Changes in QEEG prefrontal cordance as a predictor of response to antidepressants in patients with treatment resistant depressive disorder: a pilot study

INTRODUCTION: Previous studies of patients with unipolar depression have shown that early decreases of EEG cordance (a new quantitative EEG method) can predict clinical response. We examined whether early QEEG decrease represents a phenomenon associated with response to treatment with different antidepressants in patients with treatment resistant depression. METHOD: The subjects were 17 inpatients with treatment resistant depression. EEG data and response to treatment were monitored at baseline and after 1 and 4 weeks on an antidepressant treatment. QEEG cordance was computed at three frontal electrodes in theta frequency band. The prefrontal cordance combines complementary information from absolute and relative power of EEG spectra. Recent studies have shown that cordance correlates with cortical perfusion. Depressive symptoms were assessed using Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: All 17 patients completed the 4-week study. All five responders showed decreases in prefrontal cordance after the first week of treatment. Only 2 of the 12 nonresponders showed early prefrontal cordance decrease. The decrease of prefrontal QEEG cordance after week 1 in responders as well as the increase in nonresponders were both statistically significant (p-value 0.03 and 0.01, respectively) and the changes of prefrontal cordance values were different between both groups (p-value 0.001). CONCLUSION: Our results suggest that decrease in prefrontal cordance may indicate early changes of prefrontal activity in responders to antidepressants. QEEG cordance may become a useful tool in the prediction of response to antidepressants.     

Changes in brain function of depressed subjects during treatment with placebo.

OBJECTIVE: It has been proposed that 50%-75% of the efficacy of antidepressant medication represents the placebo effect, since many depressed patients improve when treated with either medication or placebo. This study examined brain function in depressed subjects receiving either active medication or placebo and sought to determine whether quantitative electroencephalography (QEEG) could detect differences in brain function between medication and placebo responders. Both QEEG power and cordance, a new measure that reflects cerebral perfusion and is sensitive to the effect of antidepressant medication, were examined. METHOD: Fifty-one subjects with major depression were enrolled in one of two independent, 9-week double-blind, placebo-controlled studies in which either fluoxetine (N=24) or venlafaxine (N=27) was the active medication. Serial QEEG recordings were performed during the course of treatment. After 9 weeks, the blind was broken and subjects were classified as medication responders, placebo responders, medication nonresponders, or placebo nonresponders. RESULTS: No significant pretreatment differences in clinical or QEEG measures were found among the four outcome groups. Placebo responders, however, showed a significant increase in prefrontal cordance starting early in treatment that was not seen in medication responders (who showed decreased cordance) or in medication nonresponders or placebo nonresponders (who showed no significant change). There was no significant change in QEEG power during treatment. CONCLUSIONS: These findings suggest that "effective" placebo treatment induces changes in brain function that are distinct from those associated with antidepressant medication. If these results are confirmed, cordance may be useful for differentiating between medication and placebo responders.     

Early reduction in prefrontal theta QEEG cordance value predicts response to venlafaxine treatment in patients with resistant depressive disorder

INTRODUCTION: Previous studies of patients with unipolar depression have shown that early decrease of prefrontal EEG cordance in theta band can predict clinical response to various antidepressants. We have now examined whether decrease of prefrontal quantitative EEG (QEEG) cordance value after 1 week of venlafaxine treatment predicts clinical response to venlafaxine in resistant patients. METHOD: We analyzed 25 inpatients who finished 4-week venlafaxine treatment. EEG data were monitored at baseline and after 1 week of treatment. QEEG cordance was computed at three frontal electrodes in theta frequency band. Depressive symptoms and clinical status were assessed using Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory-Short Form (BDI-S) and Clinical Global Impression (CGI). RESULTS: Eleven of 12 responders (reduction of MADRS >or=50%) and only 5 of 13 non-responders had decreased prefrontal QEEG cordance value after the first week of treatment (p=0.01). The decrease of prefrontal cordance after week 1 in responders was significant (p=0.03) and there was no significant change in non-responders. Positive and negative predictive values of cordance reduction for response were 0.7 and 0.9, respectively. CONCLUSION: The reduction of prefrontal theta QEEG cordance value after first week of treatment might be helpful in the prediction of response to venlafaxine.     

Changes in brain function (quantitative EEG cordance) during placebo lead-in and treatment outcomes in clinical trials for major depression

OBJECTIVE: Decreases in prefrontal electroencephalogram (EEG) cordance that are detectable as early as 48 hours after the start of medication have been related to clinical outcome in treatment trials for major depressive disorder. The relationship between brain changes during the placebo lead-in phase and medication treatment outcome is unknown. The authors hypothesized that decreases in prefrontal cordance during the placebo lead-in phase would be associated with better clinical outcome in subjects treated with antidepressants. METHOD: Data were pooled examining 51 adults with major depressive disorder from two independent double-blind placebo-controlled trials. A 1-week single-blind placebo lead-in phase preceded 8 weeks of randomized treatment with medication (fluoxetine 20 mg or venlafaxine 150 mg) or placebo. The authors obtained quantitative EEG cordance measures at baseline and at the end of the placebo lead-in period. Relationships between regional cordance changes at the end of the placebo lead-in period and clinical outcome (the final 17-item Hamilton Rating Scale for Depression scores) were examined using multiple linear regression analysis. RESULTS: As hypothesized, decreases in prefrontal cordance during the placebo lead-in period were associated with lower final Hamilton depression scale scores in subjects randomly assigned to medication. Prefrontal changes explained 19% of the variance in final Hamilton depression scale scores. CONCLUSIONS: Neurophysiological changes during a placebo lead-in period may serve as nonpharmacodynamic biomarkers of eventual treatment outcomes in clinical trials for major depressive disorder.     

Prefrontal changes and treatment response prediction in depression

A continuing challenge in the treatment of depression is how to determine whether an effective drug has been selected for a particular patient, given that individuals will respond to some antidepressants but not others. The factors that contribute to response for each person have been examined from a variety of perspectives, both psychological and physiological. Advances in neuroimaging and in quantitative electroencephalography (QEEG) have made it possible to examine features of brain activity that are associated with response. A new QEEG measure, cordance, is correlated with regional cortical perfusion, and has been used with retrospective and prospective studies to evaluate specific findings that are predictive of clinical response in major depression. We present here a series of depressed subjects treated with antidepressants of different classes; decreases in prefrontal activity were seen as early as 48 hours into treatment in responders and were absent in nonresponders. These findings suggest a role for the prefrontal region in mediating response to medications with different mechanisms of action and raise the possibility of using new QEEG measures to identify changes in brain activity that are predictive of clinical outcome from antidepressant treatment.     

Heart rate variability and cordance in rapid eye movement sleep as biomarkers of depression and treatment response

ObjectivesThe relevance of rapid eye movement (REM) sleep in affective disorders originates from its well-known abnormalities in depressed patients, who display disinhibition of REM sleep reflected by increased frequency of rapid eye movements (REM density). In this study we examined whether heart rate variability (HRV) and prefrontal theta cordance, both derived from REM sleep, could represent biomarkers of antidepressant treatment response.MethodsIn an open-label, case-control design, thirty-three in-patients (21 females) with a depressive episode were treated with various antidepressants for four weeks. Response to treatment was defined as a ≥50% reduction of HAM-D score at the end of the fourth week. Sleep EEG was recorded after the first and the fourth week of medication. HRV was derived from 3-min artifact-free electrocardiogram segments during REM sleep. Cordance was computed for prefrontal EEG channels in the theta frequency band during tonic REM sleep.ResultsHRV during REM sleep was decreased in depressed patients at week four as compared to controls (high effect size; Cohen's d > 1), and showed a negative correlation with REM density in both, healthy subjects and patients at week four. Further, the fourteen responders had significantly higher prefrontal theta cordance as compared to the nineteen non-responders after the first week of antidepressant medication; in contrast, HRV at week one did not discriminate between responders and non-responders.ConclusionsOur data suggest that HRV in REM sleep categorizes healthy subjects and depressed patients, whereas REM sleep-derived prefrontal cordance may predict the response to antidepressant treatment in depressed patients.     

Accelerated HF-rTMS in treatment-resistant unipolar depression: Insights from subgenual anterior cingulate functional connectivity

Objectives. Intensified repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) may result in fast clinical responses in treatment resistant depression (TRD). In these kinds of patients, subgenual anterior cingulate cortex (sgACC) functional connectivity (FC) seems to be consistently disturbed. So far, no de novo data on the relationship between sgACC FC changes and clinical efficacy of accelerated rTMS were available. Methods. Twenty unipolar TRD patients, all at least stage III treatment resistant, were recruited in a randomized sham-controlled crossover high-frequency (HF)-rTMS treatment study. Resting-state (rs) functional MRI scans were collected at baseline and at the end of treatment. Results. HF-rTMS responders showed significantly stronger resting-state functional connectivity (rsFC) anti-correlation between the sgACC and parts of the left superior medial prefrontal cortex. After successful treatment an inverted relative strength of the anti-correlations was observed in the perigenual prefrontal cortex (pgPFC). No effects on sgACC rsFC were observed in non-responders. Conclusions. Strong rsFC anti-correlation between the sgACC and parts of the left prefrontal cortex could be indicative of a beneficial outcome. Accelerated HF-rTMS treatment designs have the potential to acutely adjust deregulated sgACC neuronal networks in TRD patients.     

Regional cerebral blood flow changes after low-frequency transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in treatment-resistant depression

Several studies have proved that low-frequency transcranial magnetic stimulation (TMS) of the right dorsolateral prefrontal cortex (DLPFC) showed an antidepressant effect, although its mechanism is still not completely elucidated. The aim of the present study was to clarify the alteration in neuroanatomical function elicited by low-frequency TMS of the right DLPFC in treatment-resistant depression and to detect the difference between responders and nonresponders to TMS. Single-photon emission computed tomography with (99m)Tc-ethyl cysteinate dimer was performed in 14 right-handed male patients with treatment-resistant unipolar depression before and after low-frequency TMS of the right DLPFC. Five 60-second 1-Hz trains were applied and 12 treatment sessions were administered within a 3-week period (total pulses, 3,600). The Hamilton Rating Scale for Depression was administered and the regional cerebral blood flow (rCBF) was analyzed using statistical parametric mapping (SPM2). After TMS treatment in 14 patients, the score on the Hamilton Rating Scale for Depression decreased significantly, and considerable decreases in rCBF were seen in the bilateral prefrontal, orbitofrontal, anterior insula, right subgenual cingulate, and left parietal cortex, but no significant increase in rCBF occurred. Additionally, as compared with 8 nonresponders, 6 responders showed significant increases in rCBF at baseline in the left hemisphere including the prefrontal and limbic-paralimbic regions. These results suggest that the antidepressant effect of low-frequency TMS of the right DLPFC is associated with a decrease in rCBF in the limbic-paralimbic regions via the ipsilateral subgenual cingulate, and increased rCBF at baseline in the left hemisphere may be involved in the response to low-frequency TMS treatment.     

The change of QEEG prefrontal cordance as a response predictor to antidepressive intervention in bipolar depression. A pilot study

ObjectivesThe aim of the study was to examine whether the change of quantitative EEG (QEEG) theta prefrontal cordance after one week of various antidepressive interventions predicts response to a 4-week treatment in patients with bipolar depression.MethodsWe investigated 20 inpatients who completed a 4-week treatment. EEG data were monitored at baseline and after 1 week of treatment. QEEG cordance was computed at 3 frontal electrodes (Fp1, Fp2, Fz) in theta frequency band. Depressive symptoms and clinical status were assessed using Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression (CGI) and Young Mania Rating Scale (YMRS).ResultsSeven of 8 responders (reduction of MADRS ≥50%) and only 2 of 12 non-responders had decreased prefrontal theta cordance value after the first week of treatment (p = 0.02). The positive and negative predictive values of cordance reduction for response were 0.78 and 0.91, respectively. We also found significant differences in cordance value reductions between responders and non-responders after week 1 and higher baseline cordance in responders. Conclusion: The change in prefrontal theta cordance was associated with subsequent change in depressive symptoms and potentially might be a useful tool in the early detection of acute response to antidepressive interventions in bipolar depressed patients.     

Functioning and interpersonal relationships as predictors of response in treatment-resistant depression

The purpose of this study was to examine whether occupational functioning or the quality of interpersonal relationships is predictive of clinical response to a 6-week open trial of nortriptyline (NT) in patients with treatment-resistant depression (TRD). Ninety-two subjects with TRD were treated openly with NT for 6 weeks. The longitudinal interval follow-up evaluation (LIFE) scale was administered at baseline. A logistic regression was performed using occupational functioning and interpersonal relationships (over the past month and over the past 5 years) as predictors of treatment response. Unpaired t tests were performed to examine mean composite LIFE score values between responders and nonresponders. The composite scores that were statistically significant were used as single predictors of treatment status in separate logistic regression equations. Better occupational function over the past 5 years predicted better response to treatment with NT in patients with TRD. Beyond a history of nonresponse to antidepressants, long-term occupational function may be a predictor of outcome in the treatment of TRD.     

Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response.

BACKGROUND: Treatment of major depression with antidepressants is generally associated with a delay in onset of clinical response. Functional brain correlates of this phenomenon have not been previously characterized. METHODS: Time course of changes in brain glucose metabolism were measured using positron emission tomography in hospitalized unipolar depressed patients treated with fluoxetine. Time-specific and response-specific effects were examined at 1 and 6 weeks of treatment. RESULTS: Changes were seen over time, and characterized by three distinct patterns: 1) common changes at 1 and 6 weeks, 2) reversal of the 1-week pattern at 6 weeks, and 3) unique changes seen only after chronic treatment. Fluoxetine responders and nonresponders, similar at 1 week, were differentiated by their 6-week pattern. Clinical improvement was uniquely associated with limbic and striatal decreases (subgenual cingulate, hippocampus, insula, and pallidum) and brain stem and dorsal cortical increases (prefrontal, parietal, anterior, and posterior cingulate). Failed response was associated with a persistent 1-week pattern and absence of either subgenual cingulate or prefrontal changes. CONCLUSIONS: Chronic treatment and clinical response to fluoxetine was associated with a reciprocal pattern of subcortical and limbic decreases and cortical increases. Reversal in the week-1 pattern at 6 weeks suggests a process of adaptation in specific brain regions over time in response to sustained serotonin reuptake inhibition. The inverse patterns in responders and nonresponders also suggests that failure to induce these adaptive changes may underlie treatment nonresponse.     

Frontal theta cordance predicts 6-month antidepressant response to subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study

Deep brain stimulation (DBS) of subcallosal cingulate white matter (SCC) may be an effective approach for treatment-resistant depression (TRD) that otherwise fails to respond to more conventional therapies, but DBS is invasive, costly, and has potential for adverse effects. Therefore, it is important to identify potential biomarkers for predicting antidepressant response before intervention. Resting-state EEG was recorded from 12 TRD patients at pre-treatment baseline, after 4 weeks SCC DBS, and after 24 weeks SCC DBS. Lower frontal theta cordance (FTC) at baseline (and higher FTC after 4 weeks) predicted lower depression severity scores after 24 weeks. Greater FTC increases (baseline-4 weeks) predicted greater decreases in depression severity scores subsequently (4-24 weeks) and over the course of the study (baseline-24 weeks). Predictive relationships were topographically specific to theta cordance for frontal electrodes. Thus, results from this pilot study suggest that baseline FTC and changes early in treatment each have utility as biomarkers for predicting 6-month clinical response to SCC DBS for TRD.     

Aripiprazole as an adjunctive treatment for refractory unipolar depression

INTRODUCTION: Aripiprazole may be an effective adjunctive treatment in outpatients with unipolar depression that has been refractory to treatment with SSRI or SNRI medication. METHODS: Fifteen subjects with a current DSM-IV diagnosis of MDD which had not responded to SSRI or SNRI treatment were enrolled in a 12 week open-label study of aripiprazole with a maximum dose of 30 mg/day. Patients' current episode averaged 10.4+/-16.6 years, with a range of 3 months to 54 years. Baseline severity averaged 30.1+/-7.1 on HDRS-24, and 19.7+/-8.4 on BDI. Patients had been treated with a mean dose of 79.2+/-28.2 mg/day of fluoxetine equivalents for an average of 1 year prior to starting the study. Five subjects were on SNRI medications and 10 on SSRIs. RESULTS: Seven of 14 (50.0%) subjects were classified as treatment responders, as defined by at least 50% reduction in the HDRS-24 at week 12. Four subjects (28.6%) achieved remission, based on STAR D criteria (HDRS-17 score相似文献   

Personality changes in adult subjects with major depressive disorder or obsessive-compulsive disorder treated with paroxetine

BACKGROUND: Human and animal studies point to 3 dimensions of personality that change during pharmacotherapy with a selective serotonin reuptake inhibitor (SSRI). Specifically, harm avoidance has been found to decrease, social dominance has been found to increase, and hostility in social situations has been found to decrease with SSRI treatment. We sought to determine personality changes in subjects with either major depressive disorder (MDD) or obsessive-compulsive disorder (OCD) treated with paroxetine. We also sought to determine whether or not these personality changes were associated with disease state (MDD vs. OCD) or treatment response (responders vs. nonresponders). METHOD: Thirty-seven subjects diagnosed with either MDD or OCD (according to DSM-IV criteria) completed the Cattell 16 Personality Factor Inventory (16-PF) before and after treatment with paroxetine. Treatment response was defined as a Clinical Global Impressions-Improvement rating of "much" or "very much" improved and a drop in Hamilton Rating Scale for Depression score of at least 50% for MDD or Yale-Brown Obsessive Compulsive Scale score of at least 30% for OCD. RESULTS: No significant differences were found between subjects with MDD and OCD in personality change with treatment. In the whole group, treatment responders had a greater decrease than nonresponders in 16-PF factors relating to harm avoidance. An increase in social dominance factors and a decrease in factors relating to hostility in social situations were found, but these changes were not significantly different between responders and nonresponders. CONCLUSION: These findings indicate that certain personality dimensions change with SSRI treatment and that some of these changes are independent of clinical treatment response.     

Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study.

BACKGROUND: Previous studies have shown that major depression is frequently accompanied by hypercortisolemia. There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects. METHODS: Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression. RESULTS: No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean right hippocampal volume than nonresponders. CONCLUSIONS: The results of our study indicate no reduction in the volume of the hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume.     

Augmentation of antidepressants with atypical antipsychotics for treatment-resistant major depressive disorder

Objective: Atypical antipsychotics (AAPs) have been hypothesized to be beneficial in treatment‐resistant depression (TRD). This paper will review a biochemical rationale and will summarize the data regarding the effectiveness of AAPs in TRD. Method: Studies were identified using searches of Pubmed/Medline, EMBase and the Cochrane databases by cross‐referencing the term ‘depression’ with each of the six AAPs. Results: After initial positive, short case reports and clinical trials, larger studies failed to show the effectiveness of AAPs combined with antidepressants for TRD. More recently, larger scale clinical trials have supported the effectiveness of at least some of these medications. While AAPs have gained in popularity for TRD, there are nagging concerns regarding risks such as metabolic syndrome and tardive dyskinesia. Conclusion: The existing research provides some support for the beneficial effects of AAPs when combined with SSRI’s in TRD. These medications pose significant risks that must be considered in their use.     

Does elimination of placebo responders in a placebo run‐in increase the treatment effect in randomized clinical trials? A meta‐analytic evaluation

The use of a placebo run-in phase, in which placebo responders are withdrawn from a study before random assignment to treatment condition, has been criticized as favoring the active treatment in clinical trials. We compared the effect size of randomized, placebo-controlled clinical trials (in the treatment of depression with selective serotonin reuptake inhibitors [SSRIs]) that include a placebo run-in phase with those that do not, using a meta-analytic approach. This study differed from earlier meta-analytic studies in that it considered only SSRIs and included only studies using continuous measures of depression, allowing for a more refined assessment of effect size. An extensive literature search identified 43 datasets published between 1980 and 2000 comparing placebo with SSRI and using a continuous measure of depression (usually the Hamilton Depression Rating Scale). We included only studies of at least 6 weeks' duration focusing on treatment for primary acute major depression in adults 18-65 years of age. Studies focusing on depression in specific medical illnesses were not included. Analysis of efficacy was based on 3047 subjects treated with an SSRI antidepressant and 3740 subjects treated with a placebo. There was no statistically significant difference in effect size between the clinical trials that had a placebo run-in phase followed by withdrawal of placebo responders and those trials that did not. Despite the lack of a statistically significant difference between studies of withdrawing early placebo responders and those not using this procedure, this approach is likely to continue to be used widely because it produces large absolute effect sizes. It is recommended that future studies clearly describe these procedures and report the number of subjects dropped from the study for early placebo response and other reasons.     

Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS

Twenty-two depressed adults were scanned with perfusion single-photon computed emission tomography before and after 2 weeks of left perfrontal transcranial magnetic stimulation (TMS) in a parallel design, double-blind treatment study. At medication-free baseline, across all subjects, blood flow in the bilateral medial temporal lobes, left prefrontal cortex, and caudate significantly declined with increased depression severity. Also at baseline, depressed adults who responded to TMS, compared with nonresponders, showed increased inferior frontal lobe activity. Following treatment, there was an even greater difference in inferior frontal blood flow in responders compared with nonresponders, and the negative baseline correlations between depression severity and limbic and prefrontal blood flow disappeared. These results suggest that in depressed adults, 10 days of prefrontal TMS affects prefrontal and paralimbic activity, which may explain its antidepressant effects.     

Pharmacologic approaches to treatment resistant depression: Evidences and personal experience

AIM: To review evidence supporting pharmacological treatments for treatment-resistant depression (TRD) and to discuss them according to personal clinical experience.METHODS: Original studies, clinical trials, systematic reviews, and meta-analyses addressing pharmacological treatment for TRD in adult patients published from 1990 to 2013 were identified by data base queries (PubMed, Google Scholar e Quertle Searches) using terms: “treatment resistant depression”, “treatment refractory depression”, “partial response depression”, “non responder depression”, “optimization strategy”, “switching strategy”, “combination strategy”, “augmentation strategy”, selective serotonin reuptake inhibitors antidepressants (SSRI), tricyclic antidepressants (TCA), serotonin norepinephrine reuptake inhibitors antidepressants, mirtazapine, mianserine, bupropione, monoamine oxidase inhibitor antidepressant (MAOI), lithium, thyroid hormones, second generation antipsychotics (SGA), dopamine agonists, lamotrigine, psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids, S-adenosil-L-metionine, methylfolat, pindolol, sex steroids, glucocorticoid agents. Other citations of interest were further identified from references reported in the accessed articles. Selected publications were grouped by treatment strategy: (1) switching from an ineffective antidepressant (AD) to a new AD from a similar or different class; (2) combining the current AD regimen with a second AD from a different class; and (3) augmenting the current AD regimen with a second agent not thought to be an antidepressant itself.RESULTS: Switching from a TCA to another TCA provides only a modest advantage (response rate 9%-27%), while switching from a SSRI to another SSRI is more advantageous (response rate up to 75%). Evidence supports the usefulness of switching from SSRI to venlafaxine (5 positive trials out 6), TCA (2 positive trials out 3), and MAOI (2 positive trials out 2) but not from SSRI to bupropione, duloxetine and mirtazapine. Three reviews demonstrated that the benefits of intra- and cross-class switch do not significantly differ. Data on combination strategy are controversial regarding TCA-SSRI combination (positive results in old studies, negative in more recent study) and bupropion-SSRI combination (three open series studies but not three controlled trails support the useful of this combination) and positive regard mirtazapine (or its analogue mianserine) combination with ADs of different classes. As regards the augmentation strategy, available evidences supported the efficacy of TCA augmentation with lithium salts and thyroid hormone (T3), but are conflicting regard the SSRI augmentation with these two drugs (1 positive trial out of 4 for lithium and 3 out of 5 for thyroid hormone). Double-blind controlled studies showed the efficacy of AD augmentation with aripiprazole (5 positive trials out 5), quetiapine (3 positive trials out 3) and, at less extent, of fluoxetine augmentation with olanzapine (3 positive trials out 6), so these drugs received the FDA indication for the acute treatment of TRD. Results on AD augmentation with risperidone are conflicting (2 short term positive trials, 1 short-term and 1 long-term negative trials). Case series and open-label trials showed that AD augmentation with pramipexole or ropinirole, two dopamine agonists, could be an effective treatment for TRD (response rate to pramipexole 48%-74%, to ropinirole 40%-44%) although one recent double-blind placebo-controlled study does not support the superiority of pramipexole over placebo. Evidences do not justify the use of psychostimulants, omega-3 fatty acids, S-adenosil-L-metionine, methylfolate, pindolol, lamotrigine, and sex hormone as AD augmentation for TRD. Combining the available evidences with our experience we suggest treating non-responders to one SSRI bupropion or mirtazapine trial by switching to venlafaxine, and non-responders to one venlafaxine trial by switching to a TCA or, if TCA are not tolerated, combining mirtazapine with SSRI or venlafaxine. In non-responders to two or more ADs (including at least one TCA if tolerated) current AD regimen could be augmented with lithium salts (mainly in patients with bipolar depression or suicidality), SGAs (mostly aripiprazole) or DA-agonists (mostly pramipexole). In patients with severe TRD, i.e., non-responders to combination and augmentation strategies as well as to electroconvulsive therapy if workable, we suggest to try a combination plus augmentation strategy.CONCLUSION: Our study identifies alternative effective treatment strategies for TRD. Further studies are needed to compare the efficacy of different strategies in more homogeneous subpopulations.