms. Furthermore, he no longer felt that life was not worth living and noted more positive thinking. The adverse effects that he experienced that were different from the
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screening exam are: dyspepsia, constipation, dizziness, and pharyngitis. Subjective tolerance of olanzapine was high. There were no treatment-emergent extrapyramidal adverse effects as measured by AIMS and Simpson–Angus Scale. The HAMD17 score improved from 22 to 11. There are caveats to the interpretation of this study. This was an open label pilot study with a small sample size suggestive of a possible antidepressant efficacy for olanzapine. Larger randomized controlled trials will be required to provide the definitive answer to whether olanzapine is an effective antidepressant; however, there is a paucity of controlled data at this time. The use of inclusion and exclusion criteria may select a sample that is not truly representative of our clinical population with the usual co-morbid illnesses, as is the case with all controlled trials; a future large simple trial with co-morbidities will enhance generalizability. An experienced psychiatrist interviewed the patient and ruled out the presence of any psychotic symptoms at the time of the initiation of the study or any history of psychosis; however, use of an instrument such as the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) would have been preferable. Although all patients had a washout period of at least five halflives, an exact record of this washout duration was not kept. Information about the duration of the current episode other than the patient’s meeting DSM-IV criteria for major depressive disorder, the number of failed medication trials and the number of lifetime episodes was not recorded. The exact mechanism of the antidepressant action of olanzapine is unknown as is the case with all the antidepressant medications. Antagonism of the 5-HT2A receptor may play an important part as there are other antidepressants such as mirtazapine (De Boer et al., 1995), nefazadone (Meyer et al., 1999) and trazadone (Fiorella et al., 1995) that have 5-HT2A receptor antagonist properties. With these limitations in mind, this study does point to the potential of olanzapine as a therapeutic agent for the treatment of major depressive disorder without psychosis. Future placebo-controlled, randomized trials will be needed to further explore the antidepressant efficacy of olanzapine in unipolar major depressive disorder without psychosis. Acknowledgments The research reported was supported in part by a research grant from Eli Lily and by a K24 research grant MH65421 from the National Institute for Mental Health (NIMH), both awarded to YIS.
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