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While psychotropic medications for schizophrenia, bipolar disorder, and other psychiatric disorders can cause weight gain, patients can take small steps to improve their health.

15 Steps to Helping Psychiatric Patients Achieve and Maintain a Healthy Weight

VistaGen Therapeutics presented data that highlighted the proposed mechanism of action (MOA) of its phase 3 investigational drug candidate PH94B in a poster session at the Anxiety and Depression Association of America’s 2021 Virtual Annual Conference. PH94B is a nasal spray designed for the treatment social anxiety disorder (SAD) without directly activating gamma-amino butyric acid (GABA

This sets Ph94B’s MOA apart from that of benzodiazepines such as alprazolam, diazepam, and lorazepam, all direct GABA

 receptor positive modulators. VistaGen hopes to offer an alternative to displace these drugs, along with other highly-addictive benzodiazepines used for treating SAD and other anxiety disorders.

“The results are in agreement with PH94B’s lack of benzodiazepine-like side effects and safety concerns reported in PH94B clinical studies—for example, lack of sedation, cognitive impairment or abuse liability potential,” Louis Monti, MD, PhD, Vice President, Translational Medicine of VistaGen said to the press. “This study demonstrated that PH94B’s mechanism of action is through neural regulation of forward inhibitory GABAergic neurons in the limbic amygdala and is differentiated from benzodiazepines’ mechanism of action, which is through a direct local potentiating effect on GABA receptors. These data are key in understanding PH94B’s overall potential effectiveness and safety for individuals suffering from SAD and many other anxiety disorders.”

PH94B, an investigational odorless pherine nasal spray, also has therapeutic potential in a wide range of additional anxiety disorders and phobias. In phase 2 clinical trials, PH94B was self-administered in microgram-level doses and produced rapid-onset anti-anxiety effects within approximately 15 minutes.

To help differentiate PH94B’s MOA from that of benzodiazepines, VistaGen studied whether PH94B had positive modulatory effects on GABA receptors. For example, one of the key results reported in the poster presentation included no significant effect on GABA potentiation at doses up to 10 micromolar when compared to the 300% potentiation induced by diazepam, a commonly benzodiazepine.

“Given the FDA’s recent Drug Safety Communication that outlined and highlighted the safety risks associated with benzodiazepine use, the implications resulting from this study are significant,” said Mark Smith, MD, PhD, Chief Medical Officer of VistaGen. “PH94B may have the potential to displace benzodiazepines altogether and become the safer alternative to help the millions of Americans suffering from anxiety with limited options for safe, effective treatment options. These existing treatments can actually hurt instead of help. We look forward to launching our Phase 3 clinical development program for PH94B next quarter and continuing to push forward in our mission to get it into the hands of those in need as soon as possible.”

Further publications on PH94B can be found 

1. Globe Newswire staff. VistaGen’s poster presentation at the Anxiety and Depression Association of America’s 2021 Annual Conference differentiates PH94B’s mechanism of action from highly-addictive benzodiazepines. VistaGen. March 22, 2021. 

https://ir.vistagen.com/press-releases/detail/166

This social anxiety disorder treatment does not directly activate gamma-amino butyric acid (GABA-A) receptors, setting it apart from benzodiazepines. 

A Potential Benzodiazepine Replacement

In what 5 ways can anxiety present in bipolar disorder? 

5 Types of Anxious Bipolar Disorder 

C. Addressing social problems like homelessness or incarceration

What is the most important contribution by peer support staff in mental health care? Take the quiz and learn more.

Mini Quiz: Peer Support and Mental Illness

Susan J. Noonan, MD, MPH, talks about how finding a community and sharing experiences can help people going through an episode. 

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)

. Dr Noonan offers peer counseling to fellow patients, including physicians and other professionals, and can be confidentially reached through her website at 

When dealing with a serious mental illness, speaking out and sharing common experiences can help healing. 

Living Through an Episode

The association between smoking cigarettes and the risk of developing serious and potentially fatal health problems (most notably cardiovascular diseases, pulmonary diseases, and cancer), has long been accepted fact. However, an additional health problem that may also be associated with smoking has often been overlooked: pain.

Two recent papers indicate a strong association between smoking and pain.

 Among the review’s important findings is that those who suffer from chronic pain are substantially more likely to smoke than are those who do not suffer from chronic pain. Although smoking rates continue to decline in the latter group, this does not appear to be occurring in those with pain.

Cigarette smoking has been cited as a risk factor for a wide variety of painful conditions, including back pain, 

, and diabetic peripheral neuropathy. Smoking appears to be associated with both the development and severity of pain.

The second paper specifically studied the most likely locations of pain among individuals who smoke. The 

 examined data from a 2003 to 2004 National Health and Nutrition Examination Survey, which contained data from comprehensive bodily pain questionnaires in addition to questions on other health issues, including tobacco use.

 The study compared 1054 participants who smoked tobacco with 1316 participants who did not.

Those who smoked were found to be more likely to suffer chronic pain. Although the likelihood of pain was increased throughout the body, the study found that spine pain, and especially low back pain, had the strongest association with smoking. The second strongest association was between 

 and smoking. Smoking was also associated with both trunk pain, which included the chest and abdomen, and limb pain. (All statistical associations were drawn from Smuck et al.

This is an interesting and perhaps an unexpected finding. Because of the association between smoking and cardiovascular and cerebrovascular problems, it is easy to see why headaches would be fairly common among individuals who smoke. However, it might be reasonably expected that pain in the trunk and 

 would be more common than pain in the spine. The authors suggest that vascular factors may play a greater role in back pain than is often thought.

, which are becoming more popular, are any less associated with pain than traditional cigarettes remains an unanswered question.

From personal experience treating patients with chronic pain who also smoke, I know that helping them with smoking cessation attempts can be challenging. Although most patients are often well aware of the risks associated with smoking, their pain and its impact on their lives may make it more difficult for them to quit. Their pain may make them feel restricted, and their ability to participate in previously enjoyable activities is limited. Smoking is among the few such activities in which they can still indulge. They may also feel that smoking helps them cope with the pain.

 may have some analgesic effects, but abstaining from smoking may 

 individuals to suffer hyperalgesia, a lowering of the pain threshold.

 Thus, those who smoke may receive temporary relief from tobacco use, and their pain may get worse when they try to stop.

Additionally, depression and anxiety are frequent 

 among those with chronic pain, and their presence can also contribute to the challenge of getting patients to stop smoking.

Ultimately, all evidence points to the importance of convincing patients with chronic pain who also smoke that tobacco is not helpful. Indeed, tobacco may be significantly exacerbating their pain and adding to their misery.

The multitude of challenges can understandably make it difficult to persuade patients with chronic pain to stop using tobacco. Unfortunately, only a 

 of studies have sought to investigate the best treatments for attaining this goal.

Although no single optimal treatment has yet been identified, it appears that while nicotine replacement therapy can be useful, the 

 that are most successful are those that address both the pain and the smoking using psychotherapeutic interventions.

 In this way, treating tobacco use disorder and comorbid chronic pain is similar to the treatment of pain and iatrogenic opioid use disorder, where both problems must be managed together to be successful in treating either.

Of course, this raises the important issue of who treats pain and how it is treated. (For more information on psychiatry and pain, see 

Psychiatric TimesTM November 2020 Special Report

For the most part, the management of chronic pain has been under the aegis of anesthesiology, followed by physiatry and neurology, with psychiatry far down the list. However, the order of these specialties would be reversed if we asked which is best able to aid in smoking cessation. One doubts that there are many anesthesiologists, physiatrists, or neurologists who have expertise in treating patients with nicotine addiction.

As a result, it is difficult for patients with chronic pain who smoke to find health care professionals qualified to treat both issues. If it appears to patients that smoking and pain are 2 separate problems that require different medical specialties to treat them, it may make it more difficult to convince them that the issues are actually entangled. Nonetheless, the evidence suggests that managing 1 issue may aid in managing the other.

This article was posted ahead of print on November 11, 2020, and has since been updated. -Ed

Pain, nicotine, and tobacco smoking: current state of the science

2. Smuck M, Schneider BJ, Ehsanian R, et al. 

Smoking is associated with pain in all body regions, with greatest influence on spinal pain

Nicotine deprivation increases pain intensity, neurogenic inflammation, and mechanical hyperalgesia among daily tobacco smokers

Nicotine withdrawal and stress-induced changes in pain sensitivity: a cross-sectional investigation between abstinent smokers and nonsmokers

Anxiety and depression in bidirectional relations between pain and smoking: implications for smoking cessation

A reciprocal model of pain and substance use: transdiagnostic considerations, clinical implications, and future directions

7. Hooten WM, LaRowe LR, Ditre JW, et al. 

Effects of a brief pain and smoking cessation intervention in adults with chronic pain: a randomized controlled trial

Two recent papers look at the subtle and surprising links between smoking and pain in different parts of the body. 

Pain and Smoking: Is There an Association?

Jodi Aman, LCSW, talks about dealing with young people who feel they cannot handle the obstacles in their path. 

has been a psychotherapist for 24 years, consulted individuals, couples, and families in Rochester NY, and all over the world.

Young people write a story about themselves being unable to accomplish things. It needs to be rewritten. 

Feeling Inadequate

Fabry disease is a rare genetic disorder, so rare that its psychiatric consequences remain poorly understood. Although there have been studies evaluating psychological and psychiatric issues among patients with Fabry disease, very little has been written about individuals challenged by the burdensome symptoms associated with the disease, or about the emotional distress that can result from living with a 

. It is crucial that health care providers are equipped to recognize potential psychological or psychiatric challenges and are able to refer patients with Fabry disease for an appropriate assessment. A better understanding of anxiety and depression in Fabry patients has important implications for health service planning, evaluation of therapeutic treatments, and clinical management.

Fabry disease is a pan-ethnic, X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (α-GAL); that results in the progressive accumulation of globotriaosylceramide, or Gb3.

 Classic Fabry disease mutations are seen in approximately 1:22,000 to 1:40,000 males, and atypical presentations are associated with about 1:1000 to 1:3000 males and 1:6000 to 1:40,000 females with a spectrum of phenotypes.

 Phenotypes vary from the classic phenotype, to a later-onset, predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Newborn screening (NBS) studies revealed frequencies of the classic and later-onset phenotypes of up to 1 in 22,570 males and 1 in 1390 males, respectively.

As Fabry disease progresses, it results in a multisystemic disease affecting the renal, cardiac, pulmonary, ocular, and dermal systems, as well as the peripheral and central nervous systems (CNS).

 Consequently, as substrate continues to build up, cellular dysfunction triggers organ impairment and eventually system damages. This can lead to substantial morbidity and 

, especially for patients who are untreated.

Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms. The effective management of Fabry disease requires a multidisciplinary approach. It can be treated with bimonthly infusions of enzyme replacement therapy (ERT) to replace deficient α-galactosidase A, oral chaperone therapy, conventional medical treatment, or adjunct therapies.

CNS involvement precipitates cerebral micro and macro angiopathy leading to 

 at an early age, with an estimated prevalence of 6.9% in male and 4.3% in female Fabry disease patients.

 CNS alterations reported include increased occurrence of white matter lesions (WML), dilation and tortuosity of the larger intracranial arteries, signal enhancement of the lateral pulvinar on T1 weighted images, and hippocampal atrophy.

 In non-Fabry cohorts, WMLs have frequently been related to processing speed, memory, and executive functioning deficits.

 In Fabry disease, cognitive deficits have been described primarily in attention, executive functions, and psychomotor performance.

Autopsy studies in Fabry disease patients have repeatedly shown severe globotriosylceramide (Gb3) accumulation in the neurons and ganglion cells of the hippocampus, which could ultimately lead to functional deterioration of the cells, compromised energy metabolism, oxidative stress, and cellular death.

 Gb3 deposition in Fabry disease is the result of the inherited reduction of α-Galactosidase and causes clinical manifestation in early childhood, with a slight delay in girls.

 Early accumulation of Gb3 in the lysosomes of cells and subsequent cellular death could thus be responsible for such early hippocampal atrophy, as observed in some studies. Neuropathic pain and major depression have also been shown to be strongly related to reduced hippocampal volume (HV) in otherwise healthy subjects.

 Given that pain and depression are frequent symptoms in Fabry disease, the impact of both on HV decline seems expected, but research is variable. Depressive symptoms naturally fluctuate over the course of time due to symptom variability and progression of the disease.

 Placebo-controlled studies are needed to address antidepressant treatment options in patients with Fabry disease, as 

 can be a major burden on the lives of patients and families.

In Fabry disease, the presence of substrate accumulation can be traced back to the prenatal period; however, symptoms generally do not develop before early childhood.

 Affected children may experience acute and chronic neuropathic pain, described as a burning sensation and tingling in the hands and feet (acroparesthesia). They may also present with sweating abnormalities (anhidrosis, hypohidrosis) that make it difficult to exercise and perform physical activities. Abdominal pain and diarrhea have also been reported. During adolescence, gastrointestinal problems may increase in severity and frequency, and proteinuria can become elevated. Fabry crisis, manifested as severe pain radiating from the hands and feet, may occur spontaneously as a response to various environmental conditions like heat, cold, 

, and fatigue. Swelling of the affected areas (lymphedema) and redness may also be present and are predictors of future heart and renal dysfunctions. Vascular skin lesions (angiokeratomas) can appear, clustering around the umbilicus and swim trunk areas. With advancing age, patients may present with respiratory problems, cardiac and cerebrovascular manifestations, and 

 or tinnitus. Late disease is characterized by life-threatening renal failure, stroke, and severe cardiac problems.

Depression is common and underdiagnosed in Fabry disease. Previous research found that 60% of the patients enrolled in a study presented with clinical depression compared to healthy controls.

 Overall, depression is by far the most frequently reported psychiatric complication of Fabry disease, ranging from 15% to 62.5% in all series. Despite its prevalence, depression is not often discussed at clinic visits (

). Although depression and anxiety are often reported, referrals to psychologists or psychiatrists are limited, and mental health professionals are rarely involved as part of the care team.

Studies past and present have indicated that depressive symptoms in Fabry disease can be related to pain as well as social factors, including economic status.

 Conversely, the relationship between depressive symptoms and renal, cardiac, or cerebral involvement is generally less prominent; subjective health perception plays a more active role.

Differences in coping might influence the psychological well-being of Fabry patients. In a recent study, it was found that coping styles that involve avoiding emotional distress led to more depressive symptoms, while positivity and problem solving led to less depressive symptoms.

 Given the chronic multisystemic manifestations—pain, lack of sleep, and crippling fatigue—it would be extraordinary if individuals living with Fabry disease did not have to manage any psychological challenges.

Determining the importance of different factors related to depressive symptoms can aid in the identification of patients at risk and act as a starting point for specific psychological interventions to prevent or treat depressive symptoms.

Importance of Psychological and Psychiatric Evaluation

Over the past 20 years of working with patients diagnosed with Fabry disease, it has been troubling to see that common themes of depression, 

, uncertainty, and frustration are often reported before interventions for psychological difficulties are considered. In my practice, it is apparent that many individuals living with chronic conditions find it difficult to advocate for themselves. During an appointment, patients may report that they are exhausted, misunderstood, or cannot face being judged if they mention that they experience depression or anxiety. Patients often worry that telling their health care provider that they are depressed or anxious may require an additional appointment, causing them to feel overburdened. This discouragement can result in feelings of self-doubt, anger, and fear that serve to worsen depression. Also, depression associated with a chronic medical illness often aggravates the condition, especially if the illness causes pain and fatigue, or limits the ability to interact with others.

It is critical that patients with Fabry disease have the support and resources they need to understand the physical manifestations and the psychological challenges that the condition can cause. Building a broader understanding of these issues can improve quality of life, as patients no longer have to define themselves by their illness. Learning how to process and explore these issues can provide a normalizing and gratifying opportunity to be happier and enjoy more success.

There are many steps a care team can take to screen for psychological issues. Primary care encounters are often the only opportunities for patients with Fabry disease to address emotional challenges and obtain the professional attention they require. For clinicians, forging empathetic partnerships with patients, prescribing appropriate treatments, and closely monitoring symptoms and therapeutic progress are invaluable for optimal management of both affective and medical disorders.

Cognitive behavioral therapy is often considered the most effective therapy for depression and anxiety. If patients are continuously thinking about negative outcomes, they begin to have a generalized feeling of hopelessness that can lead to a depressed or anxious mood. It can be beneficial for health care providers to help patients with Fabry explore ways to manage the disease. The common approach is to challenge negative thoughts and prompt the patient to explain the basis of their negative health perceptions.

Behavioral activation is just as important as the cognitive components of therapy. To help improve mood, patients should be encouraged to set goals and regularly partake in activities that they enjoy. In addition, many patients with depression and anxiety feel empowered when they can help choose the treatment approach used to manage their disease. Having a role in deciding how treatment is approached can also help support adherence, which is critical when coping with severe symptoms.

While data on the impact of depression treatment for patients with Fabry disease are limited, a recent pilot study examined the effects of psychological counseling on depression, adaptive functioning (AF), quality of life (QOL), and subjective pain experience. Subjects completed 6 months of in-person or telecounseling with the same health psychologist, followed by 6 months without counseling. Self-report measures of depression, AF, QOL, and subjective pain were completed every 3 months. All subjects experienced improvements in depression, which were sustained during the follow-up period.

 Study findings support the efficacy of psychological treatment for depression in individuals with Fabry disease, with additional benefits achieved when health psychologists aligned closely with lysosomal storage disease treatment centers in the patient management continuum.

Patients with depression and chronic illnesses such as Fabry disease are challenging to treat, but they are exactly the type of patient that can benefit from expert care.

 A growing body of evidence supports the view that chronic medical conditions and depression are interrelated. Collaborative care for psychological challenges is a treatment model that uses a multimodal, biopsychosocial, structured, evidence-based approach, involving nonmedical specialists. It is critical that care teams work with patients to develop a shared definition of potential issues, provide education and support, target treatment goals, develop a specific treatment plan, and provide follow-up.

is a pediatric neuropsychologist with specialized training and expertise in rare genetic and neurodegenerative diseases. She served as faculty at the University of Minnesota and at the University of Colorado-Denver/Children’s Hospital Colorado where she participated in the neurometabolic, neurogenetic and neuromuscular clinic care teams. Dr Bjoraker is known nationally and internationally for her expertise in lysosomal storage diseases and other inborn errors of metabolism and neurodegenerative diseases. She is a presenter and researcher with extended publications in rare genetic diseases and experience in clinical trial development. Dr Bjoraker is also a consultant in Minneapolis, Minnesota.

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A rare genetic disorder may have unrecognized psychological consequences. 

Don’t Forget About Fabry Disease  

Stress is one of the biggest mental health issues facing Americans today. But what is stress, exactly, and how should it be treated? In this Mental Health Minute, Teralyn Sell, PhD, distinguishes between 3 kinds of stress and talks about what can (or cannot) be done about each of them.

 holds a doctorate in psychology and is the founder of Pro Recovery Rx, a supplement line dedicated to supporting brain health for individuals in addiction recovery. She also teaches a class called NeuroHealth Coach, which helps professionals integrate brain health into their daily lives.

How do you help patients understand and handle their stress? 

Share comments with your colleagues by emailing 

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

Not all stressors are alike—and different types require different treatments. 

What Are the 3 Kinds of Stress?

When hoarding disorder is suspected, it is important to assess for other psychiatric disorders that may affect the presentation and treatment of symptoms. Find out more in this quiz.

Anxiety & Stress Disorders