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“An uplifting experience” is how a prominent Southern California aesthetic medicine specialist described to me the reaction from a notable number of his patients having botulinum toxin treatments during the 

 (COVID-19) pandemic. Multiple needle sticks in their face notwithstanding, these patients took particular relish in cocooning themselves (however briefly) in a 

 of self-indulgence, effectively sequestered from the barrage of unique stressors now understood to be associated with COVID-19.

This isolated anecdote may be simple serendipity or an example of a potential intervention. A recently published article might stimulate discussion about the potential of broadly effective management with neurotoxin injections.

 used the FDA Adverse Event Reporting System (FAERS) to analyze more than 40,000 botulinum toxin treatment reports across a variety of medical and cosmetic indications including hyperhidrosis, facial rhytides, migraine prophylaxis, spasticity, and spasms. They reported a significantly lower number of depression reports across all indications and injection sites compared with patients undergoing alternative treatments for the same conditions.

They also found a significantly lower incidence of depression-related adverse events (AE) with neurotoxin treatment compared with the control groups. For example, reporting odds ratios (ROR) of botulinum toxin’s depression AE frequencies were uniformly significantly lower compared with control, ranging from 0.12 (95% CI: 0.04, 0.33) to 0.60 (95% CI: 0.48, 0.74), irrespective of indication. The ROR analysis necessitates that 

k associated with neurotoxin use has a reasonable underlying pharmacodynamic hypothesis. Therefore, these findings should be considered cautiously, as they may not reflect actual number of cases or frequencies in the general population as the FAERS system is voluntary and open to the public.

Although botulinum toxin does not have regulatory approval for the treatment of depression in the United States, this information should offer food for thought that there is a possibility that neurotoxin treatment may show promise in mitigating depressive symptoms. In fact, numerous reports corroborate the efficacy of botulinum toxin in attenuating symptoms related to major depressive disorder,

 including several randomized placebo-controlled trials and observational studies.

 Some believe that the muscles involved in facial expression, such as the corrugator muscles that elicit frowning, play a pivotal role in modulating the brain’s emotional circuitry and neural activity.14-17 Put simply, it is postulated that expressive behavior can alter emotional states, likely through afferent sensory modulation.

Botulinum toxin injections have an excellent safety profile. 

 reported no significant differences in the overall incidence of AEs, including serious AEs, in almost 2000 patients treated with botulinum toxin compared with patients treated with placebo injections based on the pooled results of 9 trials. Specifically, in trials of major depression, corrugator and procerus neurotoxin injections have noted that treatment-emergent AEs were localized to the treatment site and were temporary (headache and injection site irritation).

 That said, it will remain critical to evaluate the comparative effectiveness of neurotoxin treatment versus established psychopharmacological options and psychotherapeutic strategies and determine if and where it might fit into the current treatment paradigm.

One of the barriers is training mental health professionals on how to perform freehand injections, particularly those that require dose accuracy at multiple injection sites as with neurotoxin injections. Even with extensive experience, injection dose accuracy is difficult to achieve. 

 recently calculated that the average accuracy error associated with freehand injection of 40 consecutive 0.025 mL doses from a 1.0 cc syringe was approximately 10% for 2 highly-experienced injectors. Recognizing the urgency to achieve dose accuracy, several neurotoxin-dedicated devices have been developed and are undergoing clinical and regulatory evaluation.

In conclusion, preliminary evidence suggests botulinum toxin may have a positive impact on depressive symptoms. Additional research needs to be conducted to better determine the safety and efficacy of this treatment. If the data indicate this may be a worthwhile treatment option, administration barriers also will need to be addressed

is an independent clinical trialist and medical device consultant in San Francisco, CA. Website: 

. The author reports no conflicts of interest concerning the subject matter of this article.

1. Salari N, Hosseinian-Far A, Jalali R, et al. Prevalence of stress, anxiety, depression among the general population during the COVID-19 pandemic: a systematic review and meta-analysis. 

2. Ettman CK, Abdalla SM, Cohen GH, et al. Prevalence of Depression Symptoms in US Adults Before and During the COVID-19 Pandemic. 

Postmarketing safety surveillance data reveals antidepressant effects of botulinum toxin across various indications and injection sites

4. Alam M, Barrett KC, Hodapp RM, Arndt KA. Botulinum toxin and the facial feedback hypothesis: can looking better make you feel happier? 

5. Finzi E. Update: Botulinum Toxin for Depression: More Than Skin Deep. 

6. Parsaik AK, Mascarenhas SS, Hashmi A, et al. Role of Botulinum Toxin in Depression. 

OnabotulinumtoxinA for the treatment of major depressive disorder: a phase 2 randomized, double-blind, placebo-controlled trial in adult females

8. Chugh S, Chhabria A, Jung S, et al. Botulinum Toxin as a Treatment for Depression in a Real-world Setting. 

9. Finzi E, Rosenthal NE. Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial. 

10. Magid M, Finzi E, Kruger TH, et al. Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials. 

11. Magid M, Reichenberg JS, Poth PE, et al. Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. 

12. Wollmer MA, de Boer C, Kalak N, et al. Facing depression with botulinum toxin: a randomized controlled trial. 

13. Zamanian A, Ghanbari Jolfaei A, Mehran G, Azizian Z. Efficacy of Botox versus Placebo for Treatment of Patients with Major Depression. Iran J Public Health. 2017;46(7):982-984.

14. Franca K, Lotti T. Botulinum toxin for the treatment of depression. 

15. Hennenlotter A, Dresel C, Castrop F, et al. The link between facial feedback and neural activity within central circuitries of emotion--new insights from botulinum toxin-induced denervation of frown muscles. 

16. Kim MJ, Neta M, Davis FC, et al. Botulinum toxin-induced facial muscle paralysis affects amygdala responses to the perception of emotional expressions: preliminary findings from an A-B-A design. Biol Mood Anxiety Disord. 2014;4:11.

17. Lewis MB. The interactions between botulinum-toxin-based facial treatments and embodied emotions. 

18. Brin MF, Boodhoo TI, Pogoda JM, et al. S

afety and tolerability of onabotulinumtoxinA in the treatment of facial lines: a meta-analysis of individual patient data from global clinical registration studies in 1678 participants

Maximizing botulinum toxin injections for cosmetic and therapeutic applications with a single use, disposable, exact dose injection assist device

20. Yoelin SG, Kwolek MS, Block JE. Commentary on Botulinum Toxin injections: a call for improved accuracy. 

Although botulinum toxin does not have regulatory approval for the treatment of depression in the United States, some reports indicate neurotoxin treatment may mitigate symptoms.

An Uplifting Experience: Can Botulinum Toxin Address Depressive Symptoms?

The number of Americans over the age of 65 

 by over one-third during the past decade and is expected to rise, with important implications for planning and delivery of health care.

 The most problematic expression of population aging is the clinical condition of frailty, defined as a state of vulnerability to poor resolution of homeostasis following stress; it is a 

 of cumulative decline in multiple physiological systems over a lifespan.

 The cumulative decline erodes homeostatic reserve until minor stressor events trigger disproportionately large and negative changes in health status. Up to half of those aged 85 years and older are frail, and this is associated with increased risk of disability and other physical and mental health outcomes.

When depression, the leading cause of global disease burden,

 is also present in frail elderly patients, they tend to have higher mortality risk as they display lower physical activity levels, have a greater prevalence of fatigue and significant weight loss, have slower gait speeds, and have weaker 

 evaluated whether frailty burden predicts who will or will not respond to antidepressant medication.

. Do frail elderly adults with a depressive disorder respond differently than non-frail elderly adults with depression when standard antidepressant treatments are implemented?

. Outpatient placebo-controlled 8-week clinical trial followed by 10-months of open treatment.

. 34 men and 66 women aged 60 years or older who received a diagnosis of major depressive disorder (MDD) or persistent depressive disorder and managed as outpatients at the Clinic for Aging, Anxiety and Mood Disorders at 

. Participants were treated with antidepressant medications (escitalopram or duloxetine) in a placebo-controlled trial for 8 weeks, following which participants could continue open-label treatment for 10 months. During these 10 months they were treated as clinically indicated with both antidepressant switching and augmentation strategies. Baseline and follow-up assessments were completed pretreatment, at 8 weeks, and at 6 and 12 months. The diagnoses of depression subtypes were made based on DSM-5 clinical interview, with severity assessments based on the Hamilton Depression Rating Scale (HAM-D).

. The 100 participants in the study were all 60 years or older and had a baseline score of 16 or higher on the 24-item HAM-D. They were all assessed for frailty at baseline (3 or more deficits on gait speed, grip strength, activity level, fatigue, and weight loss) and categorized into frail (n = 49) and non-frail (n = 51). There were no intergroup differences between medical comorbidities, socioeconomic status, demographics, cognitive, or depressive variables. Participants did not have any severe medical illnesses, substance use disorders, or cognitive impairments.

. After 8 weeks of acute placebo-controlled treatment, frail adults (n = 49) showed an average HAM-D score that is 2.82 points higher than the non-frail adults (t = 2.12, df89, p = 0.037) and this difference persisted over the entire study follow-up period of 10 months. Additional analysis revealed that weak grip strength and low physical activity levels were each associated with worse response to antidepressants and lower response and remission rates over the course of the study, while slow gait speed, exhaustion, and significant weight loss were not. Patients who are frail also received more antidepressant medication trials.

This study suggests that frailty identifies a high-risk subgroup of elderly patients with depressive disorders characterized by lower antidepressant response despite several antidepressant trials, some with augmentation trials.

 assessed an interesting question: Do elderly patients with depressive disorders and comorbid frailty respond differently to antidepressants compared with non-frail elderly patients with MDD? The authors branched off a previous metanalysis6 that found no statistically valid difference in response or remission to antidepressants compared to placebo in elderly adults. They hypothesized that an extra complexity, frailty, would pose even more pronounced challenges.

 It might possibly tease out a sub-population of elderly patients that would respond differently.

 Indeed, the findings in this study support the pre-study hypothesis, as this predominantly female, elderly patient population have poor responses but also often require additional antidepressant trials and perhaps polypharmacy antidepressant augmentation.

Frailty in the context of late-life depression may indicate 

 are not sufficient, and that adjunctive interventions in the form of physical therapy and exercise, behavioral therapy, case management, and other assistance may be needed. For psychiatrists who encounter elderly patients with depression in clinical practice, it is important to comprehensively assess them beyond the standard of psychiatric diagnosis and symptom severity ratings. Physical characteristics such as activity level, strength, and mobility can provide insight into the clinical trajectories of such patients.

outlines an approach to assessment and management of depression in elderly patients. It includes a careful frailty assessment to better understand the optimal treatment course of action.

There are several limitations to this study:

• Only escitalopram and duloxetine were used in the initial placebo-controlled treatment phase. Although the open label portion included additional interventions (antidepressant switch or augmentation), it is unclear whether different antidepressants or classes of antidepressants may have had different outcomes.

• In assessing depressive symptomatology, the Hamilton Depression Rating Scale was used. Although it is the most commonly used scale for reporting symptoms in research, this is not specific, or extensively validated, for the geriatric population.

• The study seems to have included a greater proportion of women than men, which may have skewed the baseline starting characteristics and outcomes.

• Additionally, the population comprises mostly Caucasian participants, with 16 years of education on average across the spectrum. Generalization to other races and ethnic backgrounds and to those with less or more education is questionable.

• Exclusion criteria eliminated those with extensive medical illnesses and acute needs as well as those with substance use in the past 12 months. From the perspective of real-life clinical practice this seems unrealistic.

• The sample was limited to 1 site, which happens to be a geriatric specialist site. The generalization outside this system to other communities and treatment settings is unknown.

is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction Section Editor for 

1. Population and Housing Unit Estimates. United States Census Bureau. Accessed January 13, 2021. 

https://www.census.gov/programs-surveys/popest.html

2. Clegg A, Young J, Iliffe S, et al. Frailty in elderly people. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098658/

3. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. 

4. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 

5. Brown PJ, Ciarleglio A, Roose SP, et al. 

Frailty worsens antidepressant treatment outcomes in late life depression

6. Mallery L, MacLeod T, Allen M, et al. Systematic review and meta-analysis of second-generation antidepressants for the treatment of older adults with depression: questionable benefit and considerations for frailty. 

Research zeroes in on how frailty impacts depression treatment in elderly patients.

How Frailty in Older Adults With Depression Hinders Antidepressant Response

GROUP FOR THE ADVANCEMENT OF PSYCHIATRY, COMMITTEE ON WORK & ORGANIZATIONS

Work is central to many people’s lives. The average person spends one-third of their adult life working, yet psychiatrists may neglect work when assessing a patient’s well-being. We address drug use, family life, and psychiatric symptoms, but may not fully appreciate how those factors are relevant to our patient’s work.

Nonetheless, work is tied to the surge in mental health concerns precipitated by the coronavirus disease 2019 (COVID-19) pandemic. As we consider anxiety, depression, substance use, spousal and child abuse, and loneliness, all of which have been found to increase following disasters, we must not forget how the pandemic is affecting our workforce. For instance, during this time of increased social isolation, employers have been using video technology to maintain a sense of connectedness among their employees. This very much reflects the centrality of work to mental health and social cohesion.

Psychiatrists will find it difficult to ignore the centrality of work over the coming months, as the the pandemic has led to a surge in unemployment not seen since the Great Depression. Individuals filed more than 58 million initial unemployment benefit claims between March 14 and August 22, 2020, and economists 

When a patient loses their job, a psychiatrist must respond actively and swiftly. Employment fulfills essential biological, psychological, and social needs. It is the means by which we sustain ourselves, comprises a large part of our identity and social community, and determines how we spend most of our waking hours. As such, job loss is profoundly disorienting, challenging the very meaning and purpose of life. It directly affects self-esteem and perceptions of self-worth, precipitates anxiety, and increases the chance of physical and mental illness.

 Unemployment is associated with lower motivation, and an increased risk of substance abuse and suicide.

 This is compounded by the loss of structure and shared experience that work typically confers. Thus, job loss generally leads to a loss of well-being.

When a patient loses their job, the psychiatrist has 4 tasks: (1) triage and treat imminent emergencies; (2) treat acute or latent psychiatric symptoms medically or psychotherapeutically; (3) support the patient by helping them to recognize vulnerability, identify feelings, and enhance personal support systems; and (4) prompt the patient to realistically 

Treating emergencies and psychiatric disorders, as well as discussing the effects of job loss on personal and interpersonal variables can lead to improvement. Clinicians can do this informally or psychotherapeutically. Helping the patient identify their social support systems and how to use them can be helpful. As with any episode of clinically significant depression, anxiety, or psychosis, medication may be indicated.

Returning to work is the ultimate goal for the majority of our patients. To evaluate job prospects realistically, psychiatrists should take a work history once the initial crisis and reactions have been explored. Assessing a work history is not typically taught during residency training and is often not part of a clinical interview. However, a work history provides important information about a patient’s functionality (

 questions help patients identify what they wish to do for future employment, including a change in career. Expectations, skills, and qualifications can be realistically assessed by discussing patient responses. The psychiatrist can serve as a sounding board for the patient’s ideas and help the patient cultivate adaptive perceptions, expectations, and realistic future plans.

How do psychiatrists carry out this function? Perhaps the most important principle to consider is their role in serving as a source of reality testing and as a means of integrating the self. By listening to the patient’s occupational hopes and integrating these with the current reality and the work history, the psychiatrist can explore what is possible in a career. The psychiatrist and the patient may uncover a wider range options for work than the patient would discover in isolation.

It is clear that the pandemic will continue to affect the economy, the job market, and work. It is likely that many aspects of work—such as where, how, and for whom it is conducted—will change, and many changes will persist beyond the pandemic. We may wish to recall that our society, economy, and work situations were far from perfect prior to the pandemic; perhaps the crisis can be reframed as an opportunity for our patients to seek healthier and more meaningful work situations.

Job loss is likely to affect far more people than 

 itself. Psychiatrists are uniquely positioned to sustain the unemployed individual’s sense of efficacy, identity, and purpose during these difficult times. By understanding and supporting our patients, we can help them avoid the downward spiral of helplessness and despair that can otherwise follow job loss.

Dr Morrison is an assistant clinical professor of psychiatry at Chicago Medical School in Illinois. Dr Brown is a department psychiatrist at Boston Police Department in Massachusetts. Dr Sassano-Higgins is an adjunct professor of psychiatry at the University of Southern California, and chair of the Committee on Work & Organizations for the Group for the Advancement of Psychiatry. Dr VanDercar is a forensic psychiatry fellow at the University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine in Ohio. Dr Long is the president-elect for the Group for the Advancement of Psychiatry. Dr White is an adjunct voluntary faculty member at Northwell Health System in New York City, New York. 

1. Galea S, Merchant RM, Lurie N. The mental health consequences of COVID-19 and physical distancing: the need for prevention and early intervention. JAMA Intern Med. 2020;180(6):817-818.

2. Chiwaya N, J Wu. The coronavirus has destroyed the job market in every state. NBC News. Updated August 27, 2020. Accessed November 30, 2020. 

https://www.nbcnews.com/business/economy/unemployment-claims-state-see-how-covid-19-has-destroyed-job-n1183686

3. Jin RL, Shah CP, Svoboda TJ. The impact of unemployment on health: a review of the evidence. 

5. Lee AM, Wong JGW, McAlonan GM, et al. Stress and psychological distress among SARS survivors 1 year after the outbreak. 

6. Darity WA Jr. Employment discrimination, segregation, and health. 

7. Kawohl W, Nordt C. COVID-19, unemployment, and suicide. 

8. Stam K, Sieben I, Verbakel E, de Graaf PM. Employment status and subjective well-being: the role of the social norm to work. 

9. Committee on Psychiatry in Industry, Group for the Advancement of Psychiatry. Job loss, a psychiatric perspective. 

Unemployment is associated with an array of social and psychological complexities, directly affecting patients' self-esteem and perceptions of self-worth. When a patient loses their job, the psychiatrist has 4 tasks.

My Patient Lost Their Job…Now What? 

Decades of research have investigated inflammation and mental illness, suggesting that there is a robust and complex link. However, the link lacks diagnostic specificity and varies considerably among individuals, and with each stage of illness. Chronic, low-grade 

appears to precede the initial illness episode, at least in some individuals.

 Drugs that modulate the immune system may also affect an individual’s mood and have possible psychiatric adverse effects (AEs). Perhaps the best example is that interferon-α treatment of hepatitis C precipitates depressive episodes.

 is associated with reduction in inflammatory markers.

Statins are best known as competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statin treatment results in lower low-density lipoprotein cholesterol levels and in benefits to cardiovascular health. Statins also have anti-inflammatory mechanisms of action, including T-cell downregulation, suppression of cytokines, production of chemokines and C-reactive protein, and downregulation of transcription factors.3 In a post hoc, pooled analysis (N = 969) of data collected at baseline and at a 1-year follow-up from a study of patients with acute coronary syndrome, statin treatment was shown to reduce levels of interleukin (IL)-6 and IL-18. Raised levels of these cytokines appeared to predict depression after acute coronary syndrome.

Many epidemiological studies have shown that 

 is associated with a lower risk for depression (

 A population cohort study (N = 4,607,990) using Swedish national registry data investigated the relationship between statin use and the development of depression. The use of any statin was associated with an 8% decrease in risk for depression (odds ratio [OR], 0.92) compared with individuals who did not use statins.

 Elsewhere, in a cohort of individuals 55 years and older (N = 2804), statin use was associated with decreased depression (OR, 0.71).

 However, no association between statin use and depression was determined in an analysis of data from 19,114 individuals, most of whom were 70 years and older, of whom 5987 used statins.

Evidence from clinical trials suggests that, adjuvant to treatment with antidepressants, some statins are associated with better treatment outcomes. A 

 showed that treatment with lovastatin, atorvastatin, and simvastatin, adjunctive to antidepressant treatment, was superior to treatment with a placebo adjunctive to antidepressant treatment for improving depression (indexed by the Hamilton Depression Rating Scale).

 More recently, the results of a trial of rosuvastatin for young individuals with depression indicated that rosuvastatin failed to beat the placebo on the primary outcome, but it was positive on a number of secondary outcome measures, leaving the benefit uncertain.

A trial comparing simvastatin (n = 33) with placebo (n = 33) in participants with schizophrenia treated with risperidone found significantly higher reduction in the first group in negative symptom scores (P = .003) and total score (P = .001). These results measured the time period from baseline to week 8, using the Positive and Negative Syndrome Scale (PANSS).

 Simvastatin did not significantly differ from placebo for treating schizophrenia in an underpowered study (N = 36).

Two meta-analyses of statin add-on therapy in the antipsychotic treatment of schizophrenia have been conducted. 

 identified 5 randomized controlled trials (N = 236) showing improvement of PANSS total score, but not of PANSS subscale scores.

 The meta-analysis included studies of atorvastatin, lovastatin, pravastatin, and simvastatin. Risperidone was used in 3 studies; antipsychotic use was varied or not reported for 2 studies. 

 identified 6 randomized controlled trials (N = 339) showing benefit for improvement of PANSS positive and negative subscales.

 The meta-analysis by Shen et al included all 5 trials from the Nomura et al meta-analysis plus an additional trial of simvastatin versus placebo.

 have been associated with an increased risk for cardiovascular disease (CVD), independent of psychotropic medication use. This comorbidity is bidirectional, since depression is a common outcome after myocardial infarction and is also associated with higher comorbidity and mortality.

 In this context, treatment with statins may have an important dual purpose, with benefits to both mental and cardiovascular health. Evidence from a nested case-control study has shown that exposure to statins and aspirin is associated with a reduced risk of de novo major depression.

Atorvastatin, lovastatin, and simvastatin are lipophilic, while pravastatin, rosuvastatin, pitavastatin, and fluvastatin are hydrophilic. The lipophilic statins readily cross the blood-brain barrier. Hydrophilic statins or their active metabolites may also be detected in the brain, although less readily. Laboratory studies have suggested that statins may be neuroprotective against a range of neurotoxic insults, but statins themselves may be neurotoxic at higher concentrations than those obtained at therapeutic doses.

The best evidence that statins reduce markers of inflammation is derived from the JUPITER study of rosuvastatin.

 It is unclear whether brain penetrance or reduction in peripheral markers of inflammation is the more important mechanism in terms of potential therapeutic efficacy.

There is a potential for drug-drug interactions between statins and psychotropic agents (

). Psychotropic agents with lower cytochrome P450 (CYP450)activity should be considered ahead of those with known strong CYP450 activity to reduce the risk of pharmacokinetic drug-drug interactions.

 Andrade suggests that risks of pharmacokinetic drug-drug interactions between selective serotonin reuptake inhibitors (SSRIs) and statins are negligible at standard therapeutic doses for escitalopram, citalopram, and paroxetine with rosuvastatin, pitavastatin, and pravastatin; there is possible but low risk of interactions for combinations of fluvoxamine with atorvastatin, simvastatin, or lovastatin.

 A study of blood specimens collected from elderly patients (N = 194) investigated the interactions between statins and antiepileptic drugs, including the mood stabilizers lamotrigine and carbamazepine. Carbamazepine, but not lamotrigine, significantly interfered with 

, with lipids reduced for patients taking either drug but significantly greater reduction in lipids for those taking 

 Risks of adverse events may be greater in elderly cohorts compared to nonelderly individuals.

Antipsychotics may upregulate gene expression of lipid metabolism pathways, resulting in metabolic side effects, weight gain, and dyslipidemia. Individuals receiving antipsychotics may have reduced response to treatment with statins for dyslipidemia, with a common gene variant (SREBF1) for a transcription factor in the lipid metabolism pathway.

 Dyslipidemia in individuals treated with antipsychotics may benefit from personalised treatment plans, in which statins may have an important but variable role.

In the clinical setting, medication changes, dose adjustments, and polypharmacy are common in psychiatric practice and are associated with a greater risk of adverse effects. Adding a statin to an existing regimen entails an additional risk that needs to be considered when the statin is first introduced and whenever there are changes to comedications throughout the course of treatment. Case reports on statins and psychotropic comedications have identified rare adverse events of rash,25 QTc interval prolongation,

Preliminary evidence, mainly from small studies, suggests that adjuvant treatment with a statin may be beneficial for individuals taking psychotropic drugs for depression and schizophrenia. People with depression, bipolar disorder, and schizophrenia are substantially more vulnerable to metabolic syndrome and earlier age of mortality than the general population, predominantly from CVD. Such medical comorbidities warrant aggressive prophylactic therapy with available agents, including statins. Thus, there is sufficient evidence to suggest that combining statin therapy with antidepressant or antipsychotic therapy may be sensible for patients with comorbidities when both pharmacotherapies are indicated. However, adjuvant treatment with a statin purely as an augmentation strategy for psychopharmacotherapy is still experimental. Although there is a good theoretical basis and promising preliminary data, further research is required, especially larger, multisite, placebo-controlled randomized clinical trials.

 is a principal fellow in the Department of Psychiatry, University of Melbourne, a clinical associate professor at the Centre for Youth Mental Health, University of Melbourne, and a clinical associate professor in the School of Medicine, Deakin University, Melbourne, Australia. D

is a psychiatrist in the Hospital Clinic de Barcelona in Spain and a researcher at IMPACT, Univer-sity Hospital Geelong, Australia. 

is the Alfred Deakin Professor of Psychiatry and director of IMPACT, the Institute for Mental and Physical Health and Clinical Translation, Deakin University, Melbourne, Australia.

Inflammation and depression: a causal or coincidental link to the pathophysiology?

2. Qato DM, Ozenberger K, Olfson M. Prevalence of prescription medications with depression as a potential adverse effect among adults in the United States. 

3. Kim SW, Kang HJ, Jhon M, et al. Statins and inflammation: new therapeutic opportunities in psychiatry. 

4. Kim SW, Kang HJ, Bae KY, et al. Interactions between pro-inflammatory cytokines and statins on depression in patients with acute coronary syndrome. 

Prog Neuropsychopharmacol Biol Psychiatry. 

5. Köhler O, Benros ME, Nordentoft M, et al. 

Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials

6. Redlich C, Berk M, Williams LJ, . Statin use and risk of depression: a Swedish national cohort study. 

7. Feng L, Tan CH, Merchant RA, Ng TP. Association between depressive symptoms and use of HMG-CoA reductase inhibitors (statins), corticosteroids and histamine H(2) receptor antagonists in community-dwelling older persons: cross-sectional analysis of a population-based cohort. 

8. Agustini B, Mohebbi M, Woods RL, et al; ASPREE Investigator Group. Association between statin use and depressive symptoms in a large community-dwelling older population living in Australia and the USA: a cross-sectional study. 

9. Salagre E, Fernandes BS, Dodd S, Brownstein DJ, Berk M. 

Statins for the treatment of depression: a meta-analysis of randomized, double-blind, placebo-controlled trials

10. Quinn AL, Dean OM, Davey CG, et al. Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin. 

11. Tajik-Esmaeeli S, Moazen-Zadeh E, Abbasi N, et al. Simvastatin adjunct therapy for negative symptoms of schizophrenia: a randomized double-blind placebo-controlled trial. 

12. Chaudhry IB, Husain N, Drake R, et al. Add-on clinical effects of simvastatin and ondansetron in patients with schizophrenia stabilized on antipsychotic treatment: pilot study.

13. Nomura I, Kishi T, Ikuta T, Iwata N. 

Statin add-on therapy in the antipsychotic treatment of schizophrenia: a meta-analysis

Adjunctive therapy with statins in schizophrenia patients: a meta-analysis and implications

15. Van der Kooy K, van Hout H, Marwijk H, et al. Depression and the risk for cardiovascular diseases: systematic review and meta analysis. 

16. Batelaan NM, Seldenrijk A, Bot M, et al. Anxiety and new onset of cardiovascular disease: critical review and meta-analysis. 

17. Berkman LF, Blumenthal J, Burg M, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. 

18. Williams LJ, Pasco JA, Mohebbi M, et al. Statin and aspirin use and the risk of mood disorders among men. 

19. Wood WG, Eckert GP, Igbavboa U, Müller WE. Statins and neuroprotection: a prescription to move the field forward. 

20. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. 

21. Palleria C, Roberti R, Iannone LF, et al. 

Clinically relevant drug interactions between statins and antidepressants

22. Andrade C. Selective serotonin reuptake inhibitor drug interactions in patients receiving statins. 

23. Mintzer S, Trinka E, Kraemer G, et al. 

Impact of carbamazepine, lamotrigine, and levetiracetam on vascular risk markers and lipid-lowering agents in the elderly

24. Vassas TJ, Burghardt KJ, Ellingrod VL. Pharmacogenomics of sterol synthesis and statin use in schizophrenia subjects treated with antipsychotics. 

25. Walder A, Baumann P. Mood stabilizer therapy and pravastatin: higher risk for adverse skin reactions? 

26. Furst BA, Champion KM, Pierre JM, et al. Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin. 

27. Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. 

Preliminary studies suggest that adjuvant treatment with a statin may be beneficial for patients who are also prescribed psychotropic drugs for depression and schizophrenia.

The Psychiatric Potential of Statins 

A woman sits in front of a camera. She wears a straw hat, checkered dress, scarf, and a blanket over her shoulders. She looks up at the viewer, away from the dead bird she holds in her hands.

Taken in Victorian England at the dawn of photography, this was among the first photographs of an individual with a mental illness. It was captured by the so-called “father of psychiatric photography,” Hugh Welch Diamond, MD (1808 to 1886), who was the first to apply the technology of photography to the study of mental illness. He believed that his patients faces would reveal their mental states.

From 1848 to 1858, Diamond was the superintendent of the female division at the Surrey County Asylum, where he took photographs of his patients, supposedly to aid in diagnosis and treatment. His 40 collodion photographs were exhibited for expert scientific circles and the general public, and shaped ideas about what mental illness looks like. Diamond hoped that the apparent objectivity and realism of photography, in comparison to the supposedly unfaithful hand of illustrators and artists, would help to scientize psychiatry and physiognomy, and create a semantics of facial expression that directly correlated with diagnosis.

Diamond and his photographs straddled the worlds of science and art. His work is housed in various artistic and scientific museums and archives and published widely; just as Diamond’s personal biography braided together the fields of photography and psychiatry, his documentary photographs blur the distinction between art and science. In fact, Diamond was even more famous in the world of photography, which his work served to popularize.

Diamond’s photographic project endorsed many of the era’s prevailing theories—such as the value of systematic and empirical categorization based on the collection of specimens (which intersected with his antiquarian interests); ideas about physiognomy and the physical manifestation of one’s internal mental state; and the asylum reform movement that advocated for a more humane method of treatment without physical restraints. As an advocate, Diamond shaped beliefs about mental disability and the rights of mentally ill individuals. His photographs make clear why these individuals deserved to live in humane conditions. Specifically, Diamond believed that by improving his patients’ external circumstances (ie, clothes, environment, hygiene), their mental illness would consequently improve.

Critically analyzing non-verbal and visual indicators reveals the contradictions and ambiguity of using such photographic data to try to diagnose or identify mental illness. Diamond’s photographic images were not objective depictions of mental illness, but rather reflections of the predominant cultural understanding at the time. His reliance on props (a dead bird), clothing (disheveled dress, shawls and blankets), poses (head resting on the hand), and culturally determined iconography (Ophelia’s headdress from 

) to indicate mental illness seemingly contradicts the theory of physiognomy, which should not require externally imposed symbolism. The photos demonstrate the opposite of what he intended, since there is nothing intrinsic in these women’s bodies or faces that demarcate them as mentally ill.

Further, these photos did not stand on their own but required diagnostic labels and narrative case notes from another contemporary psychiatrist, John Conolly, MD. This further reflects the futility of faith in physiognomy, the belief that an invisible mental state can be rendered visible, like stigmata, without supplementary information. Diamond (and Conolly) used circular reasoning to reach their conclusions: knowing that these women were ill, or melancholic, or maniacal, they looked for such indicators that would confirm their preconceptions. Diamond’s photographs must be situated within a longer tradition, in which cultural conceptions of mental illness already underlie the images used for diagnosis.

On the one hand, his portraits perpetuate the stigmatization and pathologizing of these women. They are instances of a type. In taking the photographs, the “insane” label was forced upon them, freezing them as a permanent record in the canons of mental illness. These anonymous women are the objects of our attention because their suffering and individuality are supplanted by their images. On the other hand, Diamond’s photographs also humanize and individualize these patients, with whom we continue to engage more than 150 years later.

As Diamond said, the photos allowed viewers to “witness this exhibition of human suffering.” They could have “hardly imagine[d] this peculiar state of mental prostration” if they had never encountered someone with a mental illness.

 The realism of the documentary photographs, in comparison to artistic portraiture or medical illustrations, allows the contemporary viewer to sense the presence of a real human in the frame. Despite the inherent paternalism of asylum life and the power of the photographer, as we look into their eyes, these women regain some agency and individuality as co-creators of these lasting images. Ultimately, while Diamond’s project did not prove what he intended, these women humanize the face of mental illness. The women were silent, but their gazes speak volumes.

is a medical student at the Icahn School of Medicine at Mount Sinai, New York.

1. Diamond HW. On the application of photography to the physiognomic and mental phenomena of insanity. Gilman S, ed. 

Face of Madness: Hugh W. Diamond and the Origin of Psychiatric Photography

If a picture is worth a thousand words, how many diagnoses can it make? The photographer and psychiatrist Hugh Welch Diamond, MD, shares insights into the humanity and stigma of mental illness in Victorian England. 

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