Ongoing Antidepressant Therapy Research Articles

Med Check: Adlarity Transdermal Patch; Qulipta; Nuplazid; and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Adlarity Transdermal Patch; Qulipta; Nuplazid; and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:26 Apr 2022https://doi.org/10.1176/appi.pn.2022.05.5.35Adlarity Transdermal Patch Approved for Treatment of Alzheimer’sIn March the U.S. Food and Drug Administration (FDA) approved Adlarity (donepezil transdermal system) as a treatment for patients with mild, moderate, or severe dementia associated with Alzheimer’s disease, Corium Inc. announced. Adlarity is a once-weekly patch that continuously delivers either 5 mg or 10 mg of donepezil through the skin per day. Either the patient or a caregiver may place the patch on the patient’s back, thigh, or buttocks.The FDA approved Adlarity based on a relative bioavailability study in healthy patients that compared the transdermal system to Aricept (donepezil hydrochloride) tablets. In the study, 60 healthy volunteers received 5 mg of Adlarity per day for five weeks, after which they received either 10 mg of Adlarity or oral donepezil per day for another five weeks. At the end of the study, exposure to donepezil was similar among patients who took Adlarity and those who took oral donepezil. Adlarity is expected to be available in the early fall. Qulipta Promising for Treatment of Chronic MigraineAdults with chronic migraine who took Qulipta (atogepant) in a phase 3 trial experienced fewer monthly migraine days compared with those who took placebo, AbbVie announced in March. Qulipta is currently approved for preventing episodic migraine in adults.In the trial, more than 750 patients with at least a one-year history of chronic migraine were randomized to receive 60 mg of atogepant once a day, 30 mg of atogepant twice a day, or placebo for 12 weeks. All patients had at least 15 headache days with at least eight migraine days in the 28 days before randomization. The trial consisted of two analyses based on regulatory agency feedback in the United States and European Union.The U.S. analysis revealed that patients in the 60 mg and 30 mg atogepant arms experienced a decrease of 6.88 and 7.46 monthly migraine days, respectively, compared with patients in the placebo arm, who experienced a decrease of 5.05 monthly migraine days. The European Union analysis revealed that patients in the 60 mg and 30 mg atogepant arms experienced a decrease of 6.75 and 7.33 monthly migraine days, respectively, compared with patients in the placebo arm, who experienced a decrease of 5.09 monthly migraine days. Acadia Resubmits Nuplazid for Treatment of Alzheimer’s PsychosisAcadia Pharmaceuticals in March announced that the FDA has set an action date for the company’s resubmitted supplemental New Drug Application (sNDA) for Nuplazid (pimavanserin) for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis. The FDA’s Division of Psychiatry has also advised the company that it is planning to hold an advisory committee meeting in connection with its review.In April 2021 the FDA rejected pimavanserin for this indication, citing “a lack of statistical significance in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes as lack of substantial evidence of effectiveness to support approval.”The resubmission provides additional analyses from two previously conducted clinical studies, HARMONY and Study-019, to support the proposed indication for the drug and addresses the issues raised in the FDA’s rejection last year.Pimavanserin is currently approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Vraylar sNDA Submitted for Adjunctive Treatment of Major Depressive DisorderIn February AbbVie announced that it has submitted an sNDA for Vraylar (cariprazine) for the adjunctive treatment of major depressive disorder in patients who are receiving ongoing antidepressant therapy. Cariprazine is currently approved for the treatment of schizophrenia in adults, the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, and the treatment of depressive episodes associated with bipolar I disorder in adults.In a phase 3 study of 759 adults with major depressive disorder, patients who took 1.5 mg cariprazine daily experienced a statistically significant change from baseline to week six in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with those who took placebo. In a second study, patients who took 2 mg to 4.5 mg of cariprazine per day also experienced a significant change from baseline to week eight in the MADRS total score compared with those who took placebo. In both of these studies, no new safety events were identified. ■ ISSUES NewArchived

Association of Antidepressant Prescription Filling With Treatment Indication and Prior Prescription Filling Behaviors and Medication Experiences.

Given the wide range of uses for antidepressants, understanding indication-specific patterns of prescription filling for antidepressants provide valuable insights into how patients use these medications in real-world settings. The objective of this study was to determine the association of antidepressant prescription filling with treatment indication, as well as prior prescription filling behaviors and medication experiences. This retrospective cohort study took place in Quebec, Canada. Adults with public drug insurance prescribed antidepressants using MOXXI (Medical Office of the XXIst Century)-an electronic prescribing system requiring primary care physicians to document treatment indications and reasons for prescription stops or changes. MOXXI provided information on treatment indications, past prescriptions, and prior medication experiences (treatment ineffectiveness and adverse drug reactions). Linked claims data provided information on dispensed medications and other patient-related factors. Multivariable logistic regression models estimated the independent association of not filling an antidepressant prescription (within 90 d) with treatment indication and patients' prior prescription filling behaviors and medication experiences. Among 38,751 prescriptions, the prevalence of unfilled prescriptions for new and ongoing antidepressant therapy was 34.2% and 4.1%, respectively. Compared with depression, odds of not filling an antidepressant prescription varied from 0.74 to 1.57 by indication and therapy status. The odds of not filling an antidepressant prescription was higher among adults filling < 50% of their medication prescriptions in the past year and adults with an antidepressant prescription stopped or changed in the past year due to treatment ineffectiveness. Antidepressant prescription filling behaviors differed by treatment indication and were lower among patients with a history of poor prescription filling or ineffective treatment with antidepressants.

Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter

The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.

Med Check: Centanafadine; Dayvigo; Digital Health Devices; Pimavanserin; Meloxicam/Rizatriptan

Med Check: Centanafadine; Dayvigo; Digital Health Devices; Pimavanserin; Meloxicam/Rizatriptan

Improvement of sexual functioning during treatment of MDD with adjunctive pimavanserin: A secondary analysis.

Sexual dysfunction is common among patients with major depressive disorder (MDD). In the CLARITY study, the safety and efficacy of adjunctive pimavanserin, an inverse agonist at 5-HT2A receptors, were demonstrated when added to existing treatment for MDD. This analysis provides a detailed assessment of the effects of pimavanserin on sexual function from the CLARITY study. Patients with a diagnosis of MDD in a depressive episode, inadequate response to ongoing antidepressant therapy, and a Montgomery-Åsberg Depression Rating Scale total score >20 were randomized to pimavanserin 34 mg/day or placebo added to ongoing treatment with an immediate revision of all selective serotonin or serotonin-norepinephrine for 5 weeks (Stage 1), and nonresponders (<50% improvement from baseline in Hamilton Depression Rating Scale [HAMD-17]) were re-randomized for an additional 5 week (Stage 2). Effects of pimavanserin on the Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) and HAMD-17 Item 14 (sexual interest) were examined. Among 203 patients (51 on pimavanserin; 152 on placebo), pimavanserin demonstrated significant improvement from baseline to Week 5 on the MGH-SFI (least square [LS]mean difference -0.634, 95% confidence interval [CI] [-0.964, -0.304]; p = .0002; effect size [ES], Cohen's d: .614). Across Stages 1 and 2, the weighted LSmean difference was -0.468 (95% CI [-0.720, -0.216]; p = .0003) for pimavanserin versus placebo. Mean changes from baseline to Week 5 for MGH-SFI Items 1, 2, 3, and 5 and HAMD Item 14 were significantly (p < .05) greater with pimavanserin versus placebo. Adjunctive pimavanserin improved sexual function in patients with MDD. Adding pimavanserin to ongoing treatment for MDD may be especially useful for patients experiencing sexual dysfunction.

P14.37 Depression in patients with primary brain tumors: Relation to clinical variables and tumor characteristics

Abstract BACKGROUND Patients with brain tumor have an increased risk for depressive disorder, however, the association between depression and clinical or tumor-related variables remains mostly unclear. In this study, we analyzed the relation of depression to several clinical and tumor-related characteristics in patients with primary brain tumors. MATERIAL AND METHODS Sixty patients with newly-diagnosed (n=34) or recurrent (n=26) primary brain tumors (50 gliomas, 10 meningiomas) underwent testing with the Beck Depression Inventory-II (BDI-II). Relation of BDI-II scores to clinical and tumor-related characteristics, including age, Karnofsky Performance Status (KPS) scores, presence of antiepileptic, antidepressant, or steroid treatment, as well as tumor grade, lateralization, and lobar localization, were analyzed. In a subset of recurrent malignant glioma patients, the prognostic value of BDI-II scores on overall survival was also analyzed. RESULTS The mean total BDI-II score was 10±8 (range: 0–37); while 27% of patients (n=16) had BDI-II scores indicating at least mild depressive disorder (≥13), only a portion of them (17%) was on antidepressant treatment. No BDI-II difference was found between gliomas vs. meningiomas or newly-diagnosed vs. recurrent tumors; also, no association was found with any tumor-related characteristics. Antiepileptic or steroid therapy had no association with BDI-II scores, while higher BDI-II scores were observed in patients with ongoing antidepressant therapy (15±10 vs. 8±7, p=0.017). Higher BDI-II total and somatic subscale scores correlated with lower KPS scores (r=-0.32, p=0.014 and r=-0.31, p=0.017, respectively). In recurrent malignant glioma patients (n=18), higher depression scores were associated with shorter survival (hazard ratio: 3.7; 95% confidence interval: 1.0–13.6; p=0.048). CONCLUSION Depression affected more than ¼ of patients with primary brain tumors in this single-center cohort and was independent from most clinical and tumor-related characteristics, except KPS scores. Although most of these patients have mild depression that is often overlooked without targeted screening, higher BDI-II scores may predict shorter overall survival in recurrent malignant glioma patients. These data reinforce the importance of early recognition and treatment of depressive symptoms in patients with primary brain tumors.

N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial

BackgroundA subgroup of depressed patients with increased inflammatory activity was shown to be more susceptible to develop Treatment Resistant Depression (TRD). Earlier studies with anti-inflammatory drugs have shown benefits in the treatment of major depressive disorder (MDD), but the effects are expected to be higher in patients with increased inflammatory activity. Supplementation of N-acetylcysteine (NAC) to ongoing antidepressant therapy may positively influence outcome of depression treatment in these patients. Therefore, this study aims to investigate the efficacy of NAC supplementation in patients with insufficient response to standard antidepressant treatment, and to explore potential roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD.Methods/designA double-blind randomized placebo-controlled study comparing NAC versus placebo as add-on medication to antidepressant treatment with 12-week treatment and 8-week follow up in patients with TRD and increased inflammatory activity. Apart from clinical efficacy defined as the change in Hamilton Depression Rating Scale (HAMD)-17 score, secondary outcomes include changes in pathophysiological mechanisms related to depression as well as changes in local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). Importantly, sole patients with CRP levels with values between 0.85 and 10 mg/L will be included.DiscussionThis is the first clinical trial taking both TRD and increased inflammatory activity as inclusion criteria. This study will provide reliable evidence for the efficacy of NAC in patients with TRD displaying increased inflammatory activity. And this study also will help explore further the roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD.Trial registrationThe trial protocol has been registered on “ClinicalTrials.gov“with protocol ID “NAC-2015-TJAH” and ClinicalTrials.gov ID “NCT02972398”.

Study to Answer What Comes Next When MDD Patients Don’t Respond

VAST-D will provide valuable information about difficult-to-treat depression in a predominantly male population, including a relatively high proportion with comorbidities such as substance and alcohol use disorders and PTSD.

Two Phase III randomised double-blind studies of fixed-dose TC-5214 (dexmecamylamine) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to prior antidepressant therapy

Objectives. To evaluate the neuronal nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy in patients with major depressive disorder (MDD) and inadequate response to prior antidepressant treatment. Methods. Study 004 (D4130C00004) and Study 005 (D4130C00005) comprised an 8-week open-label antidepressant (SSRI/SNRI) treatment period followed by an 8-week randomised, active treatment with twice-daily TC-5214 (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo, adjunct to ongoing SSRI/SNRI. Primary efficacy endpoint was change in MADRS total score from randomisation (Week 8) to treatment end (Week 16). Secondary endpoints included MADRS response and remission, and changes in SDS and HAM-D-17-item scores. Safety and tolerability were monitored throughout. Results. Studies 004 and 005 randomised 640 and 696 patients, respectively, to TC-5214 or placebo. No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end. The most commonly reported adverse events (> 10%) with TC-5214 were constipation, dizziness and dry mouth. Conclusions. TC-5214 adjunct to antidepressant was generally well tolerated. However, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy.

Analysis of potentially predictive factors of efficacy of adjunct extended-release quetiapine fumarate in patients with major depressive disorder.

Identification of predictors of treatment response in patients with major depressive disorder (MDD) may facilitate improved disease management. Data were pooled from two 6-week, double-blind, placebo-controlled studies of extended-release quetiapine (quetiapine XR; 150 or 300 mg/day) as adjunct to ongoing antidepressant therapy. Effects of psychiatric history and baseline demographic and disease characteristics on efficacy outcomes (Week 6 Montgomery Åsberg Depression Rating Scale [MADRS] total score reduction) were evaluated in population subgroups (quetiapine XR both doses pooled, n = 616; placebo, n = 303). Baseline Clinical Global Impressions-Severity (CGI-S) score and previous depressive episodes on Week 6 MADRS total score change, and baseline MADRS individual item scores on Week 6 change in CGI-Improvement score, were also evaluated. No major differences between responders and non-responders to quetiapine XR were observed for patient characteristics or demographic and disease characteristics. No suggestion of a predictive association was found between baseline CGI-S score, number of depressive episodes, and baseline MADRS item scores and efficacy outcomes. These analyses showed no major differences between responders and non-responders, and no predictive association between the parameters assessed and efficacy outcomes for adjunct quetiapine XR in patients with MDD and an inadequate response to prior antidepressant therapy.

Evaluation of adjunct extended-release quetiapine fumarate on sleep disturbance and quality in patients with major depressive disorder and an inadequate response to on-going antidepressant therapy

Sleep disturbance is common in depression and is a risk factor for recurrence and suicide. This analysis evaluated the effects of adjunct extended-release quetiapine fumarate (quetiapine XR) on sleep disturbance and quality in patients with major depressive disorder (MDD) and an inadequate response to on-going antidepressant therapy. Pooled data from two 6-wk, randomized, double-blind, placebo-controlled trials were analysed post hoc. Patients received once-daily quetiapine XR [(150 mg/d), n = 309; (300 mg/d), n = 307] or placebo (n = 303) adjunct to on-going antidepressant therapy. Analyses included: change from randomization in Montgomery-Åsberg Depression Rating Scale (MADRS) Item 4 (reduced sleep) score; Hamilton Rating Scale for Depression (HAMD) Items 4 (insomnia-early), 5 (insomnia-middle) and 6 (insomnia-late) scores; HAMD sleep disturbance factor (Items 4+5+6); Pittsburgh Sleep Quality Index (PSQI) global score. Change in MADRS total score was also evaluated in patients stratified by HAMD sleep disturbance factor score (high ≥ 4 and low < 4) at randomization. At week 6, adjunct quetiapine XR (150 and 300 mg/d) reduced MADRS Item 4, HAMD Items 4, 5 and 6, HAMD sleep disturbance factor and PSQI global scores from randomization vs. placebo (all p < 0.001). In patients with high sleep disturbance, quetiapine XR (both doses) improved depressive symptoms (MADRS total score) vs. placebo from week 1 onwards (p < 0.01). Adjunct quetiapine XR improved sleep disturbance and quality vs. placebo in patients with MDD and an inadequate response to on-going antidepressant treatment, and was effective against depressive symptoms in patients experiencing high sleep disturbance.

Pooled analysis of sustained response rates for extended release quetiapine fumarate as monotherapy or adjunct to antidepressant therapy in patients with major depressive disorder

BackgroundClinical trials are not generally powered to analyze outcomes such as sustained response. We evaluated sustained response rates for patients with major depressive disorder receiving quetiapine XR as monotherapy or adjunct therapy. MethodPost hoc analyses of pooled data from four previously reported randomized, placebo-controlled studies of quetiapine XR 150 and 300mg/day as monotherapy or adjunct therapy to ongoing antidepressant. Sustained response rates (≥50% reduction in MADRS total score at specific timepoint and each subsequent visit until Week 6) were calculated at Weeks 1, 2, and 4; rates were compared using a Cochran–Mantel–Haenszel analysis. ResultsIn the monotherapy studies, the proportion of patients experiencing sustained response was greater with quetiapine XR 150mg/day versus placebo at Week 2 (20.0% vs. 13.3%; p<0.05) and Week 4 (33.3% vs. 23.3%; p<0.01) (observed cases [OC]). The corresponding sustained response rates for quetiapine XR 300mg/day were 18.0% (p=0.104) and 29.7% (p=0.063), respectively (OC).The proportion of patients experiencing sustained response was greater in the adjunct studies versus placebo at Weeks 2 and 4 for quetiapine XR 150 (Week 2, 30.1% vs. 15.2%, p<0.001; Week 4, 40.1% vs. 32.0%, p<0.05) and 300mg/day (Week 2, 29.0% vs. 15.2%, p<0.001; Week 4, 42.0% vs. 32.0%, p<0.05) (OC). LimitationsPost hoc analyses, acute treatment period; no active comparator. ConclusionsQuetiapine XR as monotherapy (150mg/day at Weeks 2 and 4) or adjunct to ongoing antidepressant therapy (150 and 300mg/day at Weeks 2 and 4) increased sustained response rates versus placebo.

P-471 - Evaluation of potential predictors of response to treatment with adjunct extended release quetiapine fumarate (quetiapine XR) in patients with MDD

Introduction Two 6-week, double-blind, placebo-controlled studies evaluated quetiapine XR (QTP-XR) adjunct to ongoing antidepressant therapy in patients with MDD and an inadequate response to prior antidepressant treatment (D14486/D14487). Objective and aim A post hoc pooled analysis examined clinical and demographic characteristics as potential predictors of response to adjunct QTP-XR Methods Pooled MITT population (n = 616 QTP-XR [both doses]; n = 303 placebo) data were analysed from the two adjunct QTP-XR (150 or 300 mg/day) studies. Effects of psychiatric history and baseline demographic and disease characteristics on efficacy were evaluated in subgroups based on Week 6 MADRS total score reduction: ≥50% reduction (responders: n = 345 QTP-XR, n = 140 placebo) versus Impact of baseline CGI-S score and number of episodes (0, 1, 2–3, 4–10, ≥10) over previous year and lifetime on Week 6 MADRS total score change was evaluated. Effect of baseline MADRS individual item (1–10) scores on Week 6 change in CGI-I score was evaluated. Results No major differences between responders and non-responders to QTP-XR were observed for patient characteristics. There was no predictive association between baseline CGI-S score, number of depressive episodes, and baseline MADRS item scores and efficacy outcomes for adjunct QTP-XR. Conclusions This pooled analysis showed no major differences between responders and non-responders, and no suggestion of a predictive association between the parameters assessed and efficacy outcomes for adjunct QTP-XR. Further investigation including logistic regression may be required. AstraZeneca funded.

Supplementation with Eicosapentaenoic Omega-3 Fatty Acid Does Not Influence Serum Brain-Derived Neurotrophic Factor in Diabetes Mellitus Patients with Major Depression: A Randomized Controlled Pilot Study

Background: Low brain-derived neurotrophic factor (BDNF) levels are observed in both depressed and diabetes patients. Animal research has shown that omega-3 polyunsaturated fatty acids increase BDNF levels. In this exploratory randomized double-blind placebo-controlled study in diabetes patients with major depression, we tested whether (a) omega- 3 ethyl-eicosapentaenoic acid (E-EPA) leads to increased serum BDNF levels and (b) whether changes in BDNF levels are associated with corresponding changes in depression. Methods: Patients received 1 g/day E-EPA (n = 13) or placebo (n = 12) for 12 weeks, in addition to ongoing antidepressant therapy. At baseline and 12-week follow-up, we determined serum BDNF levels and depression severity, using the Montgomery-Åsberg Depression Rating Scale. Results: We found no effect of E-EPA on BDNF levels (t = –0.144, p = 0.887), and changes in BDNF levels and depression severity were not significantly associated (Spearman’s ρ = –0.115, p = 0.593). Conclusion: Our study does not provide evidence that supplementation with E-EPA improves BDNF levels in depressed diabetes patients already using antidepressants.

Pooled Analysis of Adjunctive Extended Release Quetiapine Fumarate (Quetiapine XR) in Patients with Major Depressive Disorder (MDD)

Aim:To evaluate quetiapine XR as adjunct to ongoing antidepressant therapy in patients with MDD showing inadequate response to antidepressant treatment.Methods:Data were analysed from two 6-week, multicentre, double-blind, randomised, placebo-controlled studies (D1448C00006; D1448C00007), prospectively designed to be pooled. Outpatients received adjunctive quetiapine XR 150mg/day (n=309), 300mg/day (n=307), placebo (n=303). Primary endpoint: change at Week 6 in MADRS total score. Other assessments included: MADRS individual item scores, HAM-A total scores, MADRS response and remission; AE reporting.Results:Quetiapine XR 150mg/day and 300mg/day (p&lt; 0.001) reduced MADRS total scores versus placebo at Week 6 (-14.5, -14.8, -12.0) and Week 1 (-7.8, -7.3, -5.1). Subgroup analyses showed the therapeutic effect of quetiapine XR was neither limited to nor driven by factors such as gender or antidepressant class (SSRI/SNRI). Quetiapine XR demonstrated consistent improvements in individual MADRS items: 150mg/day and 300mg/day significantly improved 4/10 and 7/10 items at Week 6 versus placebo. At Week 6, MADRS response (≥50% decrease in total score) was 53.7% (p=0.063), 58.3% (p&lt; 0.01) versus 46.2%; MADRS remission (total score ≤8) was 35.6% (p&lt; 0.01), 36.5% (p&lt; 0.001) versus 24.1% for quetiapine XR 150mg/day and 300mg/day and placebo, respectively. Quetiapine XR 150mg/day and 300mg/day improved HAM-A total scores versus placebo at Week 1 (-4.8 [p&lt; 0.001], -4.2 [p&lt; 0.01], -3.0) and Week 6 (-8.9 [p&lt; 0.01], -9.1 [p&lt; 0.001], -7.3). AEs (≥10%) were dry mouth, somnolence, sedation, dizziness, fatigue, constipation and headache with quetiapine XR.Conclusion:In patients with MDD and an inadequate response to antidepressant therapy adjunctive quetiapine XR is effective and generally well tolerated.

Antidepressant Treatment and Relapse of Depression During Pregnancy

To the Editor: In their prospective naturalistic investigation, Dr Cohen and colleagues showed that among women who maintained their antidepressant use throughout the pregnancy, 26% had a relapse of major depression, compared with 68% of those who discontinued taking their antidepressants. They also found that women who increased or decreased their antidepressant use had a rate of relapse between those who maintained and those who discontinued their antidepressants (45% and 35%, respectively). The authors concluded that women with histories of depression who are euthymic while receiving antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation. These findings are very similar to those of lithium treatment for bipolar disorder during pregnancy. First, in the case of lithium continuation, Perlis et al demonstrated that changes in serum lithium level in the maintenance phase (both low to standard and standard to low) were associated with recurrence of bipolar disorder at 36 weeks (rate approximately 50%), whereas unchanged levels were associated with good prognosis (rate approximately 20%). These figures are comparable with the findings of Cohen et al. Second, in the case of lithium discontinuation, Viguera et al showed that the rate of relapse of bipolar disorder in pregnant women following lithium discontinuation was 52%. This rate was dependent on rapidity of lithium discontinuation, with a 63% relapse rate in patients with rapid (1-14 days) discontinuation and 37% relapse with gradual (15-30 days) discontinuation. If the patients in the study by Cohen et al rapidly discontinued their antidepressants within 1 to 2 weeks, their relapse rate of 68% would be comparable. Despite the differences in medication and in diagnoses, the results are very similar. Thus, the conclusion of Cohen et al can be generalized to “women with histories of mood disorder who are euthymic in the context of ongoing antidepressant or lithium therapy should be aware of the association of relapse during pregnancy with the medication discontinuation.”

Antidepressant Treatment and Relapse of Depression During Pregnancy—Reply

To the Editor: In their prospective naturalistic investigation, Dr Cohen and colleagues showed that among women who maintained their antidepressant use throughout the pregnancy, 26% had a relapse of major depression, compared with 68% of those who discontinued taking their antidepressants. They also found that women who increased or decreased their antidepressant use had a rate of relapse between those who maintained and those who discontinued their antidepressants (45% and 35%, respectively). The authors concluded that women with histories of depression who are euthymic while receiving antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation. These findings are very similar to those of lithium treatment for bipolar disorder during pregnancy. First, in the case of lithium continuation, Perlis et al demonstrated that changes in serum lithium level in the maintenance phase (both low to standard and standard to low) were associated with recurrence of bipolar disorder at 36 weeks (rate approximately 50%), whereas unchanged levels were associated with good prognosis (rate approximately 20%). These figures are comparable with the findings of Cohen et al. Second, in the case of lithium discontinuation, Viguera et al showed that the rate of relapse of bipolar disorder in pregnant women following lithium discontinuation was 52%. This rate was dependent on rapidity of lithium discontinuation, with a 63% relapse rate in patients with rapid (1-14 days) discontinuation and 37% relapse with gradual (15-30 days) discontinuation. If the patients in the study by Cohen et al rapidly discontinued their antidepressants within 1 to 2 weeks, their relapse rate of 68% would be comparable. Despite the differences in medication and in diagnoses, the results are very similar. Thus, the conclusion of Cohen et al can be generalized to “women with histories of mood disorder who are euthymic in the context of ongoing antidepressant or lithium therapy should be aware of the association of relapse during pregnancy with the medication discontinuation.”

Modafinil-Induced Reversible Hyperkinetic Nondystonic Movement Disorder in a Patient With Major Depressive Disorder

Back to table of contents Previous article Next article LETTERFull AccessModafinil-Induced Reversible Hyperkinetic Nondystonic Movement Disorder in a Patient With Major Depressive DisorderAlexander Luborzewski M.D.Francesca Regen M.D.Frank Schindler M.D.Ion Anghelescu M.D.,Alexander Luborzewski M.D.Search for more papers by this authorFrancesca Regen M.D.Search for more papers by this authorFrank Schindler M.D.Search for more papers by this authorIon Anghelescu M.D.Search for more papers by this author,Published Online:1 Apr 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Fatigue, lack of energy, and lassitude are commonly reported symptoms in major depressive disorder and are likely to persist as residual conditions in patients with partial response to antidepressant therapy. Modafinil, a newer psychostimulant, has been used as an augmentation strategy to treat persistent fatigue and sleepiness in patients with major depression who are partial responders to antidepressant treatment. 1 Furthermore, modafinil may fasten the onset and degree of resolution of symptoms of depression with fatigue when combined with selective serotonin reuptake inhibitor treatment. 2 Modafinil seems to be generally well tolerated; frequent adverse events include headaches, nausea and nervousness, which are transient in most cases. Case ReportA 76-year-old female patient with a history of major depressive disorder (DSM-IV), was admitted to the psychiatric department with a severe major depressive episode (Hamilton Depression Rating Scale) in August 2003. After partial response with venlafaxine 150 mg/d and concomitant treatment with zopiclone 7.5 mg/d for insomnia, she still suffered from severe lack of energy, persistent fatigue and lassitude. Modafinil 200 mg/d was then administered as augmentation to ongoing antidepressant therapy with rapid improvement of residual symptoms and full remission from depression after 2 weeks of treatment (Hamilton Depression Rating Scale). The patient was discharged with venlafaxine 150 mg/d and modafinil 200 mg/d and subsequently was followed at our outpatient clinic. After 4 months of continuous treatment, the patient presented with bothersome, nondystonic, hyperkinetic, involuntary movements affecting the orofacial region and the lower limbs, which had developed over the past 4 days. After discontinuation of modafinil, the drug-induced movement disorder improved and then finally disappeared completely within 4 days.Comment The authors report a case of a severe and disabling, but reversible, orofacial and lower limb hyperkinetic, nondystonic, modafinil-induced movement disorder. No such movement disorders have been observed in patients treated with modafinil for daytime sleepiness or narcolepsy even in large-scale trials. 3 Neither have there been any reports on those disorders in depressed patients receiving modafinil as an augmentation strategy. A causal relationship between the intake of modafinil and the movement disorder described seems probable, because the movement disorder developed within a timeframe of 4 months of continuous treatment with modafinil, which is in line with a case report on orofacial dyskinesias following a 10-month period of treatment with the modafinil derivative adrafinil. 4 Furthermore, the movement disorder completely resolved within 4 days after discontinuation of modafinil. This case report supports further evidence that, like in the case of antipsychotics, 5 elderly patients might have a greater risk for developing hyperkinetic movement disorders. Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany

Relapse of Major Depression During Pregnancy in Women Who Maintain or Discontinue Antidepressant Treatment

Pregnancy has historically been described as a time of emotional well-being, providing "protection" against psychiatric disorder. However, systematic delineation of risk of relapse in women who maintain or discontinue pharmacological treatment during pregnancy is necessary. To describe risk of relapse in pregnant women who discontinued antidepressant medication proximate to conception compared with those who maintained treatment with these medications. A prospective naturalistic investigation using longitudinal psychiatric assessments on a monthly basis across pregnancy; a survival analysis was conducted to determine time to relapse of depression during pregnancy. A total of 201 pregnant women were enrolled between March 1999 and April 2003 from 3 centers with specific expertise in the treatment of psychiatric illness during pregnancy. The cohort of women was recruited from (1) within the hospital clinics, (2) self-referral via advertisements and community outreach detailing the study, and (3) direct referrals from the community. Participants were considered eligible if they (1) had a history of major depression prior to pregnancy, (2) were less than 16 weeks' gestation, (3) were euthymic for at least 3 months prior to their last menstrual period, and (4) were currently or recently (<12 weeks prior to last menstrual period) receiving antidepressant treatment. Of the 201 participants, 13 miscarried, 5 electively terminated their pregnancy, 12 were lost to follow-up prior to completion of pregnancy, and 8 chose to discontinue participation in the study. Relapse of major depression defined as fulfilling Structured Clinical Interview for DSM-IV [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition] Diagnosis (SCID) criteria. Among the 201 women in the sample, 86 (43%) experienced a relapse of major depression during pregnancy. Among the 82 women who maintained their medication throughout their pregnancy, 21 (26%) relapsed compared with 44 (68%) of the 65 women who discontinued medication. Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy compared with women who maintained their medication (hazard ratio, 5.0; 95% confidence interval, 2.8-9.1; P<.001). Pregnancy is not "protective" with respect to risk of relapse of major depression. Women with histories of depression who are euthymic in the context of ongoing antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation.

Modafinil augmentation in depressed patients with partial response to antidepressants: A pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92)

Treatment-resistant depression, i.e. partial or no response to antidepressants in spite of various treatment attempts with optimized doses and combinations, is rather common. With residual symptoms such as tiredness, anhedonia and concentration disturbances, the treatment strategy has often been to use monoamino-oxidase inhibitors (MAOIs). Their use, however, is limited due to interaction problems. Modafinil is a recently developed wake-promoting drug with only minor side-effects. Pilot studies indicate that it appears to have an augmentation effect in treatment-resistant depression. This open-label study performed in the private psychiatric practice setting is the first to make a comprehensive evaluation of the target patient profile based on patient-reported symptoms. Modafinil in doses of 100–400 mg was administered as augmentation to ongoing antidepressant therapy in patients with partial response and suffering from hypersomnia. The total number of patients was 21 and 43% of these were responders (i.e. had a score reduction of >50% on the Major Depression Inventory (MDI)) as well as remitters, i.e. the remission rate was 43%. At endpoint, the responders had psychological distress scores on the Symptom Checklist (SCL-92) on the level of the general Danish population. Baseline characteristics for responders were lower scores on depression, hostility, anxiety, somatization, obsession and psychoticism. Modafinil thus appears to be an appropriate augmentation to antidepressant treatment, leading to a remission rate of 43%. However, the results from this open-label study need to be confirmed in a placebo-controlled trial.