03. Treatment-Resistant Depression: Lithium vs. Quetiapine for Augmentation?

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Risk-Benefit Rationale Guides Treatment Selection

Following the adage, try to be helpful, not hurtful, medications with the most favorable risk-benefit profile should be tried before moving on to alternatives with less favorable profiles.

This logic is evident in the STAR*D trial, in which an inadequate response was necessary in two trials of medications with more benign safety profiles.

These included SSRIs, venlafaxine, buspirone, and bupropion before moving on to options with less benign side effect profiles including nortriptyline, mirtazapine, or lithium augmentation.

After two trials with inadequate response, many clinicians might also consider augmentation with quetiapine, another option with a less favorable side effect profile. As atypical antipsychotic medications were not included in the STAR*D, we cannot turn to that source to assess relative efficacy. Luckily, a new prospective open-label trial out of the UK attempts to answer this question with a real-world comparison of lithium and quetiapine augmentation.

Study Design: Lithium vs. Quetiapine Augmentation

The study included adults with inadequate response to at least two antidepressant trials and a HAM-D score of 14 or higher. Participants were randomized to receive either quetiapine (150-300 mg/day) or lithium (target serum level 0.6-1.2).

• Exclusion criteria: Bipolar disorder or psychotic disorders
• 107 subjects randomized to quetiapine, 95 started
• 105 randomized to lithium, 84 started

Why does this matter? Because they used an intent-to-treat analysis with last observation carried forward. So, 11% of the quetiapine group and 20% of the lithium group never started the medication but were included in the final analysis using their baseline depression score.

Primary Outcomes: Symptom Burden

After 8 weeks:

• 10% (11 of 107) of quetiapine patients achieved remission on the Montgomery-Asberg Depression Rating Scale (MADRS)
• 6% (6 of 105) in the lithium group achieved remission on the MADRS

Not statistically significant. But keep in mind—this is a highly treatment-resistant population:

• All had failed at least two trials
• 60% had failed three or more

The authors suggest this chronic, fluctuating symptom profile is common in this group, so they followed patients for a full year, using a weekly self-administered Quick Inventory of Depressive Symptomatology (QIDS) to track symptoms.

Here’s how they quantified outcomes:

• QIDS scores: Mild ≥6, Moderate ≥11, Severe ≥16
• They calculated the area under the curve (AUC)—essentially, the total burden of symptoms over the year

And they found:

• The quetiapine group had 68 fewer QIDS points than the lithium group over 52 weeks
• That’s just over 1 point less per week, on average

This difference was statistically significant and represented the study’s primary outcome measure.

Discontinuation and Remission at 52 Weeks

Despite dropout concerns, the time to discontinuation was not significantly different:

• 42/84 completed lithium
• 58/95 completed quetiapine

After 1 year:

• Quetiapine: 12 of 107 in remission (11%)
• Lithium: 9 of 105 in remission (9%)

Still, not a statistically significant difference. These rates are in line with STARD findings. After 3 failed trials, STARD reported 13% remission

Side Effects and Tolerability

In STAR*D, differences in efficacy weren’t huge—but side effects were often the decisive factor. That held true here.

Dropouts due to side effects:

• Quetiapine: 46%
• Lithium: 33%

Unfortunately, the authors didn’t specify which side effects caused patients to drop out. Only one serious adverse event (acute renal failure) occurred in the lithium group.

No overall difference was found in total side effect burden measured by the Patient-Related Inventory of Side Effects (PRISE). However, the article did not include the tolerability of each reported side effect to assess severity.

Weight Gain and EPS

Only one subject in each group reported weight gain during the PRISE. As other sources report a higher prevalence of weight gain, I have to wonder if more subjects left each arm before the first PRISE at eight weeks of treatment.

38% of subjects taking lithium and 15% taking quetiapine reported tremors in the PRISE, but no other assessment of EPS-like symptoms was included in the study, which is a concern, especially for long-term antipsychotic use in major depression.

Clinical Implications

This real-world comparison provides valuable insights into the relative efficacy of lithium and quetiapine augmentation for treatment-resistant major depression.

While quetiapine showed a slight edge in reducing depressive symptoms over time, both options had similar remission rates and discontinuation patterns.

As clinicians, we must carefully weigh the risk-benefit profile of these medications for each patient.

The more concerning side effect profiles of both quetiapine and lithium may be more justifiable in bipolar depression, where alternatives with benign side effect profiles are limited.

Ultimately, the decision to use either lithium or quetiapine augmentation should be a topic of thorough discussion with our patients, considering their individual needs, preferences, and potential risks.

Abstract

Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression: a pragmatic, open-label, parallel-group, randomised controlled superiority trial in the UK

Prof. Anthony J. Cleare, Ph.D., Jess Kerr-Gaffney, Ph.D.; Prof. Kimberley Goldsmith, Ph.D.; Zohra Zenasni, M.Sc.; Nahel Yaziji, M.Sc.; Huajie Jin, Ph.D.; et al.

Background

Lithium and quetiapine are first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. We aimed to assess whether quetiapine augmentation therapy is more clinically effective and cost-effective than lithium for patients with treatment-resistant depression over 12 months.

Methods

We did this pragmatic, open-label, parallel-group, randomised controlled superiority trial at six National Health Service trusts in England. Eligible participants were adults (aged ≥18 years) with a current episode of major depressive disorder meeting DSM-5 criteria, with a score of 14 or higher on the 17-item Hamilton Depression Rating Scale at screening who had responded inadequately to two or more therapeutic antidepressant trials. Exclusion criteria included having a diagnosis of bipolar disorder or current psychosis. Participants were randomly assigned (1:1) to the decision to prescribe lithium or quetiapine, stratified by site, depression severity, and treatment resistance, using block randomisation with randomly varying block sizes. After randomisation, pre-prescribing safety checks were undertaken as per standard care before proceeding to trial medication initiation. The coprimary outcomes were depressive symptom severity over 12 months, measured weekly using the Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation. Economic analyses compared the cost-effectiveness of the two treatments from both an NHS and personal social services perspective, and a societal perspective. Primary analyses were done in the intention-to-treat population, which included all randomly assigned participants. People with lived experience were involved in the trial. The trial is completed and registered with the International Standard Randomised Controlled Trial registry, ISRCTN16387615.

Findings

Between Dec 5, 2016, and July 26, 2021, 212 participants (97 [46%] male gender and 115 [54%] female gender) were randomly assigned to the decision to prescribe quetiapine (n=107) or lithium (n=105). The mean age of participants was 42·4 years (SD 14·0 years) and 188 (89%) of 212 participants were White, seven (3%) were of mixed ethnicity, nine (4%) participants were Asian, four (2%) were Black, three (1%) were of Other ethnicity, and ethnicity was not recorded for one (1%) participant. Participants in the quetiapine group had a significantly lower overall burden of depressive symptom severity than participants in the lithium group (area under the between-group differences curve –68·36 [95% CI –129·95 to –6·76; p=0·0296). Time to discontinuation did not significantly differ between the two groups. Quetiapine was more cost-effective than lithium. 32 serious adverse events were recorded in 18 participants, one of which was deemed possibly related to the trial medication in a female participant in the lithium group. The most common serious adverse event was overdose, occurring in three (3%) of 107 participants in the quetiapine group (seven events) and three (3%) of 105 participants in the lithium group (five events).

Interpretation

Results of the trial suggest that quetiapine is more clinically effective than lithium as a first-line augmentation option for reducing symptoms of depression in the long-term management of treatment-resistant depression, and is probably more cost-effective than lithium.

Funding

National Institute for Health and Care Research Health Technology Assessment programme.

Reference

Prof. Cleare, A. Ph.D.; Kerr-Gaffney, J. Ph.D.; Prof. Goldsmith, K. Ph.D.; Zenasni, Z. M.Sc.; Yaziji, N. M.Sc.; Jin, H. Ph.D.; et al. (2025). Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression: a pragmatic, open-label, parallel-group, randomised controlled superiority trial in the UK. The Lancet Psychiatry, Volume 12, Issue 4, 276 – 28.