Repetitive transcranial magnetic stimulation (rTMS) is considered an efficacious non-invasive neuromodulation treatment for major depressive disorder (MDD). However, little is known about the ...clinical outcome of combined rTMS and psychotherapy (rTMS + PT). Through common neurobiological brain mechanisms, rTMS + PT may exert enhanced antidepressant effects compared to the respective monotherapies.
The current naturalistic study aimed to evaluate feasibility and clinical outcome of rTMS + PT in a large group of MDD patients. The second aim was to identify clinical predictors of response and remission.
A total of 196 patients with MDD were treated with at least 10 sessions of simultaneous rTMS and PT. rTMS was applied over the DLPFC, either 10 Hz left or 1 Hz right. Psychotherapy was based on principles of cognitive behavioral therapy (CBT). Symptoms were measured using the BDI each fifth session until end of treatment and at 6-month follow-up. Comparisons were made between responders and non-responders, as well as between the 10 Hz and 1 Hz protocol. Additionally, baseline variables and early BDI change were evaluated as predictors of response/remission.
1) Combining rTMS and PT resulted in a 66% response and a 56% remission rate at the end of treatment with 60% sustained remission at follow-up. Compared to previous findings in RCTs, these rates are relatively high; 2) No differences were found between the 10 Hz and 1 Hz TMS regarding clinical outcome; 3) Clinical baseline variables were not predictive of treatment outcomes; 4) Early symptom improvement (at session 10) was highly predictive of response, and may therefore be used to guide rTMS + PT continuation; 5) Based on the current findings in a large naturalistic study, future studies employing a more standardized method are warranted to draw solid conclusions on the unique effect of rTMS + PT.
•Simultaneous application of rTMS and psychotherapy may exert enhanced effects.•rTMS + PT resulted in relatively high response (66%) and remission (56%) rates.•No differences were found between patients treated with high vs. low frequency rTMS.•Symptom change after 10 sessions could predict positive treatment response.
Abstract
Side effects to antidepressant medications are common and can impact the prognosis of successful treatment outcome in people with major depressive disorder (MDD). However, few studies have ...investigated the severity of side effects over the course of treatment and their association with treatment outcome. Here we assessed the severity of side effects and the impact of treatment type and anxiety symptoms over the course of treatment, as well as whether side effects were associated with treatment outcome. Participants were
N
= 1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic MDD. Participants were randomised to receive escitalopram, sertraline, or venlafaxine-extended release with equal probability and reassessed at 8 weeks regarding Hamilton Rating Scale Depression (HRSD
17
) and Quick Inventory of Depressive Symptomatology (QIDS-SR
16
) remission and response. Severity of side effects were assessed using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale and assessed at day 4 and weeks 2, 4, 6, and 8. Frequency, intensity, and burden of side effects were greatest at week 2, then only frequency and intensity of side effects gradually decreased up to week 6. Treatment type and anxiety symptoms did not impact the severity of side effects. A greater burden—but not frequency or intensity—of side effects was associated with poorer treatment outcome and as early as 4 days post-treatment. Together, this work provides an informative mapping of the progression of side effects throughout the treatment course and their association with treatment outcome. Importantly, the burden of side effects that are present as early as 4 days post-treatment predicts poorer treatment outcome and should be monitored closely. iSPOT-D: Registry name: ClinicalTrials.gov. Registration number: NCT00693849.
Side effects (SEs) are negative reactions to an appropriately delivered treatment, which must be discriminated from unwanted events (UEs) or consequences of inadequate treatment. One hundred CBT ...therapists were interviewed for UEs and SEs in one of their current outpatients. Therapists reported 372 UEs in 98 patients and SEs in 43 patients. Most frequent were "negative wellbeing/distress" (27% of patients), "worsening of symptoms" (9%), "strains in family relations" (6%); 21% of patients suffered from severe or very severe and 5% from persistent SEs. SEs are unavoidable and frequent also in well-delivered CBT. They include both symptoms and the impairment of social life. Knowledge about the side effect profile can improve early recognition of SEs, safeguard patients, and enhance therapy outcome.
It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples ...(baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite's effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies.Clinical trial NCT00360399 "Predictors of Antidepressant Treatment Response: The Emory CIDAR" https://clinicaltrials.gov/ct2/show/NCT00360399 .
Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is ...delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 60% vs. 20/40 50%, respectively, χ(2)(1) = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.
Objective:
This report assesses whether age at onset defines a specific subgroup of major depressive disorder in 4,041 participants who entered the Sequenced Treatment Alternatives to Relieve ...Depression (STAR*D) study.
Method:
The study enrolled outpatients 18-75 years of age with nonpsychotic major depressive disorder from both primary care and psychiatric care practices. At study entry, participants estimated the age at which they experienced the onset of their first major depressive episode. This report divides the population into five age-at-onset groups: childhood onset (ages <12), adolescent onset (ages 12-17), early adult onset (ages 18-44), middle adult onset (ages 45-59), and late adult onset (ages ≥60).
Results:
No group clearly stood out as distinct from the others. Rather, the authors observed an apparent gradient, with earlier ages at onset associated with never being married, more impaired social and occupational function, poorer quality of life, greater medical and psychiatric comorbidity, a more negative view of life and the self, more lifetime depressive episodes and suicide attempts, and greater symptom severity and suicidal ideation in the index episode compared to those with later ages at onset of major depressive disorder.
Conclusions:
Although age at onset does not define distinct depressive subgroups, earlier onset is associated with multiple indicators of greater illness burden across a wide range of indicators. Age of onset was not associated with a difference in treatment response to the initial trial of citalopram.
DSM-IV major depressive disorder (MDD) is a clinical syndrome notable for heterogeneity of its clinical presentation, genetics, neurobiology, clinical course, and treatment responsiveness. In an ...attempt to make sense of this heterogeneity, clinicians and researchers have proposed a number of MDD "subtypes" based on differences in characteristic symptoms (e.g., atypical, melancholic, psychotic), onset (e.g., early vs. late, post-partum, seasonal), course of illness (e.g., single vs. recurrent, chronic, double), and severity. This article provides a brief review of the status of several of the most common subtypes in terms of their clinical features, biological correlates, course of illness, and treatment implications.
Objective:Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in ...first-step acute-phase (12 weeks) and long-term (7 months) treatment.
Method:The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care. The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology—Self-Report. Secondary outcomes included side effect burden, adverse events, quality of life, functioning, and attrition.
Results:Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram-placebo, 38.9% for bupropion-escitalopram, and 37.7% for venlafaxine-mirtazapine, and the response rates were 51.6%–52.4%. The mean number of worsening adverse events was higher for venlafaxine-mirtazapine (5.7) than for escitalopram-placebo (4.7). At 7 months, remission rates (41.8%–46.6%), response rates (57.4%–59.4%), and most secondary outcomes were not significantly different.
Conclusions:Neither medication combination outperformed monotherapy. The combination of extended-release venlafaxine plus mirtazapine may have a greater risk of adverse events.
There is no established efficacious treatment for cognitive dysfunction in unipolar and bipolar disorder. This may be partially due to lack of consensus regarding the need to screen for cognitive ...impairment in cognition trials or which screening criteria to use. We have demonstrated in 2 randomized placebo-controlled trials that 8 weeks of erythropoietin (EPO) treatment has beneficial effects on verbal memory across unipolar and bipolar disorder, with 58% of EPO-treated patients displaying a clinically relevant memory improvement as compared to 15% of those treated with placebo.
We reassessed the data from our 2 EPO trials conducted between September 2009 and October 2012 to determine whether objective performance-based memory impairment or subjective self-rated cognitive impairment at baseline was related to the effect of EPO on cognitive function as assessed by Rey Auditory Verbal Learning Test (RAVLT) total recall with multiple logistic regression adjusted for diagnosis, age, gender, symptom severity, and education levels.
We included 79 patients with an ICD-10 diagnosis of unipolar or bipolar disorder, of whom 39 received EPO and 40 received placebo (saline). For EPO-treated patients with objective memory dysfunction at baseline (n = 16) (defined as RAVLT total recall ≤ 43), the odds of a clinically relevant memory improvement were increased by a factor of 290.6 (95% CI, 2.7-31,316.4; P = .02) compared to patients with no baseline impairment (n = 23). Subjective cognitive complaints (measured with the Cognitive and Physical Functioning Questionnaire) and longer illness duration were associated with small increases in patients' chances of treatment efficacy on memory (53% and 16% increase, respectively; P ≤ .04). Diagnosis, gender, age, baseline depression severity, and number of mood episodes did not significantly change the chances of EPO treatment success (P ≥ .06). In the placebo-treated group, the odds of memory improvement were not significantly different for patients with or without objectively defined memory dysfunction (P ≥ .59) or subjective complaints at baseline (P ≥ .06).
Baseline objectively assessed memory impairments and-to a lesser degree-subjective cognitive complaints increased the chances of treatment efficacy on cognition in unipolar and bipolar disorder.
ClinicalTrials.gov identifier: NCT00916552.
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