This report was commissioned by one of my freelancing clients and published with permission.
Roughly 20-30% of people with depression don’t respond to the first antidepressant or two they try. One of the harder-to-treat subtypes of depression is atypical depression, which comes with sleeping and eating more than usual (rather than less), and high emotional sensitivity. This report is an overview of options for treatment-resistant or atypical depression.
For context, “response rates” with respect to a particular depression rating scale are the probability that a patient will see at least 50% improvement from baseline after the treatment.
HAM-D Response Rates in Treatment-Resistant or Atypical Depression
||Possible Side Effects
|Deep brain stimulation
||Complications of brain surgery
||QT prolongation (risk of sudden death)
||Weight gain, motor disorders, sedation
||Dehydration, hypothyroidism, kidney damage
|Vagus nerve stimulation
Bottom lines: SSRIs and MAOIs work better than tricyclics in atypical depression; there’s no clear indication that any particular drug is best; SSRIs and MAOIs work similarly well.
Phenelzine (Nardil, an MAOI) has a 58% response rate on the HAM-D in atypical depression, same as therapy, and significantly better than placebo. N=108.
Fluoxetine (an SSRI) and imipramine (a tricyclic) had equivalent response rates in atypical depression in clinical global impression, 51% and 53% respectively, both superior to placebo. No significant differences on the HAM-D either.
Sertraline (an SSRI) caused a 77.5% response rate on the CGI in 197 patients with atypical depression, compared to 67.5% in the moclobemide group (moclobemide is an MAOI). This difference was not statistically significant (p = 0.052).
No significant difference in response rate between fluoxetine and phenelzine in atypical depression, N=42.
Isocarboxazid (an MAOI) significantly more effective than placebo in atypical depression.
Imipramine (a tricyclic) significantly better than placebo in 76 patients with atypical depression; 45% response rate in treatment group vs. 12% in placebo.
Moclobemide had a positive response in 67% of atypical depressive patients, while the response rate was 55% with fluoxetine. This was a significant difference. N=53.
67% of atypical patients responded to fluoxetine while 0% responded to nortriptyline (a tricyclic), n=16.
119 patients with atypical depression randomized to phenelzine, imipramine, or placebo; response rate was 71% with phenelzine, 50% with imipramine, 28% with placebo. Phenelzine vs. imipramine difference was significant.
Meta-analysis: MAOIs are more effective than placebo in atypical depression (effect size = 0.42), not significantly more effective than SSRIs, and more effective than tricyclics (effect size = 0.27).
Bottom line: agomelatine is an antidepressant with a different mechanism of action than most: it’s a melatonin receptor agonist. It works comparably well to SSRIs, with less risk of sexual dysfunction.
In a placebo-controlled trial of 212 depressive patients, agomelatine had a 49% response rate on the HAM-D rating scale, significantly (p = 0.03) better than placebo.
In a placebo-controlled trial of patients randomized to agomelatine or placebo, agomelatine resulted in statistically greater improvement on HAM-D than placebo.
In a placebo-controlled trial of 238 depressive patients, agomelatine was significantly more effective than placebo, and had a HAM-D response rate of 53%.
In a randomized controlled trial of agomelatine and venlafaxine on 276 depressed patients, both treatments had comparably high remission rates, but venlafaxine was more likely to cause sexual dysfunction (8.6% vs. 2.2%.)
In a meta-study of agomelatine in depression, comprising 7460 patients, agomelatine was significantly more effective than placebo and equally effective to other antidepressants.
Bottom line: aripiprazole is an atypical antipsychotic which works comparably to other atypical antipsychotics in atypical or treatment-resistant depression. It may work when SSRIs fail.
Adjunctive aripiprazole was significantly more effective than placebo in anxious or atypical depressive patients who were already on antidepressants, as measured by MADRS score.
In an open-label study of 30 patients with treatment-resistant depression, 46.7% were rated “much improved” or “very much improved” after adjunctive treatment with aripiprazole.
Bottom line: atypical antipsychotics improve symptoms in treatment-resistant depression.
In a meta-study comprising 1500 patients with treatment-resistant depression randomized to adjunctive treatment with an atypical antipsychotic, the typical response rate was 47.4% with treatment vs 22% for placebo, with an odds ratio of 1.75.
In a meta-study comprising 3480 patients with treatment-resistant depression randomized to adjunctive atypical antipsychotics, response rates had an odds ratio of 1.69 compared to placebo. The overall response rate was 45%. Roughly similar response rates for olanzapine, risperidone, quetiapine, and aripiprazole.
Bottom line: bromantane is a Russian drug with unknown mechanism of action. It has never been tested on humans for depression. It has been reported to improve “asthenia” (a catch-all term for mood disorders) in one uncontrolled study.
In an uncontrolled Russian study of 728 patients with asthenic disorders, 90% of patients responded according to the CGI-I scale.
Bottom line: buprenorphine is an opioid used to treat opioid addiction; it has been reported to improve symptoms in treatment-resistant depression.
In an open-label study of 13 elderly patients with treatment-resistant major depression, buprenorphine resulted in a 61% response rate according to the MADRS scale after 8 weeks.
In an uncontrolled study of 7 patients with treatment-resistant major depression, 4 (57%) had a full remission after treatment with buprenorphine.
Bottom line: one study found that chromium supplementation helped with atypical depression, but it didn’t replicate.
Chromium picolinate caused response in 70% of patients with atypical depression; 0% of placebo responded. N=15.
Replication study, N=113, failed to find more response than placebo in atypical depression patients treated with chromium, but chromium did reduce carbohydrate cravings.
Bottom line: cycloserine is an antibiotic which also seems to be effective in psychiatric disorders; it has been reported to improve symptoms in treatment-resistant depression.
In a randomized study of 26 patients with treatment-resistant depression given high-dose D-cycloserine or placebo, 54% in the treatment group responded according to the HAM-D score, compared to 15% of placebo.
Deep Brain Stimulation
Bottom line: deep brain stimulation involves surgically implanting an electrode in the brain. DBS to the subcallosal cingulate gyrus is highly effective against treatment-resistant depression in uncontrolled studies, but hasn’t been confirmed in controlled studies.
In 20 patients with treatment-resistant depression who received deep brain stimulation to the subcallosal cingulate gyrus, the HAM-D response rate after 1 year was 62.5%, after 2 years, 46.2%, and after 3 years, 75%.
In an uncontrolled study of 6 patients with treatment-resistant depression receiving deep brain stimulation to the subgenual cingulate region (Brodmann 25), at 6 months 4 patients (67%) were responders according to the HDRS-17 rating score.
In an uncontrolled study of 10 patients with treatment-resistant depression receiving deep brain stimulation to the nucleus accumbens, there was a 50% response rate according to the HAM-D scale at 12 months.
In an uncontrolled study of 7 patients with treatment-resistant depression receiving deep brain stimulation to the supero-lateral branch of the medial forebrain bundle, all of them responded according to the HAM-D scale after a week; at 33 weeks follow-up, 67% were responders.
In an uncontrolled study of 8 patients with treatment-resistant depression treated with deep brain stimulation to the subgenual cingulate gyrus (Brodmann 24-25), at 6 months the response rate was 87%.
In a sham-controlled trial of 30 patients with treatment-resistant depression treated with ventral capsule/ventral striatum deep brain stimulation or control, there was no difference in response rates according to MADRS criteria.
In a systematic review of 22 studies of deep brain stimulation for depression, reported response rates are 40-70%, but most of these are from open-label trials.
Bottom line: methylfolate, a dietary supplement, may work on treatment-resistant depression. It may be relevant that depressives are more likely to be folic acid deficient than healthy people.
Folinic acid, in an uncontrolled study of 22 patients with depression unresponsive to SSRIs, had a 33% response rate according to the HAM-D rating scale.
Methylfolate at 15 mg/day in a controlled study of 75 patients with depression unresponsive to SSRIs had a response rate on the HAM-D rating scale of 32.3% compared to a placebo response rate of 14.6%, a significant difference.
In a retrospective study of 242 patients either given methylfolate + SSRI or SSRI alone, the patients given methylfolate were significantly more likely to experience major improvement (according to CGI rating) compared to the SSRI-only group.
Bottom line: ketamine is an NMDA antagonist and anaesthetic drug, used intravenously as an experimental treatment for depression. Ketamine very rapidly produces high response rates in treatment-resistant depression, but these seem to be short-lived.
In a placebo-controlled trial of 18 subjects with treatment-resistant major depression, receiving an intravenous infusion of ketamine or placebo, 71% responded the day after treatment, according to the HAM-D score, and 35% remained responders after a week.
In a placebo-controlled trial of 73 patients with treatment-resistant depression, receiving an intravenous infusion of ketamine or active control, 64% responded the day after treatment, significantly more than controls.
In a review of 20 studies of ketamine for depression, response rates at 4 hours averaged 77% and 43% at 72 hours; no studies had follow-up times of more than two weeks.
Bottom line: lithium improves symptoms of treatment-resistant depression.
In a meta-analysis of 9 trials comprising 234 patients with treatment-resistant depression, randomized to adjunctive lithium or placebo, 45% of treated patients responded according to the HAM-D scale, compared to 18% of controls, p < 0.0001.
Bottom Line: Modafinil improves symptoms in depression when added to other treatment.
Modafinil had significant effects in atypical depression: mean HAM-D changed from 34 to 9.7, n = 89.
In a systematic review of studies of modafinil in unipolar and bipolar depression, from 6 RCTs, modafinil significantly improved depression scores and remission rates relative to placebo.
Bottom line: a single use of nitrous oxide has been reported to have a short-term effect on depression.
In a placebo-controlled, blinded trial of nitrous oxide inhalation in 20 patients with treatment-resistant depression, 20% of treated patients had a response on the HAM-D after 24 hours, compared to 5% placebo responders.
Bottom line: pramipexole is a dopamine agonist used for Parkinson’s disease; some uncontrolled studies report that it improves symptoms in treatment-resistant depression.
In an uncontrolled study of 37 patients with treatment-resistant depression given adjunctive pramipexole, 67.7% of patients were responders according to the MADRS score and 74% on the Clinical Global Impression score.
In an uncontrolled study of 10 patients with treatment-resistant depression given adjunctive pramipexole, 60% responded on the MADRS score.
Bottom line: psilocybin may improve depressive symptoms but the evidence is very preliminary.
In an uncontrolled study of 12 patients with treatment-resistant depression given two doses of psilocybin, depressive symptoms according to the QIDS score were significantly reduced one week and three months after treatment.
Bottom line: SAM-E is a dietary supplement which improves symptoms in treatment-resistant depression.
In an open-label study of thirty patients with treatment-resistant depression, SAM-E supplementation caused a 50% response rate and 43% remission rate, as measured by the HAM-D rating score.
In a randomized trial of 75 patients with treatment-resistant depression, 36% of patients given 800 mg/day SAM-E had a response according to the HAM-D score, while only 17.6% of placebo patients did.
In an open-label study of 9 patients with treatment-resistant depression, 22% responded to SAM-E according to the HAM-D score.
Bottom line: selegiline has a high response rate in atypical and treatment-resistant depression, as well as depression in general. It is an MAOI but doesn’t cause the dangerous “cheese reaction” of other MAOIs.
In an open trial of 17 patients with atypical depression, 59% responded to selegiline. Selegiline was superior to placebo in a separate double-blind study.
In a randomized study of 44 patients with depression, 50% responded according to the HAM-D score, compared to 13.6% of placebo. 67% of atypical patients responded to selegiline, compared to 28.6% in placebo, n = 13.
In a randomized study of 177 patients with depression randomized to transdermal selegiline or placebo, HAM-D scores were significantly lower in the treatment group. 37% of patients responded according to the CGI score.
In a randomized study of 16 treatment-resistant older depressive patients, high-dose selegiline significantly improved scores on the HAM-D compared to placebo.
In a randomized study of 365 patients with depression treated with a selegiline patch or placebo, selegiline caused significantly (p = 0.03) more improvement in HAM-D scores; the selegiline group had a 48% response rate according to the MADRS score, compared to a 30% response rate for placebo, a statistically significant difference.
In a randomized study of 27 patients randomized to selegiline or placebo, 71% of selegiline patients responded on the HAM-D rating scale, compared to only 15% of placebo, a significant difference.
Bottom line: T3 is a thyroid hormone. It has been reported to improve symptoms in treatment-resistant depression, even in patients who are not hypothyroid.
In an uncontrolled study of 12 subjects with treatment-resistant depression, T3 (triiodothyronine) resulted in 42% of patients responding according to HAM-D criteria, and 25% experiencing remission.
In an uncontrolled study of 20 patients with treatment-resistant depression, T3 augmentation resulted in 35% of patients responding according to HAM-D criteria. All 5 subjects with atypical depression responded.
Bottom line: T4 is a thyroid hormone. It may improve symptoms in treatment-resistant depression even in people who are not hypothyroid.
In an uncontrolled study of 17 patients with treatment-resistant depression, high-dose T4 resulted in 58% of patients having a full remission.
In an uncontrolled study of nine patients with treatment-resistant depression, high-dose T4 resulted in 56% of patients responding according to the HAM-D scale.
In a meta-analysis of eight controlled studies comprising 232 euthyroid patients with refractory depression, T3 augmentation was significantly more likely to result in a response (RR = 2.09).
Bottom line: tianeptine is an antidepressant with an unusual mechanism of action: probably stimulating BDNF release. It works about as well as other antidepressants.
In a placebo-controlled study of 123 depressed patients, tianeptine did not cause a significantly higher response rate than placebo according to the MADRS score, but did cause a significant drop in mean MADRS score.
Tianeptine, in a randomized trial of 265 patients with anxious depression, caused a 78% response rate on the MADRS score, while amitriptyline caused an 83% response rate, a non-statistically-significant difference. Both treatments were safe, and tianeptine caused less sedation.
In a randomized study of 387 patients given tianeptine or fluoxetine, MADRS response rates were 58% and 56%, respectively; there was no statistically significant difference in efficacy or safety.
In a randomized study of 277 patients randomized to tianeptine or paroxetine, there was no significant difference in MADRS score, other efficacy parameters, or safety parameters.
In a retrospective study of 1858 depressed patients treated with tianeptine, 61% were responders according to the MADRS score.
Bottom line: traxoprodil is an experimental NMDA-antagonist compound which was reported to have a high response rate in treatment-resistant depression, but testing was discontinued due to cardiac adverse events.
In a study of 30 patients with treatment-resistant major depression randomized to the NMDA antagonist traxoprodil or placebo, 60% of treated patients responded according to the HAM-D scale, compared to 20% placebo. Treatment also produced better response in MADRS scores than placebo. Testing of traxoprodil was discontinued because of an increase in QT interval.
Vagus Nerve Stimulation
Vagus nerve stimulation involves surgically implanting an electrical device under the skin of the chest; it has positive effects on treatment-resistant depression, but takes a while to work.
In an open-label study of 59 patients with treatment-resistant major depression, vagus nerve stimulation caused a 31% response rate within 3 months and 44% within a year, measured on the HAM-D rating scale.
In a controlled trial of 235 patients with treatment-resistant depression or bipolar, randomized to vagus nerve stimulation or sham treatment, there was no significant difference in response rates after 10 weeks.
In a one-year trial of 329 patients with treatment-resistant depression, vagus nerve stimulation resulted in a 27% response rate for vagus nerve treatment, compared to 13% for control, significant at p< 0.011.
In a meta-analysis of six randomized controlled trials comprising 1225 patients with treatment-resistant depression, the MADRS response rate at 96 weeks was 32% for vagus nerve stimulation compared to 14% for treatment as usual, a statistically significant odds ratio at 3.19.
Bottom line: Viloxazine is a norepinephrine reuptake inhibitor which has stimulant effects. It’s unclear whether it’s an effective antidepressant.
In a randomized study of 129 depressed patients, viloxazine and imipramine caused a statistically significant improvement from baseline; there was no significant difference between drugs.
In a study of 62 severely depressed patients randomized to viloxazine or citalopram, both had a significant improvement in mean MADRS score; there was no significant difference between drugs.
In a study of 21 depressed elderly patients randomized to viloxazine or placebo, viloxazine caused a larger response on the Cronholm-Ottosson Depression Rating Scale than placebo after three weeks.
In a study of 43 depressed patients randomized to viloxazine or placebo over 7 weeks, there was no significant difference in HAM-D scores between treatment and placebo.
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