From the Editor

He’s been depressed for years and you are considering augmentation. Should you choose an antipsychotic? Which one?

These are good questions, especially when treating patients with treatment-resistant depression. In the first selection, Drs. Manish K. Jha (of the University of Texas) and Sanjay J. Mathew (of Baylor College of Medicine) look at four antipsychotics in an American Journal of Psychiatry paper. They review the literature for augmentation, including the use of cariprazine, which has just received FDA approval for this purpose. They find evidence, but “their long-term safety in patients with MDD is not well established, and they are potentially concerning regarding weight gain, metabolic dysfunction, extrapyramidal symptoms, and tardive dyskinesia.” We consider the paper and its clinical implications.

In the second selection, S. E. Stoeckl (of Harvard University) and her co-authors consider the evolution of mental health apps in a new paper for the Journal of Technology in Behavioral Science. Looking at hundreds of apps, they analyze data on updates, including new features. They find: “This study highlights the dynamic nature of the app store environments, revealing rapid and substantial changes that could present challenges for app selection, consumer safety, and assessing the economic value of apps.”

And in the third selection, Dr. Dhruv Khullar (of Cornell University) writes for The New Yorker about AI and mental health. In a long essay that touches on chatbots for therapy and screening tools for suicide prevention, he wonders if AI can help clinicians (and non-clinicians) overcome issues around access. “Can artificial minds heal real ones? And what do we stand to gain, or lose, in letting them try?”

Note: there will be no Readings for the next two weeks.


Selection 1: “Pharmacotherapies for Treatment-Resistant Depression: How Antipsychotics Fit in the Rapidly Evolving Therapeutic Landscape”

Manish K. Jha and Sanjay J. Mathew

The American Journal of Psychiatry, 1 March 2023  Online First

Major depressive disorder (MDD), an often chronic and/or recurrent condition, affects one in five adults and is the second leading cause of disability in the United States. Even with multiple sequential courses of antidepressants, over one-third of patients with MDD do not experience clinically significant improvement and may have treatment-resistant depression (TRD). The presence of TRD exacerbates the burden associated with MDD and contributes substantially to health-care-related expenses.

So begins a paper by Jha et al.

The authors focus on four FDA-approved medications.


“In initial randomized controlled trials (RCTs), 6-week augmentation with aripiprazole (2–20 mg/day) after inadequate response to an 8-week course of antidepressant treatment was associated with higher remission rates than placebo (25.4% compared with 15.2% and 26.0% compared with 15.7%), with a number needed to treat (NNT) of 10. Subsequent similarly designed RCTs had similar results, with NNTs of 9 to 11 for aripiprazole (at dosages of 3 mg/day, 3–15 mg/day, or 3–12 mg/day) compared with placebo. Augmentation with aripiprazole (at 2–15 mg/day) was also associated with higher rates of remission (44%) compared with placebo (29%) (NNT=7) in a study of elderly patients who did not attain remission with 12 weeks of treatment with extended-release venlafaxine.”


“Initial RCTs found significantly greater reductions in depressive symptoms with adjunctive brexpiprazole at 2 mg/day and 3 mg/day but not at 1 mg/day after inadequate response to 8 weeks of antidepressant treatment. However, remission rates with adjunctive brexpiprazole (14.7%, 14.9%, and 14.1% with 1, 2, and 3 mg/day, respectively) did not differ from placebo (9.0% and 10.8%), with NNTs ranging from 17 to 31. Subsequent acute-phase RCTs had similar reductions in depressive symptoms but no differences in rates of remission (NNTs of 28 and 42). A longer-term (24-week) study found that adjunctive brexpiprazole had similar rates of improvement but higher rates of adverse event–related withdrawal (6.3%) compared with placebo (3.4%).”

Extended-release quetiapine

“In two phase 3 trials of individuals with MDD who had continuing depressive symptoms after ≥6 weeks of treatment with an adequate dosage of an antidepressant… extended-release quetiapine at 300 mg/day was more effective than placebo in reducing depression severity in both studies, and the 150 mg/day dosage was more effective in one study but not the other. In a pooled analysis, rates of remission were 41.8% (NNT=11) with 150 mg/day and 46.3% (NNT=7) with 300 mg/day of extended-release quetiapine, compared with 32.0% for placebo.”


“This issue of the Journal includes a report on a phase 3 trial of cariprazine augmentation in MDD. The trial enrolled 757 patients with MDD with inadequate response (<50% improvement in depressive symptoms) to one to three antidepressants in the current episode (of adequate dosage per prescribing label and of at least 6 weeks’ duration) and randomized them in a 1:1:1 ratio to 6 weeks of augmentation with placebo, cariprazine at 1.5 mg/day, or cariprazine at 3 mg/day. This study used fixed-dose arms… The study found significantly greater improvement in depressive symptoms with cariprazine at 1.5 mg/day (−14.1 points in Montgomery-Åsberg Depression Rating Scale [MADRS] score) compared with placebo (−11.5 points in MADRS score) but not with 3 mg/day (−13.1 points in MADRS score). Remission rates at week 6 did not differ significantly among the treatment arms…”

The paper also considers other options, including ketamine. 

A few thoughts:

1. This is an excellent review with up-to-date information – including for cariprazine with a summary of the latest major study on it.

2. A note for Canadians: cariprazine has Health Canada approval, but not as an augmenting agent.

3. The clinical implications? The authors write: “As there is no clear evidence for superior efficacy of one atypical antipsychotic over another for treatment of MDD, shared decision-making approaches that incorporate information regarding tolerability, anticipated side effects, and costs may be helpful in selecting the specific atypical antipsychotic to use as an augmentation agent.” Thoughtful.

4. The paper focuses on these four antipsychotics. ECT and other types of neurostimulation aren’t mentioned (AJP published a review a few years ago). But we note that the NNT for ECT and refractory depression is much lower than 7. New isn’t necessarily better. 

5. For those interested in augmentation for the elderly, this week’s New England Journal of Medicine has an excellent paper. You can find it here:

The full AJP paper can be found here:

Selection 2: “Assessing the Dynamics of the Mental Health Apple and Android App Marketplaces”

S. E. Stoeckl, Edgardo Torres-Hernandez, Erica Camacho and John Torous

Journal of Technology in Behavioral Science, 25 January 2023  Online First

Mobile technology and smartphone apps offer one such solution with the potential to increase the capacity and improve access to mental health information, support, and interventions through scalable smartphones. In 2020, 85% of Americans owned a smartphone, and access was high across all demographics, including minority and disadvantaged populations. This high prevalence of smartphone ownership suggests that mobile health interventions have the potential to improve access and reach traditionally underserved populations… The literature indicates that apps are highly acceptable to patients, even those with serious mental illness, and feasibility is no longer a question. Results are more mixed for efficacy…

So begins a paper by Stoeckl et al.

Here’s what they did:

  • “A sample of 347 apps of the 650 apps available on MIND were reviewed between September 1, 2021, and January 5, 2022.”
  • “Apps were downloaded from the Apple iOS store and Google Play store and reviewed by eleven trained app evaluators by updating answers to 105 questions in 9 categories, according to the American Psychiatric Association App Evaluation Model (American Psychiatric Association, 2022).” 
  • “Training included instruction on the APA App Evaluation Model, reviewing each of the 105 questions and potential responses with the project manager, practicing app evaluations and reviewing potential errors, and passing an assessment of interrater reliability.”

Here’s what they found:

  • Updates. “The average app updates every 433 days, though 19% (n = 65) were updated in the last 3 months and some nearly weekly.”
  • Features. “Features also changed in 38% (n = 133) of apps. The four most common changes to app features were as follows: the addition of physical exercise, addition of goal setting related content, removal of productivity, and removal of psychoeducation content.”
  • Engagement. “Engagement features changed in 17% (n = 54) of the apps, and of those changes 52% were additions and 48% were removals.”
  • Cost. “Although 35% (n = 114) of apps were totally free and 66% (n = 216) were free to download, 41% (n = 143) offered in-app purchases, 35% (n = 114) offered subscriptions, and 20% (n = 70) had a one-time payment.”
  • Developers. “Eighty-eight percent (n = 304) of apps reviewed in this paper from MIND were from for-profit developers. Academic institutions developed 3% (n = 10) of apps, government 4% (n = 14), nonprofit companies 3% (n = 10), and healthcare providers 3% (n = 9).”

A few thoughts:

1. This is a good study.

2. It provides a nice snapshot of a marketplace that is quickly changing – making it hard for us clinicians to keep up and make timely recommendations to our patients.

3. Also interesting: most apps aren’t totally free and for-profit developers are the majority. It’s truly a marketplace.

4. Of course, the paper draws on hundreds of apps from MIND – a large database, yes, but not exhaustive.

The full JTBS paper can be found here:

Selection 3: “Can A.I. Treat Mental Illness?”

Dhruv Khullar 

The New Yorker, 27 February 2023 

In the nineteen-sixties, Joseph Weizenbaum, a computer scientist at M.I.T., created a computer program called Eliza. It was designed to simulate Rogerian therapy, in which the patient directs the conversation and the therapist often repeats her language back to her… Weizenbaum made Eliza as satire. He doubted that computers could simulate meaningful human interaction. He was alarmed, therefore, when many people who tried the program found it both useful and captivating. His own secretary asked him to leave the room so that she could spend time alone with Eliza. 

So begins an essay by Dr. Khullar. 

The essay describes several AI projects for mental health, including Woebot: 

“In 2017, Alison Darcy, a clinical research psychologist at Stanford, founded Woebot, a company that provides automated mental-health support through a smartphone app. Its approach is based on cognitive behavioral therapy, or C.B.T. – a treatment that aims to change patterns in people’s thinking. The app uses a form of artificial intelligence called natural language processing to interpret what users say, guiding them through sequences of pre-written responses that spur them to consider how their minds could work differently.” 

The essay considers a patient experience: 

“Maria, a hospice nurse who lives near Milwaukee with her husband and two teen-age children, might be a typical Woebot user. She has long struggled with anxiety and depression, but had not sought help before. ‘I had a lot of denial,’ she told me. This changed during the pandemic, when her daughter started showing signs of depression, too. Maria took her to see a psychologist, and committed to prioritizing her own mental health. At first, she was skeptical about the idea of conversing with an app – as a caregiver, she felt strongly that human connection was essential for healing. Still, after a challenging visit with a patient… she texted Woebot. ‘It sounds like you might be ruminating,’ Woebot told her.”

Maria also learns about catastrophic thinking. The author tries to use Woebot himself. “I knew that I was talking to a computer, but in a way I didn’t mind.”

The essay notes the efforts of computer scientist John Pestian and his team who started by analyzing suicide notes to find the “language of suicide.” They then focused on speech: “In the largest trial of its kind, Pestian’s team enrolled hundreds of patients, recorded their speech, and used algorithms to classify them as suicidal, mentally ill but not suicidal, or neither. About eighty-five per cent of the time, his A.I. model came to the same conclusions as human caregivers – making it potentially useful for inexperienced, overbooked, or uncertain clinicians.” They now have an algorithm used in schools to try to identify those students at risk.

The essay notes several experiments, including with Veterans Affairs (U.S.) and the National Health Service (U.K.). But the author wonders about the limits of AI. Can therapy, for example, be done by computers or is it too “deeply personal?”

When one of his patients struggles, the author has a sleepless night. “A mobile app could have seen the alert about my patient, noticed my pulse rising through a sensor in my smart watch, and guessed how I was feeling. It could have detected my restless night and, the next morning, asked me whether I needed help processing my patient’s sudden decline. I could have searched for the words to describe my feelings to my phone. I might have expressed them while sharing them with no one—unless you count the machines.”

A few thoughts:

1. This is a beautifully written essay.

2. The topic is cool.

3. Is this of interest to you as a clinician? You aren’t alone: “In 2021, digital startups that focussed on mental health secured more than five billion dollars in venture capital – more than double that for any other medical issue.”

4. Is the future of AI less spectacular? In a past Reading, we considered a Comment by Patel and Lam from Lancet Digital Health arguing that AI will help with routine tasks, such as discharge notes. You can find it here:

5. Dr. Khullar describes well the potential in areas like psychotherapy. But could AI therapy have a more defined role, not as a replacement for human therapists in every case, but perhaps offering care for less ill individuals (i.e., stepped care)?

The full New Yorker essay can be found here:

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.