Treatment-refractory Major Depression Research Articles

Vagus nerve stimulation for treatment-resistant mood disorders: a long-term naturalistic study.

BackgroundLimited therapeutic options are available for patients with treatment-refractory major depression who do not respond to routinely available therapies. Vagus nerve stimulation showed adjunctive antidepressant effect in chronic treatment resistant depression, even though available studies rarely exceed 2-year follow up.We report a naturalistic 5-year follow up of five patients who received VNS implant for resistant depression (3 patients with major depressive disorder and 2 with bipolar disorder).MethodsResponse was defined as a reduction of the 17-item HDRS total score ≥50% with respect to baseline, remission as a score ≤7.ResultsResponse and remission rates were both 40% (2/5) after 1 year, and 60% (3/5) at 5 years. Two patients withdrew from the study because of side effects or inefficacy of stimulation.ConclusionsOur case series showed that long-term VNS may be effective in reducing severity of depression in a small but significant minority of patients, although two patients had stimulation terminated because of adverse effects and/or refusal to continue the study.

Deep brain stimulation for psychiatric diseases: what are the risks?

Despite the application of deep brain stimulation (DBS) as an efficient treatment modality for psychiatric disorders, such as obsessive-compulsive disorder (OCD), Gilles de la Tourette Syndrome (GTS), and treatment refractory major depression (TRD), few patients are operated or included in clinical trials, often for fear of the potential risks of an approach deemed too dangerous. To assess the surgical risks, we conducted an analysis of publications on DBS for psychiatric disorders. A PubMed search was conducted on reports on DBS for OCD, GTS, and TRD. Forty-nine articles were included. Only reports on complications related to DBS were selected and analyzed. Two hundred seventy-two patients with a mean follow-up of 22 months were included in our analysis. Surgical mortality was nil. The overall mortality was 1.1 %: two suicides were unrelated to DBS and one death was reported to be unlikely due to DBS. The majority of complications were transient and related to stimulation. Long-term morbidity occurred in 16.5 % of cases. Three patients had permanent neurological complications due to intracerebral hemorrhage (2.2 %). Complications reported in DBS for psychiatric diseases appear to be similar to those reported for DBS in movement disorders. But class I evidence is lacking. Our analysis was based mainly on small non-randomized studies. A significant number of patients (approximately 150 patients) who were treated with DBS for psychiatric diseases had to be excluded from our analysis as no data on complications was available. The exact prevalence of complications of DBS in psychiatric diseases could not be established. DBS for psychiatric diseases is promising, but remains an experimental technique in need of further evaluation. A close surveillance of patients undergoing DBS for psychiatric diseases is mandatory.

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Study protocol for the randomised controlled trial: Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study)

BackgroundSome patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service.Methods/designPatients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone.DiscussionStrengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments.Trial registrationCurrent Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.

Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients

BackgroundThere are limited treatment options for patients with chronic, treatment-refractory major depression who do not respond to routinely-available treatments. Vagus Nerve Stimulation (VNS) may represent an alternative to ablative neurosurgery for a specific group of patients. Methods12-month response rates for 28 patients with chronic (≥2 years) major depression who had failed to respond to ≥4 adequate treatment trials in the D03 European open clinical trial of VNS were described along with response rates for 13 consecutive patients who underwent VNS within the neurosurgical treatment programme in Dundee. ResultsIn the D03 cohort (N=28), the response rate at 12 months (defined as a 50% reduction in symptom score) was 35.7%. In the Dundee VNS case series (N=13), the equivalent response rate was 30.8%. LimitationsThese data are from unblinded and open studies, and there is no control group. Other factors may have contributed to some of the improvement seen, although this is unlikely in very chronic populations. Outcomes are not reported beyond 12 months. ConclusionResponse rates at 12 months for patients with chronic and highly-refractory major depression are broadly consistent with previously published results in more heterogeneous and less refractory clinical trial populations. In highly treatment-resistant patients, the rate of response with VNS at 12m is at least twice that anticipated with ‘treatment-as-usual’.

Dorsomedial prefrontal rTMS for treatment-refractory major depression: safety, tolerability, efficacy, and predictors of clinical response

Dorsomedial prefrontal rTMS for treatment-refractory major depression: safety, tolerability, efficacy, and predictors of clinical response

The Use of Neuroimaging to Predict Treatment Response for Neurosurgical Interventions for Treatment-Refractory Major Depression and Obsessive-Compulsive Disorder

Neuroimaging has contributed profoundly to our understanding of the pathophysiology of psychiatric disorders but has had little impact on treatment. An important goal in neuroscience research is identifying biological markers that predict subsequent response to given treatments. This approach may be especially valuable when considering high-risk and high-cost treatments such as psychiatric neurosurgery. Here, we review neuroimaging findings pertaining to treatment-refractory major depression and obsessive-compulsive disorder, and imaging markers that predict response to neurotherapeutic interventions. Thus far, studies conducted with neurotherapeutic interventions have found patterns of predictive brain activity that are similar to those conducted with pharmacological treatments. The predictive neural correlates are concordant with pathophysiological models of major depressive and obsessive-compulsive disorder. These promising findings should motivate additional work establishing the reliability and cost-effectiveness of neuroimaging to predict treatment response across psychiatric diagnoses and interventions.

Long term outcome of thermal anterior capsulotomy for chronic, treatment refractory depression

BackgroundThere is very limited evidence for the efficacy of any specific therapeutic intervention in chronic, treatment refractory major depression. Thermal anterior capsulotomy (ACAPS) is a rarely performed but established therapeutic...

The use of background EEG activity to determine stimulus timing as a means of improving rTMS efficacy in the treatment of depression: A controlled comparison with standard techniques

Repetitive transcranial magnetic stimulation (rTMS) treatment of depression utilizes numerous predetermined patterns of stimulation. As an alternative to using invariant stimulus timing parameters, the interactive technique delivers individual stimuli based on the background electroencephalogram (EEG) activity. This study examines the use of an EEG-dependent technique as a means to enhance the efficacy of rTMS in the treatment of depression. Forty-four patients with treatment-refractory major depression were treated, in a randomized, doubleblind, 4-week trial, with two different rTMS stimulus timing techniques (left dorsolateral prefrontal cortex). Standard rTMS utilized 10-Hz stimuli, whereas interactive rTMS applied individual stimuli in response to a selected pattern of background EEG activity analyzed in real time. Hamilton Depression Rating Scale (HDRS) and the Beck's Depression Inventory-II (BDI) scores were recorded at baseline, 2 weeks and after the final treatment. The interactive group showed a trend toward greater efficacy than the standard group in both absolute (t=-1.68; P=.100) and percentage (t=-1.74; P=.090) change in scores on HDRS (and similarly BDI). The response rate (>50% reduction) for the interactive technique of 43% (9/21) was also different to that of the standard technique (22%; 5/23; odds ratio: 2.70). The use of EEG-based TMS stimuli has been shown to be feasible in an rTMS clinical trial in treatment-resistant depression. The EEG-based interactive technique was associated with an indication of a trend toward a greater clinical effect than the standard rTMS technique. The interactive technique thus has the potential to refine the rTMS methodology and to enhance efficacy in the treatment of depression.

Opposite effects of high and low frequency rTMS on mood in depressed patients: Relationship to baseline cerebral activity on PET

Background Optimal parameters of rTMS for antidepressant efficacy in general, or within patients, have not been adequately delineated. Methods Using a double-blind, sham-controlled, cross-over design, 22 adult patients with treatment refractory major depression ( n = 9; bipolar disorder, depressed phase) were randomized to active rTMS (20-Hz or 1-Hz) or sham rTMS conditions and given 5 rTMS treatments per week for two weeks. Repetitive TMS was administered at 100% of motor threshold for 1600 pulses over the left prefrontal cortex using a figure-eight coil. Patients initially randomized to sham rTMS were then exposed to two weeks of active rTMS with each frequency under blinded conditions. Those who received active 20-Hz and 1-Hz rTMS were crossed over to the opposite frequency for two weeks. Improvement in Hamilton Depression ratings were assessed after each two-week treatment phase. PET imaging was used to evaluate the patient's baseline absolute regional cerebral activity (blood flow and metabolism) as potential predictor of clinical response. Results Changes in depression severity on 1-Hz and 20-Hz rTMS were inversely correlated. PET scans with baseline hypoperfusion (but not hypometabolism) were associated with better improvement on 20-Hz rTMS as predicted. Limitations The magnitude of the clinical change with either frequency at 100% motor threshold was not robust, and larger studies with higher intensities of rTMS for longer durations of time should be explored. Conclusions High and low frequency rTMS exerts differential effects on depressed mood within individual subjects. The brain activity predictors and correlates of an optimal antidepressant response to rTMS remain to be better defined.

Newer Antipsychotics Show Efficacy as Depression Treatment Adjunct

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessNewer Antipsychotics Show Efficacy as Depression Treatment AdjunctJun YanJun YanSearch for more papers by this authorPublished Online:21 Dec 2007https://doi.org/10.1176/pn.42.24.0019The role of atypical antipsychotics has been extended to the treatment of depression. Aripiprazole, an atypical antipsychotic, was approved by the Food and Drug Administration in November for adjunctive treatment for depression.In addition, another atypical antipsychotic, risperidone, has also shown effectiveness for patients who continue to have symptoms on antidepressants alone, according to a randomized, placebo-controlled study.Aripiprazole, manufactured by Bristol Myers Squibb (BMS) and Otsuka Pharmaceutical, was approved on the basis of two randomized, double-blind, clinical trials in 743 adults with major depressive disorder with residual symptoms despite being treated with an antidepressant, according to a company announcement.After all patients completed a run-in period (an eight-week period in which they took an antidepressant), those who remained symptomatic were given either aripiprazole or placebo as an add-on therapy for six weeks. The patients' clinical outcomes were rated by clinicians using the Montgomery-Asberg Depression Rating Scale (MADRS).At the end of the study, the aripiprazole-plus-antidepressant group saw a reduction from baseline (end of the run-in period) in MADRS total score that was statistically significantly greater than that of the placebo-plus-antidepressant group. One of the two trials, which enrolled 362 patients, was published in the June Journal of Clinical Psychiatry by Robert Berman, M.D., and colleagues from BMS and Otsuka. The other trial has not been published, a BMS representative said. The daily dosage tested in both studies ranged from 2 mg to 20 mg.The company's announcement listed the most commonly reported adverse reactions to aripiprazole, pooled from both studies, as akathisia (24 percent), restlessness (12 percent), insomnia (8 percent), constipation (5 percent), fatigue (8 percent), and blurred vision (6 percent). The mean change from baseline in weight gain was 1.7 kg (approximately 3.7 pounds) in the aripiprazole group and 0.4 kg (0.9 pounds) in the placebo group at the end of the study.Researchers from Ortho-McNeil Janssen Scientific Affairs, led by Ramy Mahmoud, M.D., similarly found risperidone to be better than placebo as an adjunct to antidepressants. Their study was published in the November Annals of Internal Medicine.In the randomized, double-blind trial, 268 patients who remained symptomatic despite antidepressant treatment after a four-week run-in period were randomly assigned to receive either risperidone (137 patients) or placebo (131 patients). All participants continued on their original ant idepressant as well. The risperidone dosage was started at 0.25 mg and titrated up to 1.0 mg a day in three to four weeks. Depending on response, participants might have the dose increased to a maximum of 2.0 mg.The clinical improvement in participants, as measured by a reduction in total score on the 17-item Hamilton Rating Scale for Depression (HRSD-17) from baseline, was significantly higher in the risperidone group at week 4 and week 6. The authors also reported that significantly more patients in the risperidone group reached remission (HRSD-17 total score 7) than did patients in the placebo group. The rate of response, defined as at least 50 percent reduction in HRSD-17 total score from baseline, was also higher in the risperidone group than the placebo group. The difference between the groups in both response and remission rates was statistically significant at both week 4 and week 6.Twenty-six patients (19 percent) in the risperidone group and 16 (12.2 percent) in the placebo group dropped out of the study. Eight patients (5.8 percent) on risperidone and three (2.3 percent) on placebo discontinued the study prematurely because of adverse events. The most frequently reported adverse events deemed treatment-related were headache (8.8 percent), dry mouth (5.1 percent), somnolence (5.1 percent), insomnia (4.4 percent), and weight gain (4.4 percent). At the end of the study, patients on risperidone gained a mean of 2.8 pounds, significantly higher than the mean of 0.3 pounds gained by the placebo group.An abstract of “The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder: A Multi-center, Randomized, Double-Blind, Placebo-Controlled Study” is posted at<www.psychiatrist.com/abstracts/abstracts.asp?abstract=200706/060704.htm>. An abstract of “Risperidone for Treatment-Refractory Major Depression Disorder: A Randomized Trial” is posted at<www.annals.org/cgi/content/abstract/147/9/593>.▪ ISSUES NewArchived

Perospirone augmentation of paroxetine in treatment of refractory obsessive–compulsive disorder with depression

Obsessive–compulsive disorder (OCD) is often complicated by depression. We report on a patient with treatment-refractory OCD and treatment-refractory major depression who demonstrated a robust response to augmentation of paroxetine with perospirone. Perospirone is a second-generation antipsychotic agent with antagonist effects on both serotonin 5-HT 2A and dopamine D 2 receptors, as well as a unique agonist effects on serotonin 5-HT 1A receptors. Future studies would be valuable to elucidate the utility of augmentation therapy of selective serotonin reuptake inhibitors with perospirone in the treatment of refractory OCD with depression.

Raloxifene augmentation is effective in women with treatment-refractory major depression,

Raloxifene augmentation is effective in women with treatment-refractory major depression,

Use of ECT in idiopathic intracranial hypertension.

In 2001 the Second Edition of the American Psychiatric Association's Task Force Report on ECT maintained that no absolute contraindications to ECT exist. They warned, however, that ECT in persons with elevated intracranial pressure should be considered on a case-by-case risk to benefit ratio. Literature on the use of ECT in patients with elevated intracranial pressures is limited to space-occupying lesions as a cause for elevated pressures. This case report presents a 42-year-old woman with treatment-refractory major depression and idiopathic intracranial hypertension (also known as pseudotumor cerebri). Brain imaging and lumbar puncture were performed before ECT, and blood pressures were monitored closely during treatment. Treatment was successful with minimal adverse effects. With appropriate clinical observation, patients with idiopathic intracranial hypertension can be considered for ECT.

Efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of affective disorders.

Transcranial magnetic stimulation (TMS) is a relatively noninvasive technique to interfere with the function of small cortical areas through currents induced by alternating magnetic fields emanating from a handheld coil placed directly above the targeted area. This technique has clear effects on a whole range of measures of brain function and has become an important research tool in neuropsychiatry. More recently, TMS has been studied in psychiatry mainly to assess its putative therapeutic effects in treatment refractory major depression. Most studies indicate that both low-frequency TMS and higher (20 Hz) frequency repetitive TMS may have some antidepressant properties. However, definite therapeutic effects of clinical significance still remain to be demonstrated.

Venlafaxine in Treatment Refractory Geriatric Depression

ABSTRACT This study addresses the effectiveness and tolerability of venlafaxine in geriatric psychiatry outpatients with treatment refractory major depression. All patients from a geriatric psychiatry outpatient clinic with major depression who had received at least one prescription for venlafaxine during a 12 month period were examined for treatment refractory criteria. Ten patients receiving venlafaxine met strictly defined criteria for treatment refractory depression. Of these, 8 (80%) had a complete response to venlafaxine, including two patients who had previously only been stabilized by maintenance ECT (mECT). Two patients required another concurrent psychiatric medication to achieve full response (lithium and methylphenidate augmentation). Venlafaxine was generally well tolerated, with 2 (20%) patients discontinuing its use due to side effects. Of 8 patients with a past history of side effects on other antidepressants, 6 (75%) had no reported side effects with venlafaxine. However, two patients (both responders) had severe apparent withdrawal/discontinuation symptoms upon sudden cessation of venlafaxine. Of the responders, seven (88%) currently remain in remission (mean time well of 24 months), and one (12%) relapsed at 14 months. Venlafaxine thus appears to be a promising antidepressant among geriatric patients with treatment refractory depression; however, clinicians should be aware of the possibility of a severe withdrawal/discontinuation syndrome and caution patients not to suddenly discontinue venlafaxine.