Low-dose Transdermal Testosterone Augmentation Therapy Improves Depression Severity in Women

ABSTRACTBackground: Inadequate response to antidepressant monotherapy in women with major depressive disorder is common. Testosterone administration has been shown to be an effective augmentation therapy in depressed hypogonadal men with selective serotonin reuptake inhibitor-resistant depression. However, the effects of low-dose testosterone as augmentation therapy in women with treatment-resistant depression have not been studied.Methods: Low-dose transdermal testosterone (300 mcg/day, Intrinsa, Procter and Gamble Pharmaceuticals) was administered to nine women with treatment-resistant depression in an 8 week open-label pilot protocol.Results: There was a statistically significant improvement in mean Montgomery-Asberg Depression Rating Scale (MADRS) scores at 2 weeks, sustained through the 8 week period. Two-thirds of subjects achieved a response to the treatment (decrease in MADRS score of ≥50%) and 33% achieved remission (final MADRS score <10) after 8 weeks of therapy. Mean levels of fatigue, as measured by the MADRS lassitude item, significantly decreased at all time points with a mean 38% decrease from baseline to 8 weeks.Conclusion: These preliminary pilot data suggest that low-dose transdermal testosterone may be an effective augmentation therapy in women with treatment-resistant depression. Further studies are warranted.

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Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

Psychological Medicine ◽

10.1017/s0033291718001356 ◽

2018 ◽

Vol 49 (4) ◽

pp. 655-663 ◽

Cited By ~ 92

Author(s):

Fernanda Palhano-Fontes ◽

Dayanna Barreto ◽

Heloisa Onias ◽

Katia C. Andrade ◽

Morgana M. Novaes ◽

...

Keyword(s):

Rating Scale ◽

Remission Rate ◽

Controlled Trial ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Double Blind ◽

Therapeutic Value ◽

Antidepressant Effects ◽

Resistant Depression

AbstractBackgroundRecent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.MethodsTo test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.ResultsWe observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p= 0.04), and at D7 (p< 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen'sd= 0.84; D2: Cohen'sd= 0.84; D7: Cohen'sd= 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64%v.27%;p= 0.04). Remission rate showed a trend toward significance at D7 (36%v.7%,p= 0.054).ConclusionsTo our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered athttp://clinicaltrials.gov(NCT02914769).

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Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa027 ◽

2020 ◽

Vol 23 (7) ◽

pp. 426-433 ◽

Cited By ~ 2

Author(s):

Michel Nijs ◽

Ewa Wajs ◽

Leah Aluisio ◽

Ibrahim Turkoz ◽

Ella Daly ◽

...

Keyword(s):

Nasal Spray ◽

Rating Scale ◽

Maintenance Phase ◽

Induction Phase ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Treatment Frequency ◽

Resistant Depression ◽

The Impact

Abstract Background Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes. Methods This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a new oral antidepressant daily. In responders (≥50% reduction in Montgomery-Åsberg Depression Rating Scale total score from baseline), esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Åsberg Depression Rating Scale ≤ 12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression–Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase. Results Among 580 responders treated with weekly esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened. Conclusions These findings support individualization of esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice. Trial Registration ClinicalTrials.gov identifier: NCT02497287

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Repeated, low-dose oral esketamine in patients with treatment-resistant depression: pilot study

BJPsych Open ◽

10.1192/bjo.2021.1059 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Sanne Y. Smith-Apeldoorn ◽

Jolien K. E. Veraart ◽

Henricus G. Ruhé ◽

Marije aan het Rot ◽

Jeanine Kamphuis ◽

...

Keyword(s):

Low Dose ◽

Rating Scale ◽

Controlled Trial ◽

Minimum Clinically Important Difference ◽

Therapeutic Effects ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Point Change ◽

Dose Oral ◽

Resistant Depression

Background Intravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium. Aims To explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine. Method Seven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed. Results Treatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission. Conclusions These results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.

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A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression

Journal of Neurosurgery ◽

10.3171/2011.10.jns102122 ◽

2012 ◽

Vol 116 (2) ◽

pp. 315-322 ◽

Cited By ~ 205

Author(s):

Andres M. Lozano ◽

Peter Giacobbe ◽

Clement Hamani ◽

Sakina J. Rizvi ◽

Sidney H. Kennedy ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Brain Stimulation ◽

Rating Scale ◽

Depressive Symptomatology ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Open Label Trial ◽

Resistant Depression ◽

Deep Brain

Object Deep brain stimulation (DBS) has been recently investigated as a treatment for major depression. One of the proposed targets for this application is the subcallosal cingulate gyrus (SCG). To date, promising results after SCG DBS have been reported by a single center. In the present study the authors investigated whether these findings may be replicated at different institutions. They conducted a 3-center prospective open-label trial of SCG DBS for 12 months in patients with treatment-resistant depression. Methods Twenty-one patients underwent implantation of bilateral SCG electrodes. The authors examined the reduction in Hamilton Rating Scale for Depression (HRSD-17) score from baseline (RESP50). Results Patients treated with SCG DBS had an RESP50 of 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS, however, increased to 62% when defined as a reduction in the baseline HRSD-17 of 40% or more. Reductions in depressive symptomatology were associated with amelioration in disease severity in patients who responded to surgery. Conclusions Overall, findings from this study corroborate the results of previous reports showing that outcome of SCG DBS may be replicated across centers.

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Treatment resistant depression in the UK: sub-analysis of a European real-world evidence study

BJPsych Open ◽

10.1192/bjo.2021.192 ◽

2021 ◽

Vol 7 (S1) ◽

pp. S55-S55

Author(s):

Jordan Talbot ◽

Donald J MacIntyre ◽

Shanaya Rathod ◽

Joachim Morrens ◽

Allan H Young

Keyword(s):

Real World ◽

Rating Scale ◽

Response Rates ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Major Depressive ◽

Madrs Score ◽

Patient Reported ◽

Resistant Depression ◽

The Uk

AimsTreatment resistant depression (TRD) affects ≤20% of patients with major depressive disorder and is defined as failure to respond to ≥2 different antidepressants in the same major depressive episode (MDE). TRD patients’ outcomes are poor and real-world data from the UK are limited. The Treatment Resistant Depression in Europe Cohort was established to study patients being treated in local, routine clinical practice. The analysis presented here aimed to compare UK-specific data with data from other European countries included in the study.MethodA prospective, multicentre, observational cohort study of TRD patients in Italy, Germany, Spain, Portugal, the Netherlands, the UK and Belgium was conducted. Patients aged 18–74 years with current TRD, Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥20, and initiating a new treatment for depression, were eligible. Data from medical records, clinician assessments and patient-reported questionnaires were collected over time, with follow-up of ≥6 months.ResultData from 411 patients were analysed. At baseline, UK patients (n = 49) had similar depression severity to the whole European cohort (34.7% vs 32.6% of patients categorised as severe based on MADRS score, respectively). Patients had experienced the current MDE for a mean (standard deviation [SD]) of 6.1 (7.9) years vs 2.6 (3.9) years and 14.3% vs 4.9% had experienced ≥5 treatment failures during this time in the UK and whole cohort, respectively. Total mean (SD) Sheehan Disability Scale (SDS) scores of 24.5 (5.1) and 22.4 (5.5) were reported for the UK and whole cohort, respectively. Unemployment and long-term sick leave rates were 38.8% and 20.4% in the UK and 30.2% and 19.0% in the whole cohort, respectively. At 6 months, 8.9% of UK patients were in remission, and 82.2% had not responded to treatment, representing the lowest remission and highest non-response rates across all countries.ConclusionUK patients had been ill for longer and had more prior treatment failures than other countries in the study. They had high work and functional impairment, and the worst treatment outcomes of all the countries studied. UK TRD patients experience high disease burden; there is an unmet need for treatment strategies with better response rates.AcknowledgementsWe thank all participating patients. Study, and medical writing (Costello Medical, UK), funded by Janssen. AHY's independent research is funded by the National Institute for Health Research. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

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Efficacy of low-dose ketamine infusion in anxious vs nonanxious depression: revisiting the Adjunctive Ketamine Study of Taiwanese Patients with Treatment-Resistant Depression

CNS Spectrums ◽

10.1017/s1092852920001194 ◽

2020 ◽

pp. 1-6

Author(s):

Mu-Hong Chen ◽

Wei-Chen Lin ◽

Hui-Ju Wu ◽

Ya-Mei Bai ◽

Cheng-Ta Li ◽

...

Keyword(s):

Depressive Symptoms ◽

Low Dose ◽

Rating Scale ◽

Estimating Equation ◽

Antidepressant Effect ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Ketamine Infusion ◽

Resistant Depression

Abstract Background. The antidepressant effect of low-dose ketamine infusion on Taiwanese patients with anxious vs nonanxious treatment-resistant depression (ANX-TRD vs NANX-TRD) has remained unknown. Methods. In total, 71 patients with TRD were randomized to three groups. Each group had participants who received saline infusions mixed with 0 (a normal saline infusion), 0.2, and 0.5 mg/kg of ketamine. Participants were followed up for 2 weeks. Anxious depression was defined as major depressive disorder with a total score of 7 or more on the 17-item Hamilton Depression Rating Scale Anxiety-Somatization factor. Generalized estimating equation models were used to investigate the effects of treatment (ketamine vs placebo) and depression type (ANX-TRD vs NANX-TRD) in the reduction of depressive symptoms during the follow-up period. Results. Patients with ANX-TRD were less likely to respond to a single low-dose ketamine infusion than those with NANX-TRD. Among patients with NANX-TRD, low-dose ketamine infusion was significantly superior to placebo for reducing depressive symptoms. However, among patients with ANX-TRD, ketamine was not superior to placebo; nonetheless, approximately 30% of the patients responded to ketamine infusion compared to 13% who responded to the placebo. Conclusions. Low-dose ketamine infusion was effective for Taiwanese patients with NANX-TRD but not so effective for those with ANX-TRD. A higher level of anxiety severity accompanying depression was related to greater depression severity. This may confound and reduce the antidepressant effect of ketamine infusion.

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Effects of add-on tipepidine on treatment-resistant depression: an open-label pilot trial

Acta Neuropsychiatrica ◽

10.1017/neu.2015.43 ◽

2015 ◽

Vol 28 (1) ◽

pp. 51-54 ◽

Cited By ~ 5

Author(s):

Yukihiko Shirayama ◽

Masatoshi Suzuki ◽

Michio Takahashi ◽

Koichi Sato ◽

Kenji Hashimoto

Keyword(s):

Rating Scale ◽

Verbal Learning ◽

Pilot Trial ◽

Therapeutic Drug ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Blood Concentrations ◽

Resistant Depression ◽

Learning Test

ObjectiveTreatment-resistant depression is a challenging problem in the clinical setting. Tipepidine has been used as a non-narcotic antitussive in Japan since 1959.MethodsWe administered tipepidine to 11 patients with treatment-resistant depression. Tipepidine was given for 8 weeks as an augmentation.ResultsTipepidine significantly improved depression scores on the Hamilton Rating Scale for depression. Add-on treatment with tipepidine significantly improved scores on the trail making test and Rey auditory verbal learning test. However, no changes were observed in blood concentrations of stress-related hormones (adrenocorticotropic hormone, cortisol, dehydroepiandrosterone sulphate) with tipepidine augmentation.ConclusionTipepidine might be a potential therapeutic drug for treatment-resistant depression.

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Ketamine augmentation for outpatients with treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation

Australian & New Zealand Journal of Psychiatry ◽

10.1177/0004867416631828 ◽

2016 ◽

Vol 51 (1) ◽

pp. 55-64 ◽

Cited By ~ 41

Author(s):

Cristina Cusin ◽

Dawn Flosnik Ionescu ◽

Kara Jean Pavone ◽

Oluwaseun Akeju ◽

Paolo Cassano ◽

...

Keyword(s):

Rating Scale ◽

Treatment Resistance ◽

Preliminary Evidence ◽

Primary Outcome Measure ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Antidepressant Efficacy ◽

Resistant Depression ◽

Intravenous Ketamine

Objective: Preliminary evidence supports the safety and efficacy of subanesthetic ketamine as an experimental antidepressant, although its effects are often not sustained beyond one week. Studies are lacking that have examined the sustained effects of escalating ketamine doses as augmentation in outpatients with treatment-resistant depression. Therefore, the aims of this study were twofold: (1) to assess the safety and antidepressant efficacy of two-step, repeated-dose ketamine augmentation and (2) to assess the duration of ketamine’s antidepressant efficacy as augmentation to ongoing antidepressant pharmacotherapy for 3 months after the final infusion. Methods: Fourteen patients with treatment-resistant depression were eligible to receive augmentation with six open-label intravenous ketamine infusions over 3 weeks. For the first three infusions, ketamine was administered at a dose of 0.5 mg/kg over 45 minutes; the dose was increased to 0.75 mg/kg over 45 minutes for the subsequent three infusions. The primary outcome measure was response (as measured on Hamilton Depression Rating Scale–28 items). Results: After the completion of three ketamine infusions, 7.1% (1/14) responded; after all six ketamine infusions, 41.7% (5/12) completers responded and 16.7% (2/12) remitted. Intent-to-treat response and remission rates at the end of the final infusion were 35.7% (5/14) and 14.3% (2/14), respectively. However, all but one responder relapsed within 2 weeks after the final infusion. Conclusion: Repeated, escalating doses of intravenous ketamine augmentation were preliminarily found to be feasible, efficacious and well tolerated. Interaction with concomitant medications and elevated level of treatment resistance are possible factors for non-response.

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A randomized placebo-controlled trial on the antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression

10.1101/103531 ◽

2017 ◽

Cited By ~ 7

Author(s):

Fernanda Palhano-Fontes ◽

Dayanna Barreto ◽

Heloisa Onias ◽

Katia C Andrade ◽

Morgana Novaes ◽

...

Keyword(s):

Rating Scale ◽

Remission Rate ◽

Controlled Trial ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Open Label ◽

Double Blind ◽

Therapeutic Value ◽

Antidepressant Effects ◽

Resistant Depression

AbstractRecent open label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. In order to further test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. Changes in depression severity were assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale (HAM-D). Assessments were made at baseline, and at one (D1), two (D2) and seven (D7) days after dosing. We observed significant antidepressant effects of ayahuasca when compared to placebo at all timepoints. MADRS scores were significantly lower in the ayahuasca group compared to placebo (at D1 and D2: p=0.04; and at D7: p<0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’ s d=0.84; D2: Cohen’ s d=0.84; D7: Cohen’ s d=1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% vs. 27%; p=0.04), while remission rate was marginally significant at D7 (36% vs. 7%, p=0.054). To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression.

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Nicotinic acetylcholine receptor antagonists for treatment-resistant depression: A meta-analysis

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.559 ◽

2016 ◽

Vol 33 (S1) ◽

pp. s226-s226

Author(s):

W.M. Bahk ◽

Y.S. Woo ◽

H.J. Seo ◽

B.H. Yoon ◽

D.I. Jon ◽

...

Keyword(s):

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Rating Scale ◽

Meta Analysis ◽

Inadequate Response ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Receptor Antagonists ◽

Nicotinic Acetylcholine ◽

Resistant Depression

ObjectiveEmerging preclinical and clinical evidence suggests a potential role of nicotinic acetylcholine receptors in the pathophysiology of depression. Several clinical trials have investigated the efficacy of nicotinic acetylcholine receptor antagonists in treatment-resistant depression. We performed this meta-analysis to investigate whether nicotinic acetylcholine receptor antagonists significantly improve symptoms in patients with major depressive disorder who have an inadequate response to standard antidepressant therapy.MethodsA comprehensive literature search identified 6 randomized controlled trials. These 6 trials, which included 2067 participants, were pooled for this meta-analysis using a random-effects model.ResultsNicotinic acetylcholine receptor antagonists failed to show superior efficacy compared to placebo in terms of the mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) score [mean difference = –0.12 (95% CI = –0.96 to 0.71); response rate (risk ratio [RR] = 0.92 (95% CI = 0.83 to 1.02)); and remission rate [RR] = 1.01 (95% CI= 0.83 to 1.23)].ConclusionThis meta-analysis failed to confirm preliminary positive evidence for the efficacy of nicotinic acetylcholine receptor antagonists in treatment-resistant depression. Further studies investigating the efficacy of various alternative treatment strategies for treatment-resistant depression will help clinicians to better understand and choose better treatment options for these populations.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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