Major depressive disorder (MDD) is a common chronic condition (Kessler et al., 2003) that can lead to substantial disability and high economic cost (Merikangas et al., 2007; Baldessarini et al., 2017). Despite estimations that antidepressant treatments (ADTs) were prescribed to ~12% of adults (≥20 years old) and ~23% of women 40–65 years old in the United States from 2005 to 2008 (Kit et al., 2012), patients with MDD frequently lack adequate response to standard ADTs (Fava, 2003). In the STAR*D study, approximately two-thirds of patients with MDD failed to achieve depression remission following initial treatment with a selective serotonin reuptake inhibitor. Those who did not enter remission began a second treatment step from the following options: switching to another ADT, augmentation with an additional ADT or cognitive therapy, or cognitive therapy alone. Of those who completed a second treatment step, only 31% achieved remission (Rush et al., 2006; Warden et al., 2007). This lack of adequate response after multiple treatment steps is of clinical interest because patients with MDD are less likely to respond and more likely to relapse as treatment steps are added (Warden et al., 2007), indicating a need for additional, novel treatment options for MDD.
In addition to issues involving inadequate response and rates of remission, standard oral ADTs are associated with multiple sexual and gastrointestinal adverse events (AEs), which can result in decreased adherence, increased discontinuation, and potential relapses (Pollack, 1987; Remick et al., 1989; Baldessarini and Marsh, 1990; Clayton and Mcgarvey, 2006). In fact, AEs are a leading cause of discontinuation in the first few months of ADT (Demyttenaere et al., 2001). Therefore, a nonsystemic treatment option providing relief from depressive symptoms not associated with systemic AEs would be of high clinical value. A nonsystemic intervention would also lower the risk of drug–drug interactions, which are of particular concern in patients with MDD due to the high prevalence of psychiatric comorbidities that have been reported to exceed 35% (Thaipisuttikul et al., 2014). A treatment that is effective, after each exposure, for multiple months is also useful to support increased adherence due to less frequent dosing (Medic et al., 2013).
Local injections of onabotulinumtoxinA (BOTOX; onabotA) result in muscle relaxation through a multistep process that includes binding to nerve terminals, internalization, and cleaving SNAP-25 (synaptosomal-associated protein-25 kD), one of the SNARE (soluble NSF-attachment protein receptor) proteins critical for synaptic vesicle fusion to the inner surface of the cellular membrane (Rossetto et al., 2014). Impacted synaptic vesicles can neither release their neurotransmitter contents into the synaptic cleft (e.g. acetylcholine from motor neurons; CGRP from sensory neurons) nor undergo SNARE-mediated delivery of receptors or ion channels carried as vesicular cargo into neuronal membranes (e.g. TRPV1 and P2X3 in nociceptors) (Burstein et al., 2014).
Previous studies indicate a single session of therapeutic injections of onabotulinumtoxinA into facial muscles in the glabellar region may represent a novel, well-tolerated treatment option for MDD (Finzi and Wasserman, 2006; Wollmer et al., 2012; Magid et al., 2014, Finzi and Rosenthal, 2014). OnabotA corrugator and procerus injections have an acceptable record of safety (Brin et al., 2009), and in the published MDD trials, the only common treatment-emergent AEs were temporary and local to the treatment site (headache and injection site irritation) (Wollmer et al., 2012; Finzi and Rosenthal, 2014). The results of these studies indicated onabotA may produce antidepressive effects lasting several months following a single-treatment session, which may increase treatment adherence compared to daily medication. The objective of this Phase 2 study was to evaluate the efficacy, safety, and duration of effect of a single-treatment session of onabotA compared to placebo for the treatment of MDD in adult females (NCT02116361).
This study was conducted from April 2014 to December 2016 at 32 sites in the United States in compliance with ICH-E6 Good Clinical Practice guidelines, and the protocol was approved by Institutional Review Boards at each study center. All patients provided written informed consent. OnabotA is not labeled for MDD by the FDA and is still under investigation.
This was a 24-week multicenter randomized, double-blind placebo-controlled 2-dose cohort parallel-group study of 30 units (U) and 50 U onabotA in outpatient female patients with MDD. Two different injection paradigms were tested to evaluate the antidepressant effects of differential dosing of onabotA to the procerus and corrugator muscles. The total dosage (30 U or 50 U) was divided into six or eight glabellar injections, respectively (Supplementary Fig. 1, Supplemental digital content 1, http://links.lww.com/ICP/A66). All injections were intramuscular (IM) except the most lateral corrugator subcutaneous injections of the 50 U dosing paradigm. All injections were 0.1 mL containing 5 U of study drug except those given in the procerus muscle (0.2 mL, 10 U of study drug) in the 50 U cohort.
Participating sites were randomized before study initiation to administer only one dose cohort during the trial (i.e. 30 U sites or 50 U sites), due to the treatment paradigms having a different number of injections depending on dose. Patients were screened 7–14 days before randomization, and all injections were administered in a single-treatment session at baseline (Day 1). Randomization occurred 1:1:2 to onbotA 30 U, onabotA 50 U or placebo using blocks within strata and center [30 U onabotA vs. 30 U placebo (1:1), or 50 U onabotA vs. 50 U placebo (1:1)].
The present Phase 2 study only included female patients, and the rationale for this was three-fold: an attempt to reproduce the previous studies of onabotA for MDD, which enrolled a predominantly female population (77–93% of total patients) (Wollmer et al., 2012; Finzi and Rosenthal, 2014; Magid et al., 2014); an effort to keep the study design streamlined since there were two doses each with matching placebo being investigated because previous MDD studies utilized higher doses in males (Wollmer et al., 2012; Finzi and Rosenthal, 2014; Magid et al., 2014); and the higher prevalence of MDD in females, which have nearly twice the rate of 12-month prevalence compared to males (Hasin et al., 2018).
Adult females (18–65 years) with moderate to severe MDD (single episode or recurrent) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria (American Psychiatric Association, 2000) based on the Mini International Neuropsychiatric Interview (MINI) were eligible for inclusion (Sheehan et al., 1997). Patients were in a current major depressive episode lasting ≥4 weeks, and had a 17-item Hamilton Depression Rating Scale [HAMD-17] (Hamilton, 1960) score ≥ 18 and Clinical Global Impressions – Severity (CGI-S) subscale score ≥ 4 (Bridge et al., 2007).
Patients were excluded if they met any of the following criteria: taking concurrent ADTs or herbal/homeopathic remedies targeting depressive symptoms (within 2 weeks); had any prior treatment with intravenous ketamine, electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or deep-brain stimulation; any depot antipsychotic (within 12 weeks), or dermal filler injected into forehead (within 48 weeks), acupuncture to forehead muscles (within 4 weeks); or had any prior treatment or immunization to botulinum toxin; investigator-judged failure to adequately respond to ≥2 ADTs of different drug classes (any previous depressive episodes) or use of psychotropic drugs after screening; any medical condition that exposed patients to undue risk of significant AEs; a DSM-IV-TR diagnosis of any axis I disorder (non-MDD), except for stabilized generalized or social anxiety disorders or specific phobias not requiring treatment or were not the primary focus of treatment within 24 weeks; or any drug or alcohol abuse (within 12 weeks) or dependency (within 24 weeks); or a suicide risk. Intermittent or unstable use of cognitive behavioral therapy or interpersonal psychotherapy was prohibited, but a stable therapy paradigm that was established ≥12 weeks before screening and maintained throughout the study was allowed.
Study medication (onabotA) consisted of 100 U of Clostridium botulinum toxin type A, 0.5 mg of human albumin, and 0.9 mg of sodium chloride in a sterile, vacuum-dried form without preservative. One Unit corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. Placebo contained 0.9% sodium chloride in an identical form, and reconstitution procedures for placebo or onabotA were identical. Reconstituted study medication that was not administered immediately was kept in the vial (stored 2–8°C), and vials not used within 4 h were discarded.
Each study center only had access to one dosage of onabotA with matching placebo, and study centers were randomized before site initiation. At baseline (Day 1), eligible patients were randomized (1:1) to onabotA 30 U or matching placebo (30 U sites), or onabotA 50 U or matching placebo (50 U sites) using randomized blocks within strata within center. Patients were stratified according to duration of their current major depressive episode (<24 weeks vs. ≥24 weeks). Study medication was labeled with medication kit numbers, and an automated response system provided the site with the medication kit number(s), which assigned treatment groups for each randomized patient.
Of the two dose-injection paradigms evaluated, the 30 U dose group was similar to the injection paradigm used in previous studies, which demonstrated that depressive symptoms were reduced following onabotA 29 U treatments in the glabellar region (Wollmer et al., 2012; Finzi and Rosenthal, 2014). The 50 U dose group received an increased dose (by two-fold) in the procerus, which was based on the strong procerus response reported in the most common glabellar activation patterns (Almeida et al., 2010; de Almeida et al., 2012), and the rationale that this would more effectively relax corrugator muscles and maximize disruption of the neural feedback circuitry potentially involved in depression. A total dose of onabotA 15 U into the corrugator muscles for the 50 U group was chosen in an effort to achieve complete abolishment of corrugator muscle activity with this dose and injection paradigm (Pribitkin et al., 1997).
To maintain study blinding, an independent drug reconstitution was assigned at each site for study drug preparation. Due to the potential cosmetic effects of study treatment, remote telephone raters performed the same efficacy assessments as clinic staff without direct patient contact. To evaluate blinding, the patient, investigator, and remote-rater were separately asked to indicate which treatment they believe was received (blinding index) at study exit.
After randomization and treatment, a safety follow-up telephone call was conducted at week 2, and in-clinic and remote raters efficacy assessments were conducted at weeks 3, 6, 9, 12, 15, 18, and 21. For the primary efficacy variable, Montgomery–Åsberg Depression Rating Scale (MADRS) (Montgomery and Åsberg, 1979) total scores, clinician-rated assessments were conducted before the remote-rater assessments to control for potential sequence effects.
Starting from week 9, relapse was defined as a responder with a MADRS total score ≥18 or CGI-S score ≥4 or judged by the investigator at week 12 or later, and those patients were required to exit the study. Patients were also discontinued if they required concomitant medication treatment for depression or a change in their cognitive therapy regimen (from screening) at any time during the study.
Primary efficacy was assessed by MADRS total score changes at week 6 from baseline for each treatment group (onabotA 30 U or 50 U) compared to matching placebo using a mixed-effect model for repeated measures (MMRM) with unstructured covariance. Secondary efficacy parameters included changes in clinician-rated CGI-S and HAMD-17 total scores, which were analyzed by analyses of covariance (ANCOVA). Statistical analyses and determination of sample size are discussed in the Supplementary text, Supplemental digital content 1, http://links.lww.com/ICP/A66.
Physical examinations, clinical laboratory tests (hematology, chemistry, urinalysis), urine pregnancy tests (females of childbearing potential), and monitoring of AEs, vital signs, and suicide risk [patient and clinic Columbia-Suicide Severity Rating Scale (C-SSRS)] (Posner et al., 2011) were conducted. The female clinical version of the Changes in Sexual Functioning Questionnaire Short Form 14-item Version (CSFQ SF-14) (Clayton et al., 1997a, 1997b) was administered.
Patient disposition and characteristics
The modified intent-to-treat (mITT) population consisted of 255 patients who received treatment and were randomized as follows: onabotA 30 U (n = 65), 50 U (n = 65), or matching placebo [30 U (n = 58) and 50 U (n = 67)]. Of the mITT population, 220 completed through week 9 and 139 completed through week 24 (Supplementary Fig. 2, Supplemental digital content 1, http://links.lww.com/ICP/A66). Premature discontinuation rates were comparable for combined placebo (44.5%) and combined onabotA (47.7%) patients. Per-protocol exit (relapse at or after week 12) rates were onabotA 30 U (7.7%) and matching placebo (13.6%); onabotA 50 U (10.8%) and matching placebo (13.0%). Overall the discontinuation reasons and rates were similar among groups (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/ICP/A66). Patient baseline characteristics are summarized in Supplementary Table 2 (Supplemental digital content 1, http://links.lww.com/ICP/A66) and overall were generally comparable across treatment groups.
OnabotA 30 U approached statistical significance at the primary endpoint [P = 0.053; MMRM, mLOCF, week 6; least-squares mean difference (LSMD)= −3.7] (Fig. 1a), but the symptom improvement was significant [at level P < 0.05 (two-sided)] at weeks 3 and 9 (Table 1). In weeks 3–9, onabotA 30 U effect sizes were 0.348–0.521. For the ANCOVA (observed data), LSMDs from baseline to week 15 ranged from −4.0 to −5.9 but leveled off from weeks 18–21 (Fig. 1b). Prevalence of missing assessments at week 12 makes statistical comparisons after this timepoint descriptive and should be interpreted with caution. Additionally, the study design and requirement for patients to exit in the event of relapse may have positively selected for those who responded well to treatment after week 12.
OnabotA 50 U did not separate from placebo for 15 weeks following treatment (observed data, ANCOVA), but changes appeared numerically better than placebo in weeks 18–24 (Fig. 1c). Remote-rater MADRS results were similar to the trends observed in the in-clinic scores. In the onabotA 30 U group, improvement was greater with onabotA treatment compared to placebo at every visit and at week 6 treatment difference = −5.6 (P = 0.034) (Supplementary Fig. 3a, Supplemental digital content 1, http://links.lww.com/ICP/A66]. OnabotA 50 U did not separate from placebo or appear numerically improved until week 12 in the remote-rater results (Supplementary Fig. 3b, Supplemental digital content 1, http://links.lww.com/ICP/A66).
Treatment with onabotA 30 U consistently reduced CGI-S scores from baseline to week 24 (Fig. 2a), and reached significance at P < 0.05 (two-sided) for weeks 3 (observed data, ANCOVA; LSMD: −0.4; P = 0.046), week 6 (−0.5; P = 0.036), week 12 (−0.5; P = 0.050), week 15 (−0.8; P = 0.004), and week 21 (−0.5; P = 0.046). Similar to the primary efficacy variable, onabotA 50 U did not show significant treatment/placebo differences from baseline through week 15 in CGI-S scores changes (Fig. 2b), but did demonstrate a numerically greater symptom improvement compared to placebo, which became evident in weeks 18–24 (but as previously stated, these data should be interpreted with caution). OnabotA 30 U numerically reduced HAMD-17 total scores (observed data, ANCOVA) compared to placebo from baseline to week 12, but statistical significance at level P < 0.05 (two-sided) was only reached at week 15 (P = 0.032), and the differences leveled off from weeks 18–24 (Fig. 3a). Treatment with onabotA 50 U did not reduce HAMD-17 total scores (improve depressive symptoms) compared to placebo from baseline to week 15, but a numerically greater depressive symptom reduction vs. placebo was observed from weeks 18–24 (Fig. 3b).
Few patients were withdrawn from the study due to rescue interventions, and these rates were similar between the onabotA groups (n = 2; 1.5%) and placebo groups (n = 3; 2.4%). Blinding assessment results are presented in Supplementary Table 3, Supplemental digital content 1, http://links.lww.com/ICP/A66; the highest proportion of patients who believed their treatment was real medication was in the onabotA 50 U group. Clinician and remote raters consistently showed lower frequencies of belief their onabotA patients received onabotA compared to patients.
Mean durations to study exit were 131.7 and 129.4 days, for combined onabotA and placebo groups, respectively. Common AEs are summarized in Table 2. The only treatment-emergent AE that occurred in ≥10% of patients in any group was headache; eyelid ptosis and upper respiratory tract infection were the only AEs occurring in ≥5% in any onabotA group and greater than the placebo group. Although eyelid ptosis is a known local effect of onabotA injections, headache may be related to the procedure, as the incidence was similar for onabotA and placebo in the pooled 30 U and 50 U groups in the current study (onabotA, 15.4%; pbo, 15.2%), as well as in registration GL studies (Brin et al., 2009). Most AEs were considered unrelated to treatment, comparable across treatment groups, and consistent with previously published trials using a similar injection paradigm in both patients with MDD and nondepressed populations (Brin et al., 2009; Wollmer et al., 2012). Reported rates of systemic AEs, including gastrointestinal effects, were low, generally balanced across treatment groups, and did not include any sexual side effects. Additionally, suicide risk and sexual functioning (measured with the C-SSRS and CSFQ scales, respectively) rates were similar among treatment groups (Supplementary Table 4, Supplemental digital content 1, http://links.lww.com/ICP/A66).
Following a single-treatment session, neither onabotA 30 U nor 50 U demonstrated statistically significant superiority over placebo at the primary endpoint, but onabotA 30 U showed consistent numerical improvement in depressive symptoms compared to placebo up to week 15 with statistical separation from placebo for MADRS changes at weeks 3 and 9. OnabotA 30 U/placebo MADRS differences (observed, ANCOVA) of ≥4.0 points (up to week 15) and ≥2.0 points (weeks 18–24) agree with the 2-point MADRS change threshold generally considered clinically relevant in MDD trials (Montgomery and Moller, 2009). OnabotA 30 U effect sizes from weeks 3–9 ranged from 0.348 to 0.521 and were comparable to those observed in oral ADTs (Turner et al., 2008). Treatment with onabotA 30 U significantly [at level P < 0.05 (two-sided)] reduced CGI-S scores compared to placebo at each visit from week 3–21, except at weeks 9 and 18. Numerical decreases in both CGI-S scores and HAMD-17 total scores with 30 U onabotA treatment compared to placebo were observed through the end of the study. These results indicate that a single-treatment session with onabotA 30 U may have long-acting effects on depression symptoms up to 18 weeks post-treatment, which may increase adherence compared to treatments administered daily or weekly.
Treatment with onabotA 50 U did not improve depressive symptoms in the primary or second efficacy assessments. This lack of superiority to placebo may be partially attributed to high placebo response, which was considerably higher than the 30 U matching placebo response. Possible reasons for the heightened placebo response in the 50 U matching group include a greater number of injections, which is consistent with more invasive procedures corresponding to greater placebo response, possible differences in sites that administered the 50 U dose vs. 30 U dose, and potentially heightened expectations of results if patients were aware that the typical dose given in the glabellar region for cosmetic purposes was lower and at fewer injection sites. Notwithstanding the potentially clinically meaningful differences in onabotA 30 U and 50 U dose efficacy results at later timepoints, these results should be viewed with caution to prevent overinterpretation as a pharmacologic effect in MDD, given the enriched population and lack of separation between onabotA 50 U and matching placebo before required patient discontinuation in the case of lack of response at week 12. It should be noted that the results presented herein correspond to onabotA, a specific formulation of botulinum neurotoxin type A. Different formulations of botulinum neurotoxin type A have distinct safety and efficacy profiles and clinical doses expressed in units are not interchangeable from one botulinum toxin product to another.
Previous investigator-initiated trials of onabotA for MDD treatment indicated statistically significant improvement in depressive symptoms compared to placebo (Wollmer et al., 2012; Finzi and Rosenthal, 2014, Magid et al., 2014). Key differences in the designs of the present and previous trials exist, which may explain the lack of significant changes observed with onabotA 30 U treatment in some measures and/or timepoints. The present study had the largest sample population to date for an onabotA MDD trial, investigated only female patients, did not select for prior ADT resistance, or allow concomitant use of additional ADTs. A previous study of onabotA effects on MDD indicated that the antidepressive effects persisted for at least 24 weeks (Magid et al., 2014), which exceeds the duration of cosmetic effects on glabellar lines (approximately 12–16 weeks). This led investigators to hypothesize the efficacy in reducing depressive symptoms was not completely related or attributed to the paralytic effects, and the results presented herein agree with this hypothesis.
One potential theory for the reduction of depressive symptoms with onabotA treatment is the ‘facial feedback hypothesis', which states that expressive behavior can alter emotional states, likely through afferent sensory modulation (Izard, 1990, McIntosh, 1996). Corrugator muscles, which are activated during negative emotions (e.g. fear, anger, and sadness) (Ekman and Friesen, 1978), are relatively over-reactive in patients with depressive disorders (Schwartz et al., 1976). Imaging studies have shown that when subjects, without a history of psychiatric illness, mimicked angry expressions, they demonstrated decreased left amygdala activity after treatment with botulinum toxin in the glabellar region in addition to reduced functional coupling between left amygdala and dorsal brainstem (Hennenlotter et al., 2009). The decreased activity may be attributed to the reduction in motor nerve activity associated with dynamic facial expressions and/or proprioceptive sensory input following local treatment. Furthermore, facial somatic sensory afferents synapse in the descending trigeminal nucleus with monosynaptic connections to amygdala (Burstein and Potrebic, 1993), hypothalamus (Malick and Burstein, 1998), nucleus accumbens (Burstein and Giesler, 1989), and thalamus (Burstein et al., 1990), suggesting a pathway for facial afferents to directly influence limbic networks.
Limitations of this study included a relatively small sample size in each treatment group, lack of generalizability to male patients, and the study design, which effectively created two parallel studies with different treatment sites and different investigators. The exploratory and descriptive nature of data after week 12, because of the decreased number of observed values due to high attrition rates, partially due to the study design that required relapsed patients to exit, thereby positively selecting responders, is also a noted limitation. To prevent compromising of blinding by drawing attention to the neuromuscular effects of onabotA treatment, this trial did not assess any correlations between muscle contraction or effect on facial muscles, and efficacy in treating MDD.
The results presented herein are preliminary and thus require further assessment. The onabotA 30 U drug/placebo differences exceeding those generally considered clinically relevant supports moving forward to the next phase of clinical development. Future studies should consider assessment of efficacy of MDD treatment in males and mixed gender populations and its use as an adjunctive treatment to standard ADTs. The efficacy in treatment-resistant patient populations, those with known adherence issues, or sensitivity to AEs related to oral ADTs may also be informative because of the unmet treatment needs in these groups. Elucidating the potential role for this treatment in the management of MDD is important because of its many advantages, including low reported systemic adverse effects, particularly those seen with standard oral ADTs (e.g. sexual dysfunction and gastrointestinal), established safety profile, and the potential for increased compliance compared to daily oral medications because of the long-lasting effects of a single-treatment session. The limited drug/drug interactions of the local onabotA treatment allow it to be used with medications for comorbid conditions or as an adjunctive treatment with conventional ADTs.
OnabotA 30 U consistently reduced depressive symptoms throughout the 24-week observational period following a single-therapeutic session. Both onabotA treatments were well tolerated with most AEs similar to placebo and consistent with previously reported data for comparable doses in both depressed (Wollmer et al., 2012; Finzi and Rosenthal, 2014; Magid et al., 2014) and nondepressed patients (Brin et al., 2009). Additionally, headache and eyelid ptosis were temporary, local to the treatment site, and well tolerated as reported in previous onabotA trials with facial injections, including chronic migraine (Brin et al., 2009; Diener et al., 2014). OnabotA is a nonsystemic intervention with relatively low incidence gastrointestinal and no sexual side effects reported, which may offer safety and tolerability advantages compared to currently available ADTs. The long-lasting effects of a single-injection session may increase treatment adherence compared with the use of a daily oral ADT. A Phase 3 clinical trial is planned for the further assessment of botulinum toxin type A as a treatment for MDD.
Writing assistance and editorial support for the preparation of this article was provided by Cherisse Loucks, PhD and Erika von Grote, PhD of Allergan (Madison, New Jersey).
Data disclosure statement: Data reported in this article are available within the article (and/or) its Supplementary materials, http://links.lww.com/ICP/A66. Allergan will share de-identified patient-level data and/or study-level data, including protocols and clinical study reports, for Phase 2–4 trials completed after 2008 that are registered on ClinicalTrials.gov or EudraCT. The indication studied in the trial must have regulatory approval in the United States and/or the European Union and the primary manuscript from the trial must be published before data sharing. To request access to the data, the researcher must sign a data use agreement. All shared data are to be used for noncommercial purposes only. More information can be found on http://www.allerganclinicaltrials.com/.
This study was supported by funding from Allergan (Madison, New Jersey). Role of the sponsors: Allergan was involved in the study design, collection (via contracted clinical investigator sites), analysis and interpretation of data, and decision to present these results.
Clinical Trial Number: NCT02116361.
A.L., L.J., M.F.B., J.L., and A.S. are full-time employees of Allergan plc. S.D. is a previous Allergan plc full-time employee. M.E.T. has received grants from the Agency for Healthcare Research and Quality, Alkermes, Forest Laboratories (an Allergan affiliate), National Institute of Mental Health, Otsuka, PharmaNeuroboost, and Roche; has acted as an advisor or a consultant for Alkermes, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Forest Laboratories, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, Lundbeck, MedAvante, Merck, Neuronetics, Novartis, Ortho-McNeil Pharmaceuticals, Otsuka, Pamlab, Pfizer, Shire, Sunovion, and Takeda; has received royalties from American Psychiatric Association, Guilford Publications, Herald House, and W. W. Norton & Company; and holds equity in MedAvante Inc.
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