Are there effective medications for treating depression that does not improve with the first medication used?


Depression is a common problem often treated with antidepressant medication. However, many people do not get better with antidepressant treatment and have 'treatment-resistant depression' (TRD). Several different treatment approaches can be tried - such as increasing the dose of the current medication, adding another medication, or switching to a different antidepressant.

Cochrane reviewers looked at the available evidence to see which of these options may be the best treatment for people with TRD.

Search date

In December 2018, we searched eight medical databases for suitable clinical trials.

Study characteristics

We included 10 randomised controlled trials (RCTs) with 2731 participants (RCTs produce the most robust evidence). These trials investigated three different treatment strategies:

1. changing to a different antidepressant,

2. adding a second antidepressant to the current antidepressant treatment, or

3. adding a different type of medication to current antidepressant treatment - an anti-anxiety medication or an antipsychotic

We found no trials of increasing the dose of current antidepressant medication. Nine of the 10 studies included in this review were sponsored by pharmaceutical companies.

Key results

One small study investigated changing current antidepressant treatment to a different antidepressant (mianserin) or adding mianserin to current treatment. We are uncertain about the effect changing treatment to mianserin has on depressive symptoms or the likelihood of dropping out of treatment. People who added mianserin to their current antidepressant treatment showed fewer depressive symptoms, but the likelihood of dropping out was not clear.

Adding the antidepressant mirtazapine to current antidepressant treatment had little or no effect on depressive symptoms or on the likelihood of dropping out of treatment.

The effect of adding an anti-anxiety medication (buspirone) to ongoing antidepressant treatment on depressive symptoms or dropping out is currently uncertain. These findings were based on one small study.

Most studies looked at the effects of adding an antipsychotic medication (cariprazine, quetiapine, ziprasidone or olanzapine) to current antidepressant treatment. These suggested that adding cariprazine results in a small reduction in depressive symptoms; adding quetiapine reduces depressive symptoms; and adding ziprasidone probably results in a small reduction in depressive symptoms. However, our results also suggest that adding these medicines to current treatment probably increases the likelihood of dropping out of treatment. The most common reasons for dropping out were side effects or adverse events. Adding olanzapine to ongoing treatment may reduce depressive symptoms, but the effects on dropping out are uncertain (findings based on one small study).

Nearly all (9/10) of the studies assessed the effects of treatment in the short-term – six or eight weeks after beginning the new treatment – so the longer term effects of most treatments are unknown.

Quality of the evidence

We judged the quality of the evidence as high, moderate, or low for different outcomes. The main limitation we identified was that the evidence for many of the treatment options investigated came from only one study, and some of these studies also had few participants.

We rated the evidence to be low quality for:

1. switching from the current antidepressant treatment to another antidepressant (mianserin);

2. supplementing current antidepressant treatment with a second antidepressant (mianserin), or with an anti-anxiety medication (buspirone), or with the antipsychotic olanzapine.

This means we are uncertain about the effects of these treatments on depression symptoms or the likelihood of dropping out of treatment.

We rated the quality of the evidence for adding mirtazapine (an antidepressant), cariprazine (an antipsychotic) or quetiapine (an antipsychotic) to ongoing antidepressant treatment on depressive symptoms as high, meaning we are very confident in the effect of these treatment strategies.

We rated the quality of the evidence for adding the antipsychotic ziprasidone to ongoing antidepressant treatment on the effect on depressive symptoms as moderate, which means the true effect may be different from what we found, although findings are likely to be close.

We rated the quality of the evidence for adding mirtazapine (an antidepressant) to ongoing antidepressant treatment on the likelihood of dropping out of treatment as high. We rated the quality of the evidence for adding cariprazine, olanzapine or ziprasidone (all antipsychotics) on the likelihood of dropping out as moderate.

Authors' conclusions: 

A small body of evidence shows that augmenting current antidepressant therapy with mianserin or with an antipsychotic (cariprazine, olanzapine, quetiapine or ziprasidone) improves depressive symptoms over the short-term (8 to 12 weeks). However, this evidence is mostly of low or moderate quality due to imprecision of the estimates of effects. Improvements with antipsychotics need to be balanced against the increased likelihood of dropping out of treatment or experiencing an adverse event. Augmentation of current antidepressant therapy with a second antidepressant, mirtazapine, does not produce a clinically important benefit in reduction of depressive symptoms (high-quality evidence). The evidence regarding the effects of augmenting current antidepressant therapy with buspirone or switching current antidepressant treatment to mianserin is currently insufficient.

Further trials are needed to increase the certainty of these findings and to examine long-term effects of treatment, as well as the effectiveness of other pharmacological treatment strategies.

Read the full abstract...

Although antidepressants are often a first-line treatment for adults with moderate to severe depression, many people do not respond adequately to medication, and are said to have treatment-resistant depression (TRD). Little evidence exists to inform the most appropriate 'next step' treatment for these people.


To assess the effectiveness of standard pharmacological treatments for adults with TRD.

Search strategy: 

We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (March 2016), CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science (31 December 2018), the World Health Organization trials portal and for unpublished and ongoing studies, and screened bibliographies of included studies and relevant systematic reviews without date or language restrictions.

Selection criteria: 

Randomised controlled trials (RCTs) with participants aged 18 to 74 years with unipolar depression (based on criteria from DSM-IV-TR or earlier versions, International Classification of Diseases (ICD)-10, Feighner criteria or Research Diagnostic Criteria) who had not responded to a minimum of four weeks of antidepressant treatment at a recommended dose. Interventions were:

(1) increasing the dose of antidepressant monotherapy;

(2) switching to a different antidepressant monotherapy;

(3) augmenting treatment with another antidepressant;

(4) augmenting treatment with a non-antidepressant.

All were compared with continuing antidepressant monotherapy. We excluded studies of non-standard pharmacological treatments (e.g. sex hormones, vitamins, herbal medicines and food supplements).

Data collection and analysis: 

Two reviewers used standard Cochrane methods to extract data, assess risk of bias, and resolve disagreements. We analysed continuous outcomes with mean difference (MD) or standardised mean difference (SMD) and 95% confidence interval (CI). For dichotomous outcomes, we calculated a relative risk (RR) and 95% CI. Where sufficient data existed, we conducted meta-analyses using random-effects models.

Main results: 

We included 10 RCTs (2731 participants). Nine were conducted in outpatient settings and one in both in- and outpatients. Mean age of participants ranged from 42 - 50.2 years, and most were female.

One study investigated switching to, or augmenting current antidepressant treatment with, another antidepressant (mianserin). Another augmented current antidepressant treatment with the antidepressant mirtazapine. Eight studies augmented current antidepressant treatment with a non-antidepressant (either an anxiolytic (buspirone) or an antipsychotic (cariprazine; olanzapine; quetiapine (3 studies); or ziprasidone (2 studies)). We judged most studies to be at a low or unclear risk of bias. Only one of the included studies was not industry-sponsored.

There was no evidence of a difference in depression severity when current treatment was switched to mianserin (MD on Hamilton Rating Scale for Depression (HAM-D) = -1.8, 95% CI -5.22 to 1.62, low-quality evidence)) compared with continuing on antidepressant monotherapy. Nor was there evidence of a difference in numbers dropping out of treatment (RR 2.08, 95% CI 0.94 to 4.59, low-quality evidence; dropouts 38% in the mianserin switch group; 18% in the control).

Augmenting current antidepressant treatment with mianserin was associated with an improvement in depression symptoms severity scores from baseline (MD on HAM-D -4.8, 95% CI -8.18 to -1.42; moderate-quality evidence). There was no evidence of a difference in numbers dropping out (RR 1.02, 95% CI 0.38 to 2.72; low-quality evidence; 19% dropouts in the mianserin-augmented group; 38% in the control). When current antidepressant treatment was augmented with mirtazapine, there was little difference in depressive symptoms (MD on Beck Depression Inventory (BDI-II) -1.7, 95% CI -4.03 to 0.63; high-quality evidence) and no evidence of a difference in dropout numbers (RR 0.50, 95% CI 0.15 to 1.62; dropouts 2% in mirtazapine-augmented group; 3% in the control).

Augmentation with buspirone provided no evidence of a benefit in terms of a reduction in depressive symptoms (MD on Montgomery and Asberg Depression Rating Scale (MADRS) -0.30, 95% CI -9.48 to 8.88; low-quality evidence) or numbers of drop-outs (RR 0.60, 95% CI 0.23 to 1.53; low-quality evidence; dropouts 11% in buspirone-augmented group; 19% in the control).

Severity of depressive symptoms reduced when current treatment was augmented with cariprazine (MD on MADRS -1.50, 95% CI -2.74 to -0.25; high-quality evidence), olanzapine (MD on HAM-D -7.9, 95% CI -16.76 to 0.96; low-quality evidence; MD on MADRS -12.4, 95% CI -22.44 to -2.36; low-quality evidence), quetiapine (SMD -0.32, 95% CI -0.46 to -0.18; I2 = 6%, high-quality evidence), or ziprasidone (MD on HAM-D -2.73, 95% CI -4.53 to -0.93; I2 = 0, moderate-quality evidence) compared with continuing on antidepressant monotherapy.

However, a greater number of participants dropped out when antidepressant monotherapy was augmented with an antipsychotic (cariprazine RR 1.68, 95% CI 1.16 to 2.41; quetiapine RR 1.57, 95% CI: 1.14 to 2.17; ziprasidone RR 1.60, 95% CI 1.01 to 2.55) compared with antidepressant monotherapy, although estimates for olanzapine augmentation were imprecise (RR 0.33, 95% CI 0.04 to 2.69). Dropout rates ranged from 10% to 39% in the groups augmented with an antipsychotic, and from 12% to 23% in the comparison groups. The most common reasons for dropping out were side effects or adverse events.

We also summarised data about response and remission rates (based on changes in depressive symptoms) for included studies, along with data on social adjustment and social functioning, quality of life, economic outcomes and adverse events.