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The stillbirth of twins at 7 months of pregnancy. The sudden loss of an infant 3 days before his first birthday to a freak accident at home. The loss of a 9-month-old to sudden infant death syndrome (SIDS). The fourth miscarriage after 3 months of pregnancy with no clear reason why.

These tragic and unimaginable losses can complicate ongoing psychiatric care, not only in terms of identifying what is normal grief versus an abnormal depressive disorder, but also in terms of the very normal human response we all have watching another human suffer a very significant loss. For many psychiatrists and mental health professionals, it is also unclear how to best manage these struggles and losses. We talk about grief and counseling; we talk about groups; and we make referrals. But do any of us really know what to expect and what approach is associated with the best outcomes? And what happens when these 

 again, as many do, often within months of their loss?

Miscarriage is defined as the loss of a pregnancy before 20 weeks, and stillbirth is the loss after 20 weeks. It is estimated that 11% to 16% of pregnancies end in 

 in women who knew they were pregnant, though this is likely an underestimate due to underreporting.

 Of women who experience a miscarriage, 50% to 80% will become pregnant again.

 Stillbirth occurs in 1 in 160 births, which amounts to 24,000 stillborn babies each year in the US.

 Infant mortality is the death of an infant before 1 year of age. In the US in 2019, the infant mortality rate was 5.6 deaths per 1000 live births.

Unlike postpartum depression, which the American College of Obstetricians and Gynecologists has identified as a pressing issue for pregnant women requiring a systematic and simple screening tool in the postpartum time period,

 no such protocol following miscarriage or stillbirth has been established. Because of this, epidemiological studies of psychological distress following perinatal loss are still in their infancy with small cohorts, and therefore firm conclusions regarding prevalence rates of psychiatric illness and symptoms are difficult to draw.

According to a small number of standardized studies, grief, depression, and/or anxiety are the most common psychological reactions following miscarriage.

 Grief is seen shortly after 40% of miscarriages and can represent a normal adaptive response, but it can also go on to develop into pathological grief characterized by despair, strong feelings of worthlessness, hopelessness, and difficulty engaging with normal life. In the early weeks of loss, 36% of women were found to have moderate to severe depressive symptoms and 10% to 50% go on to meet criteria for major depressive disorder. Risks for post-miscarriage emotional distress include later gestational age, miscarriage of planned pregnancy, prior struggles with infertility, having no living children, poor social support, and a history of poor coping.

 One retrospective cohort study out of Germany compared 12,000 women with spontaneous abortion and 12,000 without spontaneous abortion. They found that a year after miscarriage, 8.9% of women who experienced a miscarriage were diagnosed with depression, anxiety, or adjustment disorder versus 5.7% in women without a miscarriage (OR 1.53).

In terms of future pregnancies, a meta-analysis found a paucity of studies looking at mental health during future pregnancies following perinatal loss. They did, however, conclude that women experience 

 in the first trimester of pregnancy following reproductive loss.

Women after stillbirth describe prolonged grief, bereavement, anxiety, depression, guilt, and self-blame. Some small studies have shown that women are at 

 Women also experience increased rates of anxiety and depression in future pregnancies after a stillbirth.

In a study of mothers who experienced SIDS, researchers found that prolonged grief disorder was experienced by 50%. They also reported daily, intrusive, emotional pain or yearning in 68.1% of subjects. Further, they also experienced symptoms of grief; loss of self-identity; and confidence, anger, and diminished trust of others. The historical prognosis for grief is that disbelief, anger, yearning, and depression peak at 6 months, then decline as acceptance increases. With infant loss, the researchers found that there was never a time when acceptance exceeded the negative grief factors. Many women reflected that “the emphasis on acceptance fails to recognize their challenges as mothers who are responsible for maintaining memories and the value of their deceased children’s lives. They shared the difficulties they face over time as their deceased infants are less remembered or considered, noting that it contributes to their anger and inability to embrace acceptance.”

While we have some sense that these women suffer tremendously following perinatal loss, the body of literature is lacking rigorous studies of diagnosable psychiatric illness, symptom course and severity, and clear prevalence rates. We also do not currently have a sense of why these women are suffering: Is this simply a response to trauma, or could there be a biological process related to the inflammatory and hormonal dysregulation that led to miscarriage or stillbirth? Like postpartum depression, is there a role for post-pregnancy biological processes that seem to leave some women more vulnerable to mood and anxiety disorders in the immediate 

Perhaps most shockingly and sadly, there is a paucity of research on how to best treat women who experience perinatal loss. We do not have specific, validated screening tools to help better evaluate and identify women suffering in the wake of pregnancy and child loss. And perhaps because of the above, we do not have clear treatment guidelines or resident and provider education around treating women following miscarriage, stillbirth, and infant loss. We can and should do better.

While we wait for more research, where do we turn now when our patients experience perinatal or infant loss? First, we can start by being present, supportive, and bearing witness to their experience. Next, we can work hard to not rush along their grief process by focusing on acceptance. We can look for therapists and support groups experienced with perinatal and infant loss, such as through Postpartum Support International (PSI) (

Loss & Grief in Pregnancy & Postpartum | Postpartum Support International (PSI)

) or Miscarriage, Infant Death, and Stillbirth (MIS) Support groups (

We can see these patients frequently and continue to work on all the things that we, as psychiatrists, are trained for: 

, depression, relationships, sleep, appetite, and finding meaning. We can involve spouses and family members in our sessions to help increase familial support and sharing, as social support may protect against later emotional distress.

 And we can be vigilant during their future pregnancies to screen and treat them for psychiatric illness and to acknowledge that they may be experiencing conflicting feelings, anxiety, sadness, and even grief.

Finally, and importantly, we must take care of ourselves to be able to take care of our patients. Miscarriage, stillbirth, and infant loss can bring with it new and unique forms of countertransference and emotional reactions for us, the providers. Many of us will experience pregnancy, parenthood, and even loss while treating these patients, and exposure to this type of loss can bring up our own fears and personal histories. With the more widespread use of telehealth, many of us will see patients through these incredible losses within days or hours of their experience, and that means early and raw exposure to our patients suffering. It is vital to take a moment after seeing these patients to check in with yourself about your reactions and then to find trusted peer and supervisory colleagues to assist in processing your experience. As always, psychiatry and mental health provision is a team sport, and we are all in this together!

1. Centers for Disease Control and Prevention. New CDC data: COVID-19 vaccination safe for pregnant people. August 11, 2021. Accessed October 27, 2021. 

https://www.cdc.gov/media/releases/2021/s0811-vaccine-safe-pregnant.html

2. Blackmore ER, Côté-Arsenault D, Tang W, et al. 

Previous prenatal loss as a predictor of perinatal depression and anxiety.

3. Centers for Disease Control and Prevention. What is stillbirth? November 16, 2020. Accessed October 27, 2021. 

https://www.cdc.gov/ncbddd/stillbirth/facts.html#ref

4. Centers for Disease Control and Prevention. Infant mortality. September 8, 2021. Accessed October 27, 2021. 

https://www.cdc.gov/reproductivehealth/maternalinfanthealth/infantmortality.htm

5. Committee on Obstetric Practice; the American College of Obstetricians and Gynecologists. Screening for perinatal depression. November 2018. Accessed October 27, 2021. 

https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2018/11/screening-for-perinatal-depression

Psychological morbidity following miscarriage.

7. Nynas J, Narang P, Kolikonda MK, Lippmann S. (2015). 

Depression and anxiety following early pregnancy loss: recommendations for primary care providers. 

8. Jacob L, Polly I, Kalder M, Kostev K. 

Prevalence of depression, anxiety, and adjustment disorders in women with spontaneous abortion in Germany–a retrospective cohort study.

The presence of anxiety, depression and stress in women and their partners during pregnancies following perinatal loss: a meta-analysis.

Do stillbirth, miscarriage, and termination of pregnancy increase risks of attempted and completed suicide within a year? A population‐based nested case–control study.

11. Gravensteen IK, Jacobsen EM, Sandset PM, et al. 

Anxiety, depression and relationship satisfaction in the pregnancy following stillbirth and after the birth of a live-born baby: a prospective study.

12. Goldstein RD, Lederman RI, Lichtenthal WG, et al. 

The grief of mothers after the sudden unexpected death of their infants.

The psychological impact of stillbirth on women: a systematic review.

Loss and suffering can be hard for both patient and provider. Here’s what we know, what we need to learn, and how to protect yourself as a clinician. 

The Unimaginable: Pregnancy and Infant Loss in Psychiatric Practice

VistaGen Therapeutics announced new mechanism of action data from a study in laboratory rats that demonstrated a single intranasal dose of PH94B was largely confined to the nasal passages and minimal or undetectable in most other tissues, including the central nervous system (CNS). This supports the proposed mechanism of action of PH94B: binding to receptors of peripheral neurons in the nasal passages, not to neuronal receptors in the CNS, and limiting molecule movement to the circulatory system.

“In this study, the absence of radiolabeled PH94B in the rodent brain is an encouraging sign that PH94B may have limited circulatory systemic exposure when administered intranasally,” stated Mark Smith, MD, PhD, Chief Medical Officer of VistaGen. “Furthermore, the tissue distribution of radiolabeled carbon-14 PH94B was minimal in the tested lab animals, with the highest concentration primarily in the nasal turbinates. These findings strongly support a local disposition of PH94B in the olfactory receptor neurons and an absence of binding of PH94B in the central nervous system. We believe that this is another positive indication supporting the clinical development of PH94B.”

PH94B is an investigational, odorless, CNS pherine nasal spray with a rapid onset of approximately 15 minutes. The investigation agent is intended for the treatment of social anxiety disorder (SAD), with therapeutic potential in multiple additional anxiety disorders. The investigation agent is intended for the treatment of social anxiety disorder (SAD), with therapeutic potential in multiple additional anxiety disorders. PH94B is administered intranasally in microgram doses, and it activates peripheral nasal chemosensory neurons that trigger neural circuits in the brain to suppress fear and anxiety.

“We are very excited about these new study results, which further highlight how the mechanism of action of PH94B is fundamentally differentiated from all current anti-anxiety therapies,” said Shawn K. Singh, Chief Executive Officer of VistaGen. “When combined with previously announced preclinical electrophysiology data demonstrating that the mechanism of action of PH94B does not involve direct activation of GABA-A receptors, which is in distinct contrast to the mechanism of action of benzodiazepines, we see a growing body of evidence suggesting that PH94B has potential to achieve anti-anxiety effects without requiring systemic uptake or causing benzodiazepine-like side effects and safety concerns.”

VistaGen has initiated 2 ongoing phase 3 clinical trials of PH94B—PALISADE-1 and PALISADE-2—for potential acute treatment of anxiety in adults with SAD; the US Food and Drug Administration has granted it fast track designation.

“At a time when the current drug treatment paradigm for social anxiety disorder, or SAD, is falling far short of delivering necessary relief without worrisome potential consequences, an innovative treatment alternative is imperative. If successfully developed in our ongoing PALISADE Phase 3 Program, PH94B has the potential to fill that void as the first fast-acting, on demand acute treatment of anxiety for more than 23 million Americans who suffer from SAD,” Singh said further.

1. VistaGen Therapeutics. VistaGen Therapeutics reports new preclinical mechanism of action data supporting PH94B’s potential anti-anxiety activity via peripheral nasal neurons without entry into the brain. October 5, 2021. 

https://www.globenewswire.com/news-release/2021/10/05/2308651/0/en/VistaGen-Therapeutics-Reports-New-Preclinical-Mechanism-of-Action-Data-Supporting-PH94B-s-Potential-Anti-Anxiety-Activity-via-Peripheral-Nasal-Neurons-without-Entry-into-the-Brain.html

PH94B for the treatment of social anxiety disorder further differentiates its mechanism of action from benzodiazepines in a new lab rat preclinical study. 

New Investigational Social Anxiety Disorder Drug Differentiates Mechanism of Action

Matcha Sustains Caffeine's Benefits

A study compared matcha, a highly caffeinated green tea, to other sources of caffeine. Which had the greatest cognitive benefits? 

The Cognitive Benefits of Matcha

Susan J. Noonan, MD, MPH shares strategies to assist patients in overcoming their fears about the COVID-19 pandemic.

To see the previous video on reentry anxiety, watch 

Reentry Anxiety: The Challenge of Returning to "Normal"

is a physician consultant and Certified Peer Specialist in the Department of Psychiatry at McLean Hospital and the Massachusetts General Hospital. She is the author of four books and a blog on managing depression, most recently 

Helping Others With Depression: Words to Say, Things to Do (December 2020)

mental health and wellness virtual coaching practice, opening in July 2021, known as Noonan Wellness Coaching,and can be confidentially reached through her website at 

What are some ways to overcome anxieties about returning to "normal"?


Tackling Reentry Anxiety: Strategies for Coping

, Hannah Simon, MD, introduces a new series on teen and tween mental health. Her first guest is Andrew Chen, MD, MS, the chief medical officer for USA Nordic, the national leadership organization for Nordic Combined and Ski Jumping in the United States. They discuss the importance of mental wellbeing for peak athletic performance, the programs available for Olympic athletes, and how health care providers can help students succeed—in everything from the big game to the big test.

- Dr Chen’s path from medical school to the Olympic Games

- Simone Biles and fighting the stigma surrounding mental illness

- The mental health challenges facing school-aged children during the pandemic

- The importance of diet and nutrition for athletic performance and mental wellbeing

- 5 personality attributes that Olympians share (and what psychiatrists can learn from them)

is a child and adolescent psychiatry fellow at New York-Presbyterian Hospital.

Thanks to Columbia University Department of Psychiatry for allowing us to present the Caring for Teens and Tweens podcast with experts in the field of psychiatry.

What can Olympians teach mental health professionals about caring for student athletes—and others too? 

5 Personality Traits of Olympic Athletes

Tales From the Clinic: The Art of Psychiatry,

 we cover an intriguing case of dual substance use super-imposed on mood, anxiety, and trauma clinical picture. A significant challenge for this group of patients is the need for patient, methodical, consistent care to unravel the complex multifaceted triggers and perpetuating factors for continued maladaptive behaviors. The case description spans years of treatment and, while the details may seem sensational, they reflect the reality of what the addiction treatment clinic team encounters. In addition, there is much difficulty in hearing and processing patient accounts of trauma, which could lead to physician burnout.

“Ms Martin” is a 45-year-old female with bipolar disorder, generalized anxiety disorder, and suspected borderline personality disorder. She was transferred to the substance use disorders clinic by another psychiatrist after a diagnosis of opioid use disorder was obvious. At the time of her transfer, she was involved in prostitution to finance her roughly 25 tablets of acetaminophen and hydrocodone daily. Her opioid use disorder history had a protracted course, with her first exposure to prescription opioids at the age of 16 following a significant injury requiring surgical intervention. Her longest lifetime period of sobriety was 2 years.

Her immediate environment was not conducive to recovery, as she lived in a trailer with a male roommate who had mutual acquaintances that provided pain pills. In addition, Ms Martin engaged in sexual activity with the roommate in exchange for opioids. As time progressed, the relationship became physically abusive; she left after her roommate tried to hit her with a vacuum cleaner when she “didn’t do a good job cleaning the trailer.” At the time, she had been in treatment for 1 year, was started in medication-assisted therapy (MAT), and had been prescribed buprenorphine. She moved into an apartment with her mother, which greatly reduced access to opioids. She responded very well to MAT, with an absence of significant relapses as evidenced by the drug screenings during her monthly visits.

Three years into treatment, Ms Martin met a new boyfriend. Her urine drug screen (UDS) resulted positive for amphetamine. He provided her with substances that boosted her energy and aided in weight loss. She was not fully aware of what she was taking, but she thought it might have been amphetamine since it came in a “large jar with many capsules.” Testing verified the presence of methamphetamine.

These results were shared with Ms Martin, to her genuine surprise, and she expressed earnest motivation to stop methamphetamine use. Unfortunately, over the next year, she eventually met criteria for stimulant (methamphetamine) use disorder. This paralleled toxic developments in her relationship. She described a continued strong sexual attachment to her partner, and she remained intimate with him despite knowledge that he was simultaneously sexually active with her mother. She later bashfully admitted engaging in group intercourse with her partner and mother. During intercourse she described her partner’s derogatory and sadistic tendencies, which she felt she “deserved.”

Eventually, she developed disgust toward him. This resulted in an internal conflict because while she described feeling revolted by him, she simultaneously experienced severe loneliness and feelings of abandonment when he did not give her attention. This fueled further methamphetamine use as she wanted to be “skinny and pretty.”

The ongoing sexual relationship between her partner and mother resulted in significant tension within the apartment they all shared. On multiple occasions, Ms Martin described anxiety that her partner and mother were colluding against her. Methamphetamine use may have intensified these feelings. Although at times she expressed a desire to leave, she felt she had nowhere to go. Her partner contributed to paying bills, which further complicated her situation.

For the next year, Ms Martin continued to express significant ambivalence about her relationship. She recognized how the situation placed a strain on her relationship with her mother, yet she simultaneously feared the rejection, abandonment, and loneliness that would result from a breakup. She described symptoms of anxiety and sadness when away from her partner, and he was using methamphetamine pills as a tool to control her. She compared her “love-hate” relationship with her significant other with that of her relationship with the methamphetamine pills.

In addition to work in building Ms Martin’s feelings of self-worth and autonomy, a motivational interviewing style was utilized to help her resolve some of her ambivalence toward the relationship. Although she voiced much more change talk to end the relationship, compared to sustain talk, she had difficulty committing to ending the relationship.

Due to the alarming rate of opioid overdoses secondary to fentanyl, clinicians and those struggling with substance use are becoming aware that the product purchased is not always as marketed. Anecdotal reports of increasing concomitant opioid and amphetamine use abound, but the condition is not well understood, nor systematically studied. In the case of this patient, confirmatory test showed methamphetamine, whereas she believed she was getting amphetamine or methylphenidate; she may have inadvertently gained access to a supply of methamphetamine.

Currently, there are no US Food and Drug Administration-approved treatments for methamphetamine use disorder. Some studies suggest the use of bupropion, naltrexone, and mirtazapine may have some limited efficacy in 

 In addition to treating Ms Martin’s SUD, the team addressed co-occurring mood and anxiety symptoms (she had witnessed her brother injured in a car accident). Her initial regimen included duloxetine and aripiprazole for depression, anxiety, and mood stabilization. Bupropion was not tried due to her concern of its risk of exacerbating her anxiety, and she declined mirtazapine due to its risk of weight gain because she already struggled with her body image. After Ms Martin expressed concerns that aripiprazole may be contributing to her weight gain, she was switched to cariprazine with the perceived potential benefit of weight-neutrality, since a desire for weight loss was a contributing factor to continued methamphetamine use. Another potential benefit of cariprazine includes preliminary interest in the D3 receptor affecting addictive behaviors.

Methylphenidate and lisdexamfetamine were other pharmacological therapies considered for treatment, given that Ms Martin has shown good response to replacement therapy such as buprenorphine. However, agonist substitution, while an excellent harm reduction approach, still faces stigma and resistance in clinical practice, especially for stimulant use.

According to the Centers for Disease Control, 40.4% of adults using methamphetamine within the last year also misused prescription opioids, and 16.9% used heroin between 2015 and 2018. In the United States there has been an increase in overdose deaths and hospital admissions involving 

 After limited availability of ephedrine and pseudoephedrine due to regulations, synthesis returned partially back to using phenyl-2-propanone (P2P).

 Due to increased purity and potency, there is concern that the P2P formulation may be contributing to addiction.

 This is something to keep in mind when treating a patient diagnosed with both opioid and stimulant use disorders. Unfortunately, there is no guideline as to whether MAT should be discontinued if a co-occurring substance use is still ongoing.

Ms Martin maintained abstinence from opioids while on MAT, but continued to use methamphetamine pills. The treatment team wondered if she was truly benefiting from the current level of care, and considered tapering off buprenorphine and referring her to a residential treatment program or a methadone clinic. However, Ms Martin did not have the financial resources for the latter and, in regards to the former, expressed anxiety and fear about being separated from her dog as well as the feeling of “being locked up.” Thus, her treatment team sought to maximize psychosocial support and psychotherapy interventions, but she had stopped going to group therapy and declined virtual therapy sessions.

With continued work, despite ongoing significant trauma, interpersonal conflict, financial instability, and continued methamphetamine use, Ms Martin increased engagement in treatment and is adherent with all medication management visits. The treatment team ultimately decided not to taper off the buprenorphine, given her gradual progress toward treatment goals was a product of a harm-reduction approach. She could have benefited from inpatient rehabilitation. However, reluctance to go into rehabilitation is common in patients with SUD. Additionally, most states do not allow involuntary inpatient SUD treatment as they do for involuntary psychiatric care, so patients have to suffer legal repercussion to be forced to attend court-ordered rehabilitation. Finally, many residential treatment programs may not be able to accommodate patients on MAT, as some are not yet comfortable with a harm-reduction approach or medical model of addictions treatment.

This case highlights several clinical and psychotherapeutic challenges that may arise in the treatment of substance use disorders. First, it is important to look for the presence of significant trauma in a patient with several barriers to care preventing access to psychotherapy, as there is a known link between a history of trauma and the development of 

 In this case, Ms Martin was a victim of physical, emotional, and sexual abuse. Unfortunately, there are limited standardized or manualized approaches to addressing trauma in patients with substance use disorders. When trauma informed therapy is available, access is often limited.

Similarly, another significant factor contributing to Ms Martin’s ambivalence about leaving the relationship was the codependency that existed with her partner.

Medication management visits typical to community psychiatry practice are likely not of sufficient length to address complex issues involving psychopharmacology and psychotherapy. Although the COVID-19 pandemic has accelerated the development of telepsychiatry, many patients do not have the technological means to make these visits and may not have private and safe living spaces where they can share sensitive information.

Additionally, drug use is perpetuated by perceived benefits, and cessation of use does not happen unless the patient appreciates the negative impact of substance use on their lives. When Ms Martin finally understood she was taking methamphetamine, it created an opportunity to see its use as a problem instead of an agent for cognitive enhancement/weight loss.

Methamphetamine is commonly used to improve sexual function. In fact, 

 has described methamphetamine as increasing sexual desire, pleasure, reducing the refractory period between intercourse, exacerbating impulsiveness, and impacting behavioral inhibition.

 In this case, it would be worth further exploring that idea, as the patient’s partner was supplying methamphetamine and requesting particular sexual demands.

A major challenge in the field continues to be the lack of available effective pharmacologic treatments for stimulant use disorders. Contingency management in combination with community reinforcement is a proven effective behavioral treatment for stimulant use disorders, as confirmed by 

 However, there are considerable barriers to implementing contingency management at this time, including public stigma and limited Medicaid support.

Lastly, in the context of treatment, it is often easy to feel patients are to blame for maladaptive, promiscuous, or risky behaviors. Countertransference feelings or bias may hinder patients getting expanded treatment options, especially if they display anger and hostility upon exploration of sensitive topics in session.

However, despite significant barriers to care, the presence of trauma, and ongoing struggles with stimulant use, patients demonstrate resilience and often continue to express desire for full recovery. Cognitive-behavioral therapy, relapse prevention, mindfulness, and psychodynamic therapies are all useful in treatment, but the level of complexity of patients with SUD often means a prolonged course of treatment with multiple modalities needed.

is a PGY-4 general psychiatry resident in the Menninger Department of Psychiatry & Behavioral Sciences at Baylor College of Medicine. He plans to pursue a fellowship in Addiction Psychiatry after graduation.

is an associate professor and addiction-boarded faculty at Harris Health System in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. 

 is associate professor, Menninger Department of Psychiatry & Behavioral Sciences, Baylor College of Medicine, and Ben Taub Adult Outpatient Services director, medical director, Stabilization, Treatment & Rehabilitation (STAR) Program for Psychosis. She also serves on

1. Colfax GN, Santos GM, Das M, et al Mirtazapine to reduce methamphetamine use: a randomized controlled trial. 

2. Elkashef AM, Rawson RA, Anderson AL, et al. Bupropion for the treatment of methamphetamine dependence. 

3. Trivedi MH, Walker R, Ling W, et al. Bupropion and naltrexone in methamphetamine use disorder. 

4. Jones CM, Underwood N, Compton W. Increases in methamphetamine use among heroin treatment admissions in the United States, 2008-2017. 

5. Maxwell JC, Brecht M-L. Methamphetamine: Here we go again? 

6. Dolatshahi B, Farhoudian A, Falahatdoost M, et al. A qualitative study of the relationship between methamphetamine abuse and sexual dysfunction in male substance abusers. 

7. Wiechelt SA, Straussner SLA. Introduction to the special issue: Examining the relationship between trauma and addiction. 

8. Colfax G, Shoptaw S. The methamphetamine epidemic: Implications for HIV prevention and treatment. 

9. De Crescenzo F, Ciabattini M, D’Alò GL, et al. Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis. 

10. McMahan VM, Kingston S, Newman A, et al. Interest in reducing methamphetamine and opioid use among syringe services program participants in Washington State. 

A patient presents with multiple substance use disorders super-imposed on mood and anxiety disorders. Where does a clinician even begin?

I Had to Use

For many young patients (and their parents) the back-to-school season is an anxious time. How will they navigate their new classes? Will they get along with their teachers? Will they make friends? Their active imaginations can invent a hundred scary scenarios.

But what if their brilliant imaginations could help them build resilience instead? In this Mental Health Minute, Victoria Harris, DPsych, MA, offers practical tips and techniques to help children overcome their fears through the power of their creativity.

is a Humanistic & Integrative Psychotherapist and Supervisor in private practice who specializes in using creative techniques. She has trained in child psychotherapy and play therapy and researched the use of creative techniques in psychotherapy at Dublin City University. she helped develop a well-being school programme for 3rd & 4th class in Ireland for the charity 

 uses metaphor to help children navigate anxiety and loss will be released on October 5th, 2021. Dr. Harris believes strongly in early intervention and using creativity as a tool for healing.

How do you prepare patients for the back-to-school season? 

Share comments with your colleagues by emailing 

. Comments may be shared online pending review and editing for style.

These imaginative exercises can help clinicians establish a strong therapeutic alliance with nervous youngsters. 

Looking for a Way to Beat Back-to-School Anxiety? Maybe It’s Time to Get Creative

As the need grows for equitable, accessible, and affordable mental health treatment, digital therapeutics—app-based treatments—show promise for filling these gaps, particularly to target anxiety. The high prevalence of anxiety disorders “vastly exceeds the capacities of mental health services” to 

Anxiety has risen since the beginning of the COVID-19 pandemic. The US Census Bureau reported that adults were 3 times more likely to screen positive for anxiety disorders in 2020 compared with 2019 (31% vs 8%). A cross-sectional 

of individuals conducted in China February 2020 found the prevalence of generalized anxiety disorder (GAD) to be 35.1%; a meta-analysis found an average anxiety prevalence of 32% during the pandemic (17 studies, n = 63,439).

 A study of patients diagnosed with COVID-19 between January and August 2020 (n = 62,000+) found that 1 in 5 patients with no psychiatric history received a new mental health diagnosis, with the greatest health risk being for anxiety disorders.

Digital therapeutics can be designed to specifically target a behavioral or psychological mechanism of action, and they can be developed with user-centered design principles to maximize engagement. However, to date, very few digital therapeutics have been tested for efficacy, and even fewer have been studied regarding mechanism of action. There seem to be 2 categories of digital therapeutics emerging: those that are commercially developed with little supporting evidence or plans for evaluation and those with academic or government backing (and often not easily available to consumers).

 The former has the advantage of maximizing curb appeal: Resources can be devoted toward developing engaging user experiences using the latest design techniques, and companies can push a digital therapeutic to market rapidly. Scientists have developed evidence-based digital therapeutics, yet few are publicly available. They appear more slowly than their commercial counterparts, and those that do appear usually fail to attract users and user engagement.

 However, both face the same fate: No matter how shiny an app is, it still takes time to run rigorous clinical trials to determine efficacy (and mechanism).

John Torous, MD, Digital Section Editor for 

 and chair of the American Psychiatric Association’s Smartphone App Evaluation Task Force, put it bluntly when interviewed for an article on digital therapeutics in Nature: “Right now it almost feels like the Wild West of health care.”

How can the busy health care clinician keep up-to-date on the latest trends, determine which digital therapeutics are evidence based, and give informed answers when patients ask which apps to use? Is there enough evidence for prescribers to pull out their proverbial digital prescription pad to recommend an app-based treatment for anxiety?

After considering the recent literature, there are a few questions clinicians should consider.

Why Should There Be an Effect? What Mechanism Is Being Targeted?

A good place to start is to consider if a digital therapeutic is mechanistically based. Although many apps assert that they are scientifically based, very few live up to this claim. The National Institutes of Health established a 

 called the Science of Behavior Change (SOBC) to focus on mechanisms of change in behavioral interventions as a way to both strengthen intervention development and “increase rigor, transparency, and dissemination of common terminology, methods, and measures.”

 The basic idea behind SOBC is to measure if a behavioral intervention engages a hypothesized mechanism of change and if engaging that target leads to change in a health outcome. If this approach sounds similar to that taken for the development of any new drug, it should, because it is. It was modeled after the experimental medicine approach. However, a significant research-practice gap exists in the digital mental health field, especially in the field of anxiety interventions.

Findings of a recent study looking at the frequency of evidence-based treatment elements in apps for anxiety showed that the most commonly included elements were psychoeducation (53%), relaxation (47%), meditation (41%), and mindfulness (29%) (

 Yet, the inclusion of an element does not automatically translate to targeting a specific mechanism or therapeutic benefit. Another recent review found that 67% of apps for anxiety lacked involvement of any health professional in their development, and just 4% had been empirically evaluated.

This unfortunate lack of focus on mechanism is not due to an absence of information on how anxiety can develop and be perpetuated. For example, decades-old research has suggested potential mechanisms of action, such as targeting worry-driven negative reinforcement, yet 

 have these been incorporated into digital therapeutic devopment.

With apps that can reach thousands, and even millions, of potential patients, it is much easier to collect data from a convenience sample, look for reductions in some type of scale, and then claim it to be an evidence-based treatment for anxiety. However, there is a world of difference between someone who is mildly anxious (after all, who is not these days?), and someone whose anxiety is severe enough to land them firmly in the realm of needing treatment for a DSM-diagnosed anxiety disorder. For example, a 

 of randomized controlled trials of mindfulness apps reported significant effect sizes for reductions in anxiety, but every study recruited individuals from app users and the general population and specific nonclinical groups (largely students and employees).

 Of these, only a single study included individuals with mild to moderate anxiety using the General Anxiety Disorder-7 (GAD-7) cutoff of 14 to exclude individuals who reported severe anxiety (GAD-7: 5-9, mild; 10-14, moderate; 15+, severe anxiety).

 of internet-based cognitive behavioral therapy (iCBT) used GAD-7 scores of ≥ 8 as a minimum cutoff to recruit individuals with mild to moderate symptoms of anxiety, individuals in the United Kingdom’s National Health System (NHS) and “who may be eligible and require iCBT” as part of the Improving Access to Psychological Therapies (IAPT) program.

 Additionally, 2 studies of app-based mindfulness training for anxiety (Unwinding Anxiety) have used GAD-7 scores of ≥ 10 as minimum cutoff for inclusion of anxious physicians and individuals with GAD, respectively.

 Taken together, these results suggest that the majority of studies are drawing convenience samples from nonclinical populations, and that can lead to problematic inferences on the efficacy and utility of digital therapeutics in individuals with moderate to severe anxiety—those that would be most likely to seek or be referred to treatment—unless they have been specifically studied in these populations.

What Is the Evidence? Is There a Clinically Relevant Reduction in Symptoms?

Popularity does not equal evidence for efficacy. A number of app-based programs have put a primary focus on increasing their user base rather than developing digital therapeutics for anxiety. Although there is nothing inherently wrong with this approach—it is just a different focus—seeing a lot of individuals use an app can lead to a false sense of efficacy. Most studies to date are small pilot studies, often run by the app developers rather than by independent researchers, and the results have yet to be replicated. Additionally, many studies are run relative to wait-list control groups. Although this is better than no control group, it does not assess basic confounding components that are covered by a treatment as usual control group, such as receiving some type of treatment and expectancy effects (which, if performed well, will include the usual clinical care delivered by their therapist or doctor).

As previously mentioned, only a few published studies have examined digital therapeutics in individuals with moderate to severe anxiety: 1 in the general population (mainly recruited from users who were already signed up for the app Pacifica) with baseline GAD-7 scores of between 5 and 14; 1 (iCBT) in the UK’s NHS in individuals with baseline GAD-7 scores of ≥ 8; 1 (Unwinding Anxiety) in anxious physicians with baseline GAD-7 scores of ≥ 10; and 1 (Unwinding Anxiety) in individuals with GAD with baseline GAD-7 scores of ≥ 10.

In the first study, a randomized controlled trial that compared the Pacifica app to a wait-list control, only 35% of the app and 47% of wait-list participants completed the study. A composite anxiety score, using an average score of standardized GAD-7 and Depression and Anxiety Stress Scale-21 (anxiety component) scores, showed a statistically significant drop in both groups after 4 weeks (wait-list control, 0.23 composite point; Pacifica, 0.66 composite point), which was reported as statistically significantly different. In the second study, a randomized controlled trial of iCBT (Silvercloud) vs wait-list control, individuals in the iCBT group showed a statistically significant 35% reduction in GAD-7 scores at 8 weeks (baseline, 12.7; 8-week follow-up, 8.2) relative to a 15% reduction in the control group (baseline, 12.7; 8-week follow-up, 10.8). Retention was 82% and 76%, respectively.

In the third study, a single-arm trial of the Unwinding Anxiety app, anxious physicians demonstrated a statistically significant reduction in GAD-7 scores of 48% and 57% after 1 and 3 months, respectively (baseline, 11.5; 1-month, follow-up, 6.0; 3-month follow-up, 5.0). Retention was 60%. In the fourth randomized controlled trial looking at Unwinding Anxiety vs treatment as usual (TAU), individuals randomized to Unwinding Anxiety showed a statistically significant 67% reduction in GAD-7 scores (baseline, 12.0; 2-month follow-up, 3.0) relative to a 14% reduction in the TAU group at 2 months (baseline, 13.0; 2-month follow-up, 10.0). Retention was 88% for the Unwinding Anxiety group and 100% for the TAU group.

When prescribing a medication or suggesting that a patient try a behavioral treatment, we fall back on the ideals of the Hippocratic oath that we took at the beginning of medical school: First, do no harm. Although digital therapeutics do not carry the traditional adverse effect risk profile of a medication, it is important to approach information in a parallel manner: Ingesting information is not free of unintended consequences. For example, 

 for bipolar disorder found the presentation of information that could lead to harm (eg, encouraging individuals to drink liquor to help them sleep during manic episodes).

 Additionally, privacy is a concern, as apps can easily collect personal information ranging from symptoms to geolocation.

Digital therapeutics have the potential to live up to their promise: Mechanistic and evidence-based treatments that can be widely disseminated at low cost. To date, very few have demonstrated efficacy, and these studies would benefit from replication and extension of their findings. As clinicians consider recommending app-based treatments, it is important to stay abreast of emerging study results, and as they evaluate apps for their patients, they must keep those aforementioned important questions in mind (

is an associate professor of psychiatry at the Warren Alpert Medical School of Brown University, executive medical director of behavioral health at Sharecare Inc, and author of Unwinding Anxiety. Twitter: @judbrewer. He owns stock in, and serves as a paid consultant for, Sharecare Inc, the company that owns the Unwinding Anxiety app described in this article. The financial interest has been disclosed to and is being managed by his institution, Brown University, in accordance with its Conflict of Interest and Conflict of Commitment policies.

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Unwinding Anxiety: New Science Shows How to Break the Cycles of Worry and Fear to Heal Your Mind

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Key questions to consider when evaluating a digital therapeutic for anxiety. 

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