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Esketamine bests quetiapine for severe depression in head-to-head trial
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
AT ECNP 2023
Zuranolone: FAQs for clinicians and patients
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
Running vs. meds for depression: Is there a clear winner?
BARCELONA – However, running provides greater physical health benefits while adherence is greater with drug treatment.
“Both interventions helped with the depression to around the same extent,” study presenter Brenda W.J.H. Penninx, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam said in a release.
However, medication “generally had worse impact on body weight, heart rate variability, and blood pressure, whereas running therapy led to improved effect on general fitness and heart rate,” Dr. Penninx added.
The findings were presented at the annual congress of the European College of Neuropsychopharmacology and recently published in the Journal of Affective Disorders.
Research gap
Previous research suggests exercise interventions can have a therapeutic effect equivalent to antidepressants, but their impact on physical health has been “poorly examined in a psychiatric population, the investigators note.
The authors note that depressive and anxiety disorders “cause immense suffering by compromising both mental and physical health,” and the need for effective treatments is “pressing.”
Although antidepressant medication is considered a “standard first-line treatment” alongside psychotherapy, the drugs are “not effective for all and [are] often associated with side effects.”
The Mood Treatment with Antidepressant or Running (MOTAR) study was a partially randomized pragmatic trial in adults with depression and/or anxiety disorder, as determined using the DSM-IV algorithms with the Composite International Diagnostic Interview (CIDI).
The 16-week intervention study included 141 patients with depression and/or anxiety. The mean age was 38.2 years and 58% were women. Participants were offered a choice of treatment: 16 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) or a 16-week group-based running therapy.
Patients without a strong preference for treatment allocation were randomly assigned to either antidepressant medication or running therapy, while those unwilling to be randomized were allocated to their preferred intervention.
A total of 22 patients were randomly assigned to receive antidepressant treatment and 13 to running therapy. A total of 36 participants chose antidepressant treatment, while 83 chose the running therapy.
Running therapy involved 16 weeks of supervised 45-minute outdoor running sessions to a target of two to three sessions per week, in line with U.S. Centers for Disease Control and Prevention/American College of Sports Medicine recommendations.
Physical health benefits
Treatment adherence in the antidepressant group, defined as still using treatment at the posttreatment assessment, was 82.2% vs. 52.1% among running therapy participants, where adherence was specified as completing more than 22 sessions.
Remission was defined as no longer meeting the criteria of a current depressive or anxiety disorder via CIDI at week 16.
On intention-to-treat analysis, this requirement was met by 44.8% of patients taking antidepressants and 43.3% of those in the running therapy group (P = .88).
However, running therapy patients showed significant improvements in weight (P = .001), waist circumference (P = .011), systolic and diastolic blood pressure (P = .011 and P = .002, respectively), heart rate (P = .033), and heart rate variability (P = .006).
The investigators note the more favorable physical health changes in the running therapy group were attributable to “larger improvements in the running therapy group but also due to larger deterioration in the antidepressant group.”
Antidepressants are generally safe and effective and work for most people, said Dr. Penninx. She also noted that untreated depression leads to worse outcomes, so “antidepressants are generally a good choice.”
Nevertheless, she said, “we need to extend our treatment arsenal as not all patients respond to antidepressants or are willing to take them.”
The study’s results, she added, suggest that “implementing exercise therapy is something we should take much more seriously, as it could be a good, and maybe even better, choice for some of our patients.”
Francesca Cirulli, PhD, senior researcher and group leader at the National Institute of Health, Rome, said in an interview that the study is notable because it is one of the first to prospectively measure the effects of antidepressants and running on physical health.
Dr. Cirulli suggested that running therapy could be tried ahead of treatment with antidepressants if patients prefer physical exercise and can adhere to it. However, she said, the findings also suggest that an increase in physical activity should accompany treatment with antidepressant medications.
Overall, Dr. Cirulli said “the message should not be that everyone can be helped by running and antidepressants are bad,” but rather “these are both helpful, but not excellent, interventions against depression.”
‘Important limitations’
In a comment, Eduard Vieta, MD, PhD, chair of the department of psychiatry and psychology at the University of Barcelona Hospital Clinic, noted the study has “very important limitations.”
Among the limitations: the inclusion of nonrandomized patients who received the treatment of their choice, causing obvious bias and the “lack of binding and power issues” over the number of patients enrolled.
Dr. Vieta also said that the results “seem obvious, because it is known that exercise improves physical health.”
The trial therefore shows, “if you can find people who are able to do exercise while depressed and adhere to it, those would benefit from that practice,” he noted.
Also commenting on the research, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said the results are confirmatory and “again show physical health can influence mental health.”
However, Dr. Ruhe underlined, while it is “common practice” to allow patients to follow their treatment preference and is “understandable from a pragmatic point of view,” the group comparison may be “biased,” compared with a “truly randomized study.”
“For example, patients in the antidepressant group were more depressed, which might be associated with less chance of persisting engagement in the exercises,” he said. “So, we have to be careful not to overinterpret the comparisons between groups, which the authors acknowledge properly.”
Turning to the difference in adherence between the two interventions, Dr. Ruhe said the results show adopting, and adhering to, a lifestyle habit is more difficult than taking a pill.
“This is not exclusively found in psychiatry, indicating that we also have to focus on how to improve compliance to healthy behavior. This could have tremendous impact on health care more generally, but also on psychiatric diseases,” Dr. Ruhe said.
The MOTAR study was funded by a NWO-VICI grant. Funding for the inflammatory markers was provided by ZonMw: The Netherlands Organization for Health Research and Development. The study authors and clinicians interviewed for this story declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
BARCELONA – However, running provides greater physical health benefits while adherence is greater with drug treatment.
“Both interventions helped with the depression to around the same extent,” study presenter Brenda W.J.H. Penninx, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam said in a release.
However, medication “generally had worse impact on body weight, heart rate variability, and blood pressure, whereas running therapy led to improved effect on general fitness and heart rate,” Dr. Penninx added.
The findings were presented at the annual congress of the European College of Neuropsychopharmacology and recently published in the Journal of Affective Disorders.
Research gap
Previous research suggests exercise interventions can have a therapeutic effect equivalent to antidepressants, but their impact on physical health has been “poorly examined in a psychiatric population, the investigators note.
The authors note that depressive and anxiety disorders “cause immense suffering by compromising both mental and physical health,” and the need for effective treatments is “pressing.”
Although antidepressant medication is considered a “standard first-line treatment” alongside psychotherapy, the drugs are “not effective for all and [are] often associated with side effects.”
The Mood Treatment with Antidepressant or Running (MOTAR) study was a partially randomized pragmatic trial in adults with depression and/or anxiety disorder, as determined using the DSM-IV algorithms with the Composite International Diagnostic Interview (CIDI).
The 16-week intervention study included 141 patients with depression and/or anxiety. The mean age was 38.2 years and 58% were women. Participants were offered a choice of treatment: 16 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) or a 16-week group-based running therapy.
Patients without a strong preference for treatment allocation were randomly assigned to either antidepressant medication or running therapy, while those unwilling to be randomized were allocated to their preferred intervention.
A total of 22 patients were randomly assigned to receive antidepressant treatment and 13 to running therapy. A total of 36 participants chose antidepressant treatment, while 83 chose the running therapy.
Running therapy involved 16 weeks of supervised 45-minute outdoor running sessions to a target of two to three sessions per week, in line with U.S. Centers for Disease Control and Prevention/American College of Sports Medicine recommendations.
Physical health benefits
Treatment adherence in the antidepressant group, defined as still using treatment at the posttreatment assessment, was 82.2% vs. 52.1% among running therapy participants, where adherence was specified as completing more than 22 sessions.
Remission was defined as no longer meeting the criteria of a current depressive or anxiety disorder via CIDI at week 16.
On intention-to-treat analysis, this requirement was met by 44.8% of patients taking antidepressants and 43.3% of those in the running therapy group (P = .88).
However, running therapy patients showed significant improvements in weight (P = .001), waist circumference (P = .011), systolic and diastolic blood pressure (P = .011 and P = .002, respectively), heart rate (P = .033), and heart rate variability (P = .006).
The investigators note the more favorable physical health changes in the running therapy group were attributable to “larger improvements in the running therapy group but also due to larger deterioration in the antidepressant group.”
Antidepressants are generally safe and effective and work for most people, said Dr. Penninx. She also noted that untreated depression leads to worse outcomes, so “antidepressants are generally a good choice.”
Nevertheless, she said, “we need to extend our treatment arsenal as not all patients respond to antidepressants or are willing to take them.”
The study’s results, she added, suggest that “implementing exercise therapy is something we should take much more seriously, as it could be a good, and maybe even better, choice for some of our patients.”
Francesca Cirulli, PhD, senior researcher and group leader at the National Institute of Health, Rome, said in an interview that the study is notable because it is one of the first to prospectively measure the effects of antidepressants and running on physical health.
Dr. Cirulli suggested that running therapy could be tried ahead of treatment with antidepressants if patients prefer physical exercise and can adhere to it. However, she said, the findings also suggest that an increase in physical activity should accompany treatment with antidepressant medications.
Overall, Dr. Cirulli said “the message should not be that everyone can be helped by running and antidepressants are bad,” but rather “these are both helpful, but not excellent, interventions against depression.”
‘Important limitations’
In a comment, Eduard Vieta, MD, PhD, chair of the department of psychiatry and psychology at the University of Barcelona Hospital Clinic, noted the study has “very important limitations.”
Among the limitations: the inclusion of nonrandomized patients who received the treatment of their choice, causing obvious bias and the “lack of binding and power issues” over the number of patients enrolled.
Dr. Vieta also said that the results “seem obvious, because it is known that exercise improves physical health.”
The trial therefore shows, “if you can find people who are able to do exercise while depressed and adhere to it, those would benefit from that practice,” he noted.
Also commenting on the research, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said the results are confirmatory and “again show physical health can influence mental health.”
However, Dr. Ruhe underlined, while it is “common practice” to allow patients to follow their treatment preference and is “understandable from a pragmatic point of view,” the group comparison may be “biased,” compared with a “truly randomized study.”
“For example, patients in the antidepressant group were more depressed, which might be associated with less chance of persisting engagement in the exercises,” he said. “So, we have to be careful not to overinterpret the comparisons between groups, which the authors acknowledge properly.”
Turning to the difference in adherence between the two interventions, Dr. Ruhe said the results show adopting, and adhering to, a lifestyle habit is more difficult than taking a pill.
“This is not exclusively found in psychiatry, indicating that we also have to focus on how to improve compliance to healthy behavior. This could have tremendous impact on health care more generally, but also on psychiatric diseases,” Dr. Ruhe said.
The MOTAR study was funded by a NWO-VICI grant. Funding for the inflammatory markers was provided by ZonMw: The Netherlands Organization for Health Research and Development. The study authors and clinicians interviewed for this story declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
BARCELONA – However, running provides greater physical health benefits while adherence is greater with drug treatment.
“Both interventions helped with the depression to around the same extent,” study presenter Brenda W.J.H. Penninx, PhD, professor of psychiatric epidemiology at the VU University Medical Center in Amsterdam said in a release.
However, medication “generally had worse impact on body weight, heart rate variability, and blood pressure, whereas running therapy led to improved effect on general fitness and heart rate,” Dr. Penninx added.
The findings were presented at the annual congress of the European College of Neuropsychopharmacology and recently published in the Journal of Affective Disorders.
Research gap
Previous research suggests exercise interventions can have a therapeutic effect equivalent to antidepressants, but their impact on physical health has been “poorly examined in a psychiatric population, the investigators note.
The authors note that depressive and anxiety disorders “cause immense suffering by compromising both mental and physical health,” and the need for effective treatments is “pressing.”
Although antidepressant medication is considered a “standard first-line treatment” alongside psychotherapy, the drugs are “not effective for all and [are] often associated with side effects.”
The Mood Treatment with Antidepressant or Running (MOTAR) study was a partially randomized pragmatic trial in adults with depression and/or anxiety disorder, as determined using the DSM-IV algorithms with the Composite International Diagnostic Interview (CIDI).
The 16-week intervention study included 141 patients with depression and/or anxiety. The mean age was 38.2 years and 58% were women. Participants were offered a choice of treatment: 16 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram (Lexapro) or a 16-week group-based running therapy.
Patients without a strong preference for treatment allocation were randomly assigned to either antidepressant medication or running therapy, while those unwilling to be randomized were allocated to their preferred intervention.
A total of 22 patients were randomly assigned to receive antidepressant treatment and 13 to running therapy. A total of 36 participants chose antidepressant treatment, while 83 chose the running therapy.
Running therapy involved 16 weeks of supervised 45-minute outdoor running sessions to a target of two to three sessions per week, in line with U.S. Centers for Disease Control and Prevention/American College of Sports Medicine recommendations.
Physical health benefits
Treatment adherence in the antidepressant group, defined as still using treatment at the posttreatment assessment, was 82.2% vs. 52.1% among running therapy participants, where adherence was specified as completing more than 22 sessions.
Remission was defined as no longer meeting the criteria of a current depressive or anxiety disorder via CIDI at week 16.
On intention-to-treat analysis, this requirement was met by 44.8% of patients taking antidepressants and 43.3% of those in the running therapy group (P = .88).
However, running therapy patients showed significant improvements in weight (P = .001), waist circumference (P = .011), systolic and diastolic blood pressure (P = .011 and P = .002, respectively), heart rate (P = .033), and heart rate variability (P = .006).
The investigators note the more favorable physical health changes in the running therapy group were attributable to “larger improvements in the running therapy group but also due to larger deterioration in the antidepressant group.”
Antidepressants are generally safe and effective and work for most people, said Dr. Penninx. She also noted that untreated depression leads to worse outcomes, so “antidepressants are generally a good choice.”
Nevertheless, she said, “we need to extend our treatment arsenal as not all patients respond to antidepressants or are willing to take them.”
The study’s results, she added, suggest that “implementing exercise therapy is something we should take much more seriously, as it could be a good, and maybe even better, choice for some of our patients.”
Francesca Cirulli, PhD, senior researcher and group leader at the National Institute of Health, Rome, said in an interview that the study is notable because it is one of the first to prospectively measure the effects of antidepressants and running on physical health.
Dr. Cirulli suggested that running therapy could be tried ahead of treatment with antidepressants if patients prefer physical exercise and can adhere to it. However, she said, the findings also suggest that an increase in physical activity should accompany treatment with antidepressant medications.
Overall, Dr. Cirulli said “the message should not be that everyone can be helped by running and antidepressants are bad,” but rather “these are both helpful, but not excellent, interventions against depression.”
‘Important limitations’
In a comment, Eduard Vieta, MD, PhD, chair of the department of psychiatry and psychology at the University of Barcelona Hospital Clinic, noted the study has “very important limitations.”
Among the limitations: the inclusion of nonrandomized patients who received the treatment of their choice, causing obvious bias and the “lack of binding and power issues” over the number of patients enrolled.
Dr. Vieta also said that the results “seem obvious, because it is known that exercise improves physical health.”
The trial therefore shows, “if you can find people who are able to do exercise while depressed and adhere to it, those would benefit from that practice,” he noted.
Also commenting on the research, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said the results are confirmatory and “again show physical health can influence mental health.”
However, Dr. Ruhe underlined, while it is “common practice” to allow patients to follow their treatment preference and is “understandable from a pragmatic point of view,” the group comparison may be “biased,” compared with a “truly randomized study.”
“For example, patients in the antidepressant group were more depressed, which might be associated with less chance of persisting engagement in the exercises,” he said. “So, we have to be careful not to overinterpret the comparisons between groups, which the authors acknowledge properly.”
Turning to the difference in adherence between the two interventions, Dr. Ruhe said the results show adopting, and adhering to, a lifestyle habit is more difficult than taking a pill.
“This is not exclusively found in psychiatry, indicating that we also have to focus on how to improve compliance to healthy behavior. This could have tremendous impact on health care more generally, but also on psychiatric diseases,” Dr. Ruhe said.
The MOTAR study was funded by a NWO-VICI grant. Funding for the inflammatory markers was provided by ZonMw: The Netherlands Organization for Health Research and Development. The study authors and clinicians interviewed for this story declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ECNP 2023
Burnout in medical profession higher among women, younger clinicians
The poster child for a burned-out physician is a young woman practicing in primary care, according to a new study of more than 1,300 clinicians.
The study, published in JAMA Network Open. investigated patterns in physician burnout among 1,373 physicians at Massachusetts General Physicians Organization, a hospital-owned group practice. It assessed burnout in 3 years: 2017, 2019, and 2021.
Respondents were queried about their satisfaction with their career and compensation, as well as their well-being, administrative workload, and leadership and diversity.
Female physicians exhibited a higher burnout rate than male physicians (odds ratio, 1.47; 95% confidence interval, 1.02-2.12), while among primary care physicians (PCPs), the burnout rate was almost three times higher than among those in internal medicine (OR, 2.82; 95% CI, 1.76-4.50). Among physicians with 30 or more years of experience, the burnout rate was lower than among those with 10 years of experience or less (OR, 0.21; 95% CI, 0.13-0.35).
The fact that burnout disproportionately affects female physicians could reflect the additional household and family obligations women are often expected to handle, as well as their desire to form relationships with their patients, according to Timothy Hoff, PhD, a professor of management, healthcare systems, and health policy at Northeastern University, Boston.
“Female physicians tend to practice differently than their male counterparts,” said Dr. Hoff, who studies primary care. “They may focus more on the relational aspects of care, and that could lead to a higher rate of burnout.”
The study used the Maslach Burnout Inventory and three burnout subscales: exhaustion, cynicism, and reduced personal efficacy. The cohort was composed of 50% men, 67% White respondents, and 87% non-Hispanic respondents. A little over two-thirds of physicians had from 11 to 20 years of experience.
About 93% of those surveyed responded; by comparison, response rates were between 27% and 32% in previous analyses of physician burnout, the study authors say. They attribute this high participation rate to the fact that they compensated each participant with $850, more than is usually offered.
Hilton Gomes, MD, a partner at a concierge primary care practice in Miami – who has been practicing medicine for more than 15 years – said the increased rates of burnout among his younger colleagues are partly the result of a recent shift in what is considered the ideal work-life balance.
“Younger generations of doctors enter the profession with a strong desire for a better work-life balance. Unfortunately, medicine does not typically lend itself to achieving this balance,” he said.
Dr. Gomes recalled a time in medical school when he tried to visit his former pediatrician, who couldn’t be found at home.
“His wife informed me that he was tending to an urgent sick visit at the hospital, while his wife had to deal with their own grandson’s fracture being treated at urgent care,” Dr. Gomes said. “This illustrates, in my experience, how older generations of physicians accepted the demands of the profession as part of their commitment, and this often involved putting our own families second.”
Dr. Gomes, like many other PCPs who have converted to concierge medicine, previously worked at a practice where he saw nearly two dozen patients a day for a maximum of 15 minutes each.
“The structure of managed care often results in primary care physicians spending less time with patients and more time on paperwork, which is not the reason why physicians enter the field of medicine,” Dr. Gomes said.
Physicians are not alone in their feelings of physical and mental exhaustion. In the Medscape Physician Assistant Burnout Report 2023, 16% of respondents said the burnout they experienced was so severe that they were thinking of leaving medicine.
In 2022, PCP burnout cost the United States $260 million in excess health care expenditures. Burnout has also increased rates of physician suicide over the past 50 years and has led to a rise in medical errors.
Physicians say that programs that teach them to perform yoga and take deep breaths – which are offered by their employers – are not the solution.
“We sort of know what the realities of physician burnout are now; the imperative is to address it,” Dr. Hoff said. “We need studies that focus on the concepts of sustainability.”
The study was funded by the Massachusetts General Physicians Organization. A coauthor reports receiving a grant from the American Heart Association. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
The poster child for a burned-out physician is a young woman practicing in primary care, according to a new study of more than 1,300 clinicians.
The study, published in JAMA Network Open. investigated patterns in physician burnout among 1,373 physicians at Massachusetts General Physicians Organization, a hospital-owned group practice. It assessed burnout in 3 years: 2017, 2019, and 2021.
Respondents were queried about their satisfaction with their career and compensation, as well as their well-being, administrative workload, and leadership and diversity.
Female physicians exhibited a higher burnout rate than male physicians (odds ratio, 1.47; 95% confidence interval, 1.02-2.12), while among primary care physicians (PCPs), the burnout rate was almost three times higher than among those in internal medicine (OR, 2.82; 95% CI, 1.76-4.50). Among physicians with 30 or more years of experience, the burnout rate was lower than among those with 10 years of experience or less (OR, 0.21; 95% CI, 0.13-0.35).
The fact that burnout disproportionately affects female physicians could reflect the additional household and family obligations women are often expected to handle, as well as their desire to form relationships with their patients, according to Timothy Hoff, PhD, a professor of management, healthcare systems, and health policy at Northeastern University, Boston.
“Female physicians tend to practice differently than their male counterparts,” said Dr. Hoff, who studies primary care. “They may focus more on the relational aspects of care, and that could lead to a higher rate of burnout.”
The study used the Maslach Burnout Inventory and three burnout subscales: exhaustion, cynicism, and reduced personal efficacy. The cohort was composed of 50% men, 67% White respondents, and 87% non-Hispanic respondents. A little over two-thirds of physicians had from 11 to 20 years of experience.
About 93% of those surveyed responded; by comparison, response rates were between 27% and 32% in previous analyses of physician burnout, the study authors say. They attribute this high participation rate to the fact that they compensated each participant with $850, more than is usually offered.
Hilton Gomes, MD, a partner at a concierge primary care practice in Miami – who has been practicing medicine for more than 15 years – said the increased rates of burnout among his younger colleagues are partly the result of a recent shift in what is considered the ideal work-life balance.
“Younger generations of doctors enter the profession with a strong desire for a better work-life balance. Unfortunately, medicine does not typically lend itself to achieving this balance,” he said.
Dr. Gomes recalled a time in medical school when he tried to visit his former pediatrician, who couldn’t be found at home.
“His wife informed me that he was tending to an urgent sick visit at the hospital, while his wife had to deal with their own grandson’s fracture being treated at urgent care,” Dr. Gomes said. “This illustrates, in my experience, how older generations of physicians accepted the demands of the profession as part of their commitment, and this often involved putting our own families second.”
Dr. Gomes, like many other PCPs who have converted to concierge medicine, previously worked at a practice where he saw nearly two dozen patients a day for a maximum of 15 minutes each.
“The structure of managed care often results in primary care physicians spending less time with patients and more time on paperwork, which is not the reason why physicians enter the field of medicine,” Dr. Gomes said.
Physicians are not alone in their feelings of physical and mental exhaustion. In the Medscape Physician Assistant Burnout Report 2023, 16% of respondents said the burnout they experienced was so severe that they were thinking of leaving medicine.
In 2022, PCP burnout cost the United States $260 million in excess health care expenditures. Burnout has also increased rates of physician suicide over the past 50 years and has led to a rise in medical errors.
Physicians say that programs that teach them to perform yoga and take deep breaths – which are offered by their employers – are not the solution.
“We sort of know what the realities of physician burnout are now; the imperative is to address it,” Dr. Hoff said. “We need studies that focus on the concepts of sustainability.”
The study was funded by the Massachusetts General Physicians Organization. A coauthor reports receiving a grant from the American Heart Association. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
The poster child for a burned-out physician is a young woman practicing in primary care, according to a new study of more than 1,300 clinicians.
The study, published in JAMA Network Open. investigated patterns in physician burnout among 1,373 physicians at Massachusetts General Physicians Organization, a hospital-owned group practice. It assessed burnout in 3 years: 2017, 2019, and 2021.
Respondents were queried about their satisfaction with their career and compensation, as well as their well-being, administrative workload, and leadership and diversity.
Female physicians exhibited a higher burnout rate than male physicians (odds ratio, 1.47; 95% confidence interval, 1.02-2.12), while among primary care physicians (PCPs), the burnout rate was almost three times higher than among those in internal medicine (OR, 2.82; 95% CI, 1.76-4.50). Among physicians with 30 or more years of experience, the burnout rate was lower than among those with 10 years of experience or less (OR, 0.21; 95% CI, 0.13-0.35).
The fact that burnout disproportionately affects female physicians could reflect the additional household and family obligations women are often expected to handle, as well as their desire to form relationships with their patients, according to Timothy Hoff, PhD, a professor of management, healthcare systems, and health policy at Northeastern University, Boston.
“Female physicians tend to practice differently than their male counterparts,” said Dr. Hoff, who studies primary care. “They may focus more on the relational aspects of care, and that could lead to a higher rate of burnout.”
The study used the Maslach Burnout Inventory and three burnout subscales: exhaustion, cynicism, and reduced personal efficacy. The cohort was composed of 50% men, 67% White respondents, and 87% non-Hispanic respondents. A little over two-thirds of physicians had from 11 to 20 years of experience.
About 93% of those surveyed responded; by comparison, response rates were between 27% and 32% in previous analyses of physician burnout, the study authors say. They attribute this high participation rate to the fact that they compensated each participant with $850, more than is usually offered.
Hilton Gomes, MD, a partner at a concierge primary care practice in Miami – who has been practicing medicine for more than 15 years – said the increased rates of burnout among his younger colleagues are partly the result of a recent shift in what is considered the ideal work-life balance.
“Younger generations of doctors enter the profession with a strong desire for a better work-life balance. Unfortunately, medicine does not typically lend itself to achieving this balance,” he said.
Dr. Gomes recalled a time in medical school when he tried to visit his former pediatrician, who couldn’t be found at home.
“His wife informed me that he was tending to an urgent sick visit at the hospital, while his wife had to deal with their own grandson’s fracture being treated at urgent care,” Dr. Gomes said. “This illustrates, in my experience, how older generations of physicians accepted the demands of the profession as part of their commitment, and this often involved putting our own families second.”
Dr. Gomes, like many other PCPs who have converted to concierge medicine, previously worked at a practice where he saw nearly two dozen patients a day for a maximum of 15 minutes each.
“The structure of managed care often results in primary care physicians spending less time with patients and more time on paperwork, which is not the reason why physicians enter the field of medicine,” Dr. Gomes said.
Physicians are not alone in their feelings of physical and mental exhaustion. In the Medscape Physician Assistant Burnout Report 2023, 16% of respondents said the burnout they experienced was so severe that they were thinking of leaving medicine.
In 2022, PCP burnout cost the United States $260 million in excess health care expenditures. Burnout has also increased rates of physician suicide over the past 50 years and has led to a rise in medical errors.
Physicians say that programs that teach them to perform yoga and take deep breaths – which are offered by their employers – are not the solution.
“We sort of know what the realities of physician burnout are now; the imperative is to address it,” Dr. Hoff said. “We need studies that focus on the concepts of sustainability.”
The study was funded by the Massachusetts General Physicians Organization. A coauthor reports receiving a grant from the American Heart Association. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Depression tied to higher all-cause and cardiovascular mortality
In a large prospective study, a graded higher risk of all-cause mortality and mortality from cardiovascular disease (CVD) and ischemic heart disease (IHD) emerged in adults with moderate to severe depressive symptoms, compared with those with no such symptoms.
Participants with mild depressive symptoms had a 35%-49% higher risk of all-cause and CVD mortality, respectively, while for those with moderate to severe depressive symptoms, the risk of all-cause, CVD, and IHD mortality was 62%, 79%, and 121% higher, respectively.
“This information highlights the importance for clinicians to identify patients with depressive symptoms and help them engage in treatment,” lead author Zefeng Zhang, MD, PhD, of the division for heart disease and stroke prevention at the U.S. Centers for Disease Control and Prevention, Atlanta, said in an interview.
The study appears in JAMA Network Open.
A nonclassic risk factor for CVD death
This graded positive association between depressive symptoms and CVD death was observed in data from the National Health and Nutrition Examination Survey 2005-2018, which were linked with the National Death Index through 2019 for adults aged 20 and older. Data analysis occurred from March 1 to May 26, 2023. According to the authors, their analyses extend findings from previous research by assessing these associations in a large, diverse, and nationally representative sample. Using more nuanced CVD-related causes of death, depressive symptoms emerged as a nontraditional risk factor for CVD mortality.
The study
In a total cohort of 23,694, about half male, mean overall age 44.7 years, prevalences of mild and moderate to severe depression were 14.9% and 7.2%, respectively, with depressive symptoms assessed by the nine-item Patient Health Questionnaire asking about symptoms over the past 2 weeks.
Adults with depression had significantly lower CV health scores in six of the American Heart Association Life’s Essential 8 metrics for heart health. For all-cause mortality, hazard ratios were 1.35 (95% confidence interval, 1.07-1.72) for mild depressive symptoms vs. none and 1.62 (95% CI, 1.24-2.12) for moderate to severe depressive symptoms vs. none.
The corresponding hazard ratios were 1.49 (95% CI, 1.11-2.0) and 1.79 (95% CI,1.22-2.62) for CVD mortality and 0.96 (95% CI, 0.58-1.60) and 2.21 (95% CI, 1.24-3.91) for IHD death, with associations largely consistent across subgroups.
At the highest severity of depressive symptoms (almost daily for past 2 weeks), feeling tired or having little energy, poor appetite or overeating, and having little interest in doing things were significantly associated with all-cause and CVD mortality after adjusting for potential confounders.
Approximately 11%-16% of the positive associations could be explained by lifestyle factors such as excess alcohol consumption, overeating, and inactivity as per the AHA’s Life’s Essential 8 metrics.
“Taken together with the body of literature on associations between depression and CVD mortality, these findings can support public health efforts to develop a comprehensive, nationwide strategy to improve well-being, including both mental and cardiovascular health,” Dr. Zhang and associates wrote.
This research was funded by the U.S. Centers for Disease Control and Prevention. The authors had no conflicts of interest to disclose.
In a large prospective study, a graded higher risk of all-cause mortality and mortality from cardiovascular disease (CVD) and ischemic heart disease (IHD) emerged in adults with moderate to severe depressive symptoms, compared with those with no such symptoms.
Participants with mild depressive symptoms had a 35%-49% higher risk of all-cause and CVD mortality, respectively, while for those with moderate to severe depressive symptoms, the risk of all-cause, CVD, and IHD mortality was 62%, 79%, and 121% higher, respectively.
“This information highlights the importance for clinicians to identify patients with depressive symptoms and help them engage in treatment,” lead author Zefeng Zhang, MD, PhD, of the division for heart disease and stroke prevention at the U.S. Centers for Disease Control and Prevention, Atlanta, said in an interview.
The study appears in JAMA Network Open.
A nonclassic risk factor for CVD death
This graded positive association between depressive symptoms and CVD death was observed in data from the National Health and Nutrition Examination Survey 2005-2018, which were linked with the National Death Index through 2019 for adults aged 20 and older. Data analysis occurred from March 1 to May 26, 2023. According to the authors, their analyses extend findings from previous research by assessing these associations in a large, diverse, and nationally representative sample. Using more nuanced CVD-related causes of death, depressive symptoms emerged as a nontraditional risk factor for CVD mortality.
The study
In a total cohort of 23,694, about half male, mean overall age 44.7 years, prevalences of mild and moderate to severe depression were 14.9% and 7.2%, respectively, with depressive symptoms assessed by the nine-item Patient Health Questionnaire asking about symptoms over the past 2 weeks.
Adults with depression had significantly lower CV health scores in six of the American Heart Association Life’s Essential 8 metrics for heart health. For all-cause mortality, hazard ratios were 1.35 (95% confidence interval, 1.07-1.72) for mild depressive symptoms vs. none and 1.62 (95% CI, 1.24-2.12) for moderate to severe depressive symptoms vs. none.
The corresponding hazard ratios were 1.49 (95% CI, 1.11-2.0) and 1.79 (95% CI,1.22-2.62) for CVD mortality and 0.96 (95% CI, 0.58-1.60) and 2.21 (95% CI, 1.24-3.91) for IHD death, with associations largely consistent across subgroups.
At the highest severity of depressive symptoms (almost daily for past 2 weeks), feeling tired or having little energy, poor appetite or overeating, and having little interest in doing things were significantly associated with all-cause and CVD mortality after adjusting for potential confounders.
Approximately 11%-16% of the positive associations could be explained by lifestyle factors such as excess alcohol consumption, overeating, and inactivity as per the AHA’s Life’s Essential 8 metrics.
“Taken together with the body of literature on associations between depression and CVD mortality, these findings can support public health efforts to develop a comprehensive, nationwide strategy to improve well-being, including both mental and cardiovascular health,” Dr. Zhang and associates wrote.
This research was funded by the U.S. Centers for Disease Control and Prevention. The authors had no conflicts of interest to disclose.
In a large prospective study, a graded higher risk of all-cause mortality and mortality from cardiovascular disease (CVD) and ischemic heart disease (IHD) emerged in adults with moderate to severe depressive symptoms, compared with those with no such symptoms.
Participants with mild depressive symptoms had a 35%-49% higher risk of all-cause and CVD mortality, respectively, while for those with moderate to severe depressive symptoms, the risk of all-cause, CVD, and IHD mortality was 62%, 79%, and 121% higher, respectively.
“This information highlights the importance for clinicians to identify patients with depressive symptoms and help them engage in treatment,” lead author Zefeng Zhang, MD, PhD, of the division for heart disease and stroke prevention at the U.S. Centers for Disease Control and Prevention, Atlanta, said in an interview.
The study appears in JAMA Network Open.
A nonclassic risk factor for CVD death
This graded positive association between depressive symptoms and CVD death was observed in data from the National Health and Nutrition Examination Survey 2005-2018, which were linked with the National Death Index through 2019 for adults aged 20 and older. Data analysis occurred from March 1 to May 26, 2023. According to the authors, their analyses extend findings from previous research by assessing these associations in a large, diverse, and nationally representative sample. Using more nuanced CVD-related causes of death, depressive symptoms emerged as a nontraditional risk factor for CVD mortality.
The study
In a total cohort of 23,694, about half male, mean overall age 44.7 years, prevalences of mild and moderate to severe depression were 14.9% and 7.2%, respectively, with depressive symptoms assessed by the nine-item Patient Health Questionnaire asking about symptoms over the past 2 weeks.
Adults with depression had significantly lower CV health scores in six of the American Heart Association Life’s Essential 8 metrics for heart health. For all-cause mortality, hazard ratios were 1.35 (95% confidence interval, 1.07-1.72) for mild depressive symptoms vs. none and 1.62 (95% CI, 1.24-2.12) for moderate to severe depressive symptoms vs. none.
The corresponding hazard ratios were 1.49 (95% CI, 1.11-2.0) and 1.79 (95% CI,1.22-2.62) for CVD mortality and 0.96 (95% CI, 0.58-1.60) and 2.21 (95% CI, 1.24-3.91) for IHD death, with associations largely consistent across subgroups.
At the highest severity of depressive symptoms (almost daily for past 2 weeks), feeling tired or having little energy, poor appetite or overeating, and having little interest in doing things were significantly associated with all-cause and CVD mortality after adjusting for potential confounders.
Approximately 11%-16% of the positive associations could be explained by lifestyle factors such as excess alcohol consumption, overeating, and inactivity as per the AHA’s Life’s Essential 8 metrics.
“Taken together with the body of literature on associations between depression and CVD mortality, these findings can support public health efforts to develop a comprehensive, nationwide strategy to improve well-being, including both mental and cardiovascular health,” Dr. Zhang and associates wrote.
This research was funded by the U.S. Centers for Disease Control and Prevention. The authors had no conflicts of interest to disclose.
FROM JAMA NETWORK OPEN
CBT effectively treats sexual concerns in menopausal women
PHILADELPHIA – . Four CBT sessions specifically focused on sexual concerns resulted in decreased sexual distress and concern, reduced depressive and menopausal symptoms, and increased sexual desire and functioning, as well as improved body image and relationship satisfaction.
An estimated 68%-87% of perimenopausal and postmenopausal women report sexual concerns, Sheryl Green, PhD, CPsych, an associate professor of psychiatry and behavioral neurosciences at McMaster University and a psychologist at St. Joseph’s Healthcare’s Women’s Health Concerns Clinic, both in Hamilton, Ont., told attendees at the meeting.
“Sexual concerns over the menopausal transition are not just physical, but they’re also psychological and emotional,” Dr. Green said. “Three common challenges include decreased sexual desire, a reduction in physical arousal and ability to achieve an orgasm, and sexual pain and discomfort during intercourse.”
The reasons for these concerns are multifactorial, she said. Decreased sexual desire can stem from stress, medical problems, their relationship with their partner, or other causes. A woman’s difficulty with reduced physical arousal or ability to have an orgasm can result from changes in hormone levels and vaginal changes, such as vaginal atrophy, which can also contribute to the sexual pain or discomfort reported by 17%-45% of postmenopausal women.
Two pharmacologic treatments exist for sexual concerns: oral flibanserin (Addyi) and injectable bremelanotide (Vyleesi). But many women may be unable or unwilling to take medication for their concerns. Previous research from Lori Brotto has found cognitive behavioral therapy and mindfulness interventions to effectively improve sexual functioning in women treated for gynecologic cancer and in women without a history of cancer.
“Sexual function needs to be understood from a bio-psychosocial model, looking at the biologic factors, the psychological factors, the sociocultural factors, and the interpersonal factors,” Sheryl Kingsberg, PhD, a professor of psychiatry and reproductive biology at Case Western Reserve University and a psychologist at University Hospitals in Cleveland, said in an interview.
“They can all overlap, and the clinician can ask a few pointed questions that help identify what the source of the problem is,” said Dr. Kingsberg, who was not involved in this study. She noted that the International Society for the Study of Women’s Sexual Health has an algorithm that can help in determining the source of the problems.
“Sometimes it’s going to be a biologic condition for which pharmacologic options are nice, but even if it is primarily pharmacologic, psychotherapy is always useful,” Dr. Kingsberg said. “Once the problem is there, even if it’s biologically based, then you have all the things in terms of the cognitive distortion, anxiety,” and other issues that a cognitive behavioral approach can help address. “And access is now much wider because of telehealth,” she added.
‘Psychology of menopause’
The study led by Dr. Green focused on peri- and postmenopausal women, with an average age of 50, who were experiencing primary sexual concerns based on a score of at least 26 on the Female Sexual Function Index (FSFI). Among the 20 women recruited for the study, 6 had already been prescribed hormone therapy for sexual concerns.
All reported decreased sexual desire, 17 reported decreased sexual arousal, 14 had body image dissatisfaction related to sexual concerns, and 6 reported urogenital problems. Nine of the women were in full remission from major depressive disorder, one had post-traumatic stress syndrome, and one had subclinical generalized anxiety disorder.
After spending 4 weeks on a wait list as self-control group for the study, the 15 women who completed the trial underwent four individual CBT sessions focusing on sexual concerns. The first session focused on psychoeducation and thought monitoring, and the second focused on cognitive distortions, cognitive strategies, and unhelpful beliefs or expectations related to sexual concerns. The third session looked at the role of problematic behaviors and behavioral experiments, and the fourth focused on continuation of strategies, long-term goals, and maintaining gains.
The participants completed eight measures at baseline, after the 4 weeks on the wait list, and after the four CBT sessions to assess the following:
- Sexual satisfaction, distress, and desire, using the FSFI, the Female Sexual Distress Scale-Revised (FSDS-R), and the Female Sexual Desire Questionnaire (FSDQ).
- Menopause symptoms, using the Greene Climacteric Scale (GCS).
- Body image, using the Dresden Body Image Questionnaire (DBIQ).
- Relationship satisfaction, using the Couples Satisfaction Index (CSI).
- Depression, using the Beck Depression Inventory-II (BDI-II).
- Anxiety, using the Hamilton Anxiety Rating Scale (HAM-A).
The women did not experience any significant changes while on the wait list except a slight decrease on the FSDQ concern subscale. Following the CBT sessions, however, the women experienced a significant decrease in sexual distress and concern as well as an increase in sexual dyadic desire and sexual functioning (P = .003 for FSFI, P = .002 for FSDS-R, and P = .003 for FSDQ).
Participants also experienced a decrease in depression (P < .0001) and menopausal symptoms (P = .001) and an increase in body-image satisfaction (P = .018) and relationship satisfaction (P = .0011) after the CBT sessions. The researchers assessed participants’ satisfaction with the Client Satisfaction Questionnaire after the CBT sessions and reported some of the qualitative findings.
“The treatment program was able to assist me with recognizing that some of my sexual concerns were normal, emotional as well as physical and hormonal, and provided me the ability to delve more deeply into the psychology of menopause and how to work through symptoms and concerns in more manageable pieces,” one participant wrote. Another found helpful the “homework exercises of recognizing a thought/feeling/emotion surrounding how I feel about myself/body and working through. More positive thought pattern/restructuring a response the most helpful.”
The main complaint about the program was that it was too short, with women wanting more sessions to help continue their progress.
Not an ‘either-or’ approach
Dr. Kingsberg said ISSWSH has a variety of sexual medicine practitioners, including providers who can provide CBT for sexual concerns, and the American Association of Sexuality Educators, Counselors and Therapists has a referral directory.
“Keeping in mind the bio-psychosocial model, sometimes psychotherapy is going to be a really effective treatment for sexual concerns,” Dr. Kingsberg said. “Sometimes the pharmacologic option is going to be a really effective treatment for some concerns, and sometimes the combination is going to have a really nice treatment effect. So it’s not a one-size-fits-all, and it doesn’t have to be an either-or.”
The sexual concerns of women still do not get adequately addressed in medical schools and residencies, Dr. Kingsberg said, which is distinctly different from how male sexual concerns are addressed in health care.
“Erectile dysfunction is kind of in the norm, and women are still a little hesitant to bring up their sexual concerns,” Dr. Kingsberg said. “They don’t know if it’s appropriate and they’re hoping that their clinician will ask.”
One way clinicians can do that is with a global question for all their patients: “Most of my patients have sexual questions or concerns; what concerns do you have?”
“They don’t have to go through a checklist of 10 things,” Dr. Kingsberg said. If the patient does not bring anything up, providers can then ask a single follow up question: “Do you have any concerns with desire, arousal, orgasm, or pain?” That question, Dr. Kingsberg said, covers the four main areas of concern.
The study was funded by the Canadian Institute of Health Research. Dr. Green reported no disclosures. Dr. Kingsberg has consulted for or served on the advisory board for Alloy, Astellas, Bayer, Dare Bioscience, Freya, Reunion Neuroscience, Materna Medical, Madorra, Palatin, Pfizer, ReJoy, Sprout, Strategic Science Technologies, and MsMedicine.
PHILADELPHIA – . Four CBT sessions specifically focused on sexual concerns resulted in decreased sexual distress and concern, reduced depressive and menopausal symptoms, and increased sexual desire and functioning, as well as improved body image and relationship satisfaction.
An estimated 68%-87% of perimenopausal and postmenopausal women report sexual concerns, Sheryl Green, PhD, CPsych, an associate professor of psychiatry and behavioral neurosciences at McMaster University and a psychologist at St. Joseph’s Healthcare’s Women’s Health Concerns Clinic, both in Hamilton, Ont., told attendees at the meeting.
“Sexual concerns over the menopausal transition are not just physical, but they’re also psychological and emotional,” Dr. Green said. “Three common challenges include decreased sexual desire, a reduction in physical arousal and ability to achieve an orgasm, and sexual pain and discomfort during intercourse.”
The reasons for these concerns are multifactorial, she said. Decreased sexual desire can stem from stress, medical problems, their relationship with their partner, or other causes. A woman’s difficulty with reduced physical arousal or ability to have an orgasm can result from changes in hormone levels and vaginal changes, such as vaginal atrophy, which can also contribute to the sexual pain or discomfort reported by 17%-45% of postmenopausal women.
Two pharmacologic treatments exist for sexual concerns: oral flibanserin (Addyi) and injectable bremelanotide (Vyleesi). But many women may be unable or unwilling to take medication for their concerns. Previous research from Lori Brotto has found cognitive behavioral therapy and mindfulness interventions to effectively improve sexual functioning in women treated for gynecologic cancer and in women without a history of cancer.
“Sexual function needs to be understood from a bio-psychosocial model, looking at the biologic factors, the psychological factors, the sociocultural factors, and the interpersonal factors,” Sheryl Kingsberg, PhD, a professor of psychiatry and reproductive biology at Case Western Reserve University and a psychologist at University Hospitals in Cleveland, said in an interview.
“They can all overlap, and the clinician can ask a few pointed questions that help identify what the source of the problem is,” said Dr. Kingsberg, who was not involved in this study. She noted that the International Society for the Study of Women’s Sexual Health has an algorithm that can help in determining the source of the problems.
“Sometimes it’s going to be a biologic condition for which pharmacologic options are nice, but even if it is primarily pharmacologic, psychotherapy is always useful,” Dr. Kingsberg said. “Once the problem is there, even if it’s biologically based, then you have all the things in terms of the cognitive distortion, anxiety,” and other issues that a cognitive behavioral approach can help address. “And access is now much wider because of telehealth,” she added.
‘Psychology of menopause’
The study led by Dr. Green focused on peri- and postmenopausal women, with an average age of 50, who were experiencing primary sexual concerns based on a score of at least 26 on the Female Sexual Function Index (FSFI). Among the 20 women recruited for the study, 6 had already been prescribed hormone therapy for sexual concerns.
All reported decreased sexual desire, 17 reported decreased sexual arousal, 14 had body image dissatisfaction related to sexual concerns, and 6 reported urogenital problems. Nine of the women were in full remission from major depressive disorder, one had post-traumatic stress syndrome, and one had subclinical generalized anxiety disorder.
After spending 4 weeks on a wait list as self-control group for the study, the 15 women who completed the trial underwent four individual CBT sessions focusing on sexual concerns. The first session focused on psychoeducation and thought monitoring, and the second focused on cognitive distortions, cognitive strategies, and unhelpful beliefs or expectations related to sexual concerns. The third session looked at the role of problematic behaviors and behavioral experiments, and the fourth focused on continuation of strategies, long-term goals, and maintaining gains.
The participants completed eight measures at baseline, after the 4 weeks on the wait list, and after the four CBT sessions to assess the following:
- Sexual satisfaction, distress, and desire, using the FSFI, the Female Sexual Distress Scale-Revised (FSDS-R), and the Female Sexual Desire Questionnaire (FSDQ).
- Menopause symptoms, using the Greene Climacteric Scale (GCS).
- Body image, using the Dresden Body Image Questionnaire (DBIQ).
- Relationship satisfaction, using the Couples Satisfaction Index (CSI).
- Depression, using the Beck Depression Inventory-II (BDI-II).
- Anxiety, using the Hamilton Anxiety Rating Scale (HAM-A).
The women did not experience any significant changes while on the wait list except a slight decrease on the FSDQ concern subscale. Following the CBT sessions, however, the women experienced a significant decrease in sexual distress and concern as well as an increase in sexual dyadic desire and sexual functioning (P = .003 for FSFI, P = .002 for FSDS-R, and P = .003 for FSDQ).
Participants also experienced a decrease in depression (P < .0001) and menopausal symptoms (P = .001) and an increase in body-image satisfaction (P = .018) and relationship satisfaction (P = .0011) after the CBT sessions. The researchers assessed participants’ satisfaction with the Client Satisfaction Questionnaire after the CBT sessions and reported some of the qualitative findings.
“The treatment program was able to assist me with recognizing that some of my sexual concerns were normal, emotional as well as physical and hormonal, and provided me the ability to delve more deeply into the psychology of menopause and how to work through symptoms and concerns in more manageable pieces,” one participant wrote. Another found helpful the “homework exercises of recognizing a thought/feeling/emotion surrounding how I feel about myself/body and working through. More positive thought pattern/restructuring a response the most helpful.”
The main complaint about the program was that it was too short, with women wanting more sessions to help continue their progress.
Not an ‘either-or’ approach
Dr. Kingsberg said ISSWSH has a variety of sexual medicine practitioners, including providers who can provide CBT for sexual concerns, and the American Association of Sexuality Educators, Counselors and Therapists has a referral directory.
“Keeping in mind the bio-psychosocial model, sometimes psychotherapy is going to be a really effective treatment for sexual concerns,” Dr. Kingsberg said. “Sometimes the pharmacologic option is going to be a really effective treatment for some concerns, and sometimes the combination is going to have a really nice treatment effect. So it’s not a one-size-fits-all, and it doesn’t have to be an either-or.”
The sexual concerns of women still do not get adequately addressed in medical schools and residencies, Dr. Kingsberg said, which is distinctly different from how male sexual concerns are addressed in health care.
“Erectile dysfunction is kind of in the norm, and women are still a little hesitant to bring up their sexual concerns,” Dr. Kingsberg said. “They don’t know if it’s appropriate and they’re hoping that their clinician will ask.”
One way clinicians can do that is with a global question for all their patients: “Most of my patients have sexual questions or concerns; what concerns do you have?”
“They don’t have to go through a checklist of 10 things,” Dr. Kingsberg said. If the patient does not bring anything up, providers can then ask a single follow up question: “Do you have any concerns with desire, arousal, orgasm, or pain?” That question, Dr. Kingsberg said, covers the four main areas of concern.
The study was funded by the Canadian Institute of Health Research. Dr. Green reported no disclosures. Dr. Kingsberg has consulted for or served on the advisory board for Alloy, Astellas, Bayer, Dare Bioscience, Freya, Reunion Neuroscience, Materna Medical, Madorra, Palatin, Pfizer, ReJoy, Sprout, Strategic Science Technologies, and MsMedicine.
PHILADELPHIA – . Four CBT sessions specifically focused on sexual concerns resulted in decreased sexual distress and concern, reduced depressive and menopausal symptoms, and increased sexual desire and functioning, as well as improved body image and relationship satisfaction.
An estimated 68%-87% of perimenopausal and postmenopausal women report sexual concerns, Sheryl Green, PhD, CPsych, an associate professor of psychiatry and behavioral neurosciences at McMaster University and a psychologist at St. Joseph’s Healthcare’s Women’s Health Concerns Clinic, both in Hamilton, Ont., told attendees at the meeting.
“Sexual concerns over the menopausal transition are not just physical, but they’re also psychological and emotional,” Dr. Green said. “Three common challenges include decreased sexual desire, a reduction in physical arousal and ability to achieve an orgasm, and sexual pain and discomfort during intercourse.”
The reasons for these concerns are multifactorial, she said. Decreased sexual desire can stem from stress, medical problems, their relationship with their partner, or other causes. A woman’s difficulty with reduced physical arousal or ability to have an orgasm can result from changes in hormone levels and vaginal changes, such as vaginal atrophy, which can also contribute to the sexual pain or discomfort reported by 17%-45% of postmenopausal women.
Two pharmacologic treatments exist for sexual concerns: oral flibanserin (Addyi) and injectable bremelanotide (Vyleesi). But many women may be unable or unwilling to take medication for their concerns. Previous research from Lori Brotto has found cognitive behavioral therapy and mindfulness interventions to effectively improve sexual functioning in women treated for gynecologic cancer and in women without a history of cancer.
“Sexual function needs to be understood from a bio-psychosocial model, looking at the biologic factors, the psychological factors, the sociocultural factors, and the interpersonal factors,” Sheryl Kingsberg, PhD, a professor of psychiatry and reproductive biology at Case Western Reserve University and a psychologist at University Hospitals in Cleveland, said in an interview.
“They can all overlap, and the clinician can ask a few pointed questions that help identify what the source of the problem is,” said Dr. Kingsberg, who was not involved in this study. She noted that the International Society for the Study of Women’s Sexual Health has an algorithm that can help in determining the source of the problems.
“Sometimes it’s going to be a biologic condition for which pharmacologic options are nice, but even if it is primarily pharmacologic, psychotherapy is always useful,” Dr. Kingsberg said. “Once the problem is there, even if it’s biologically based, then you have all the things in terms of the cognitive distortion, anxiety,” and other issues that a cognitive behavioral approach can help address. “And access is now much wider because of telehealth,” she added.
‘Psychology of menopause’
The study led by Dr. Green focused on peri- and postmenopausal women, with an average age of 50, who were experiencing primary sexual concerns based on a score of at least 26 on the Female Sexual Function Index (FSFI). Among the 20 women recruited for the study, 6 had already been prescribed hormone therapy for sexual concerns.
All reported decreased sexual desire, 17 reported decreased sexual arousal, 14 had body image dissatisfaction related to sexual concerns, and 6 reported urogenital problems. Nine of the women were in full remission from major depressive disorder, one had post-traumatic stress syndrome, and one had subclinical generalized anxiety disorder.
After spending 4 weeks on a wait list as self-control group for the study, the 15 women who completed the trial underwent four individual CBT sessions focusing on sexual concerns. The first session focused on psychoeducation and thought monitoring, and the second focused on cognitive distortions, cognitive strategies, and unhelpful beliefs or expectations related to sexual concerns. The third session looked at the role of problematic behaviors and behavioral experiments, and the fourth focused on continuation of strategies, long-term goals, and maintaining gains.
The participants completed eight measures at baseline, after the 4 weeks on the wait list, and after the four CBT sessions to assess the following:
- Sexual satisfaction, distress, and desire, using the FSFI, the Female Sexual Distress Scale-Revised (FSDS-R), and the Female Sexual Desire Questionnaire (FSDQ).
- Menopause symptoms, using the Greene Climacteric Scale (GCS).
- Body image, using the Dresden Body Image Questionnaire (DBIQ).
- Relationship satisfaction, using the Couples Satisfaction Index (CSI).
- Depression, using the Beck Depression Inventory-II (BDI-II).
- Anxiety, using the Hamilton Anxiety Rating Scale (HAM-A).
The women did not experience any significant changes while on the wait list except a slight decrease on the FSDQ concern subscale. Following the CBT sessions, however, the women experienced a significant decrease in sexual distress and concern as well as an increase in sexual dyadic desire and sexual functioning (P = .003 for FSFI, P = .002 for FSDS-R, and P = .003 for FSDQ).
Participants also experienced a decrease in depression (P < .0001) and menopausal symptoms (P = .001) and an increase in body-image satisfaction (P = .018) and relationship satisfaction (P = .0011) after the CBT sessions. The researchers assessed participants’ satisfaction with the Client Satisfaction Questionnaire after the CBT sessions and reported some of the qualitative findings.
“The treatment program was able to assist me with recognizing that some of my sexual concerns were normal, emotional as well as physical and hormonal, and provided me the ability to delve more deeply into the psychology of menopause and how to work through symptoms and concerns in more manageable pieces,” one participant wrote. Another found helpful the “homework exercises of recognizing a thought/feeling/emotion surrounding how I feel about myself/body and working through. More positive thought pattern/restructuring a response the most helpful.”
The main complaint about the program was that it was too short, with women wanting more sessions to help continue their progress.
Not an ‘either-or’ approach
Dr. Kingsberg said ISSWSH has a variety of sexual medicine practitioners, including providers who can provide CBT for sexual concerns, and the American Association of Sexuality Educators, Counselors and Therapists has a referral directory.
“Keeping in mind the bio-psychosocial model, sometimes psychotherapy is going to be a really effective treatment for sexual concerns,” Dr. Kingsberg said. “Sometimes the pharmacologic option is going to be a really effective treatment for some concerns, and sometimes the combination is going to have a really nice treatment effect. So it’s not a one-size-fits-all, and it doesn’t have to be an either-or.”
The sexual concerns of women still do not get adequately addressed in medical schools and residencies, Dr. Kingsberg said, which is distinctly different from how male sexual concerns are addressed in health care.
“Erectile dysfunction is kind of in the norm, and women are still a little hesitant to bring up their sexual concerns,” Dr. Kingsberg said. “They don’t know if it’s appropriate and they’re hoping that their clinician will ask.”
One way clinicians can do that is with a global question for all their patients: “Most of my patients have sexual questions or concerns; what concerns do you have?”
“They don’t have to go through a checklist of 10 things,” Dr. Kingsberg said. If the patient does not bring anything up, providers can then ask a single follow up question: “Do you have any concerns with desire, arousal, orgasm, or pain?” That question, Dr. Kingsberg said, covers the four main areas of concern.
The study was funded by the Canadian Institute of Health Research. Dr. Green reported no disclosures. Dr. Kingsberg has consulted for or served on the advisory board for Alloy, Astellas, Bayer, Dare Bioscience, Freya, Reunion Neuroscience, Materna Medical, Madorra, Palatin, Pfizer, ReJoy, Sprout, Strategic Science Technologies, and MsMedicine.
AT NAMS 2023
Federal Health Care Data Trends 2023
In this issue:
- Limb Loss and Prostheses
- Neurology
- Cardiology
- Mental Health
- Diabetes
- Rheumatoid Arthritis
- Respiratory illnesses
- Women's Health
- HPV and Related Cancers
In this issue:
- Limb Loss and Prostheses
- Neurology
- Cardiology
- Mental Health
- Diabetes
- Rheumatoid Arthritis
- Respiratory illnesses
- Women's Health
- HPV and Related Cancers
In this issue:
- Limb Loss and Prostheses
- Neurology
- Cardiology
- Mental Health
- Diabetes
- Rheumatoid Arthritis
- Respiratory illnesses
- Women's Health
- HPV and Related Cancers
Data Trends 2023: Depression
1. Moradi Y et al. BMC Psychiatry. 2021;21(1):510. doi:10.1186/s12888-021-03526-2
2. Ziobrowski HN et al. J Affect Disord. 2021;290:227-236. doi:10.1016/j.jad.2021.04.033
3. Szukis H et al. Curr Med Res Opin. 2021;37(8):1393-1401. doi:10.1080/03007995.2021.1918073
4. Levey DF et al. Nat Neurosci. 2021;24(7):954-963. doi:10.1038/s41593-021-00860-2
5. Madore MR et al. J Affect Disord. 2022;297:671-678. doi:10.1016/j.jad.2021.10.025
6. Cheng CM et al. Adv Exp Med Biol. 2021;1305:333-349. doi:10.1007/978-981-33-6044-0_18
1. Moradi Y et al. BMC Psychiatry. 2021;21(1):510. doi:10.1186/s12888-021-03526-2
2. Ziobrowski HN et al. J Affect Disord. 2021;290:227-236. doi:10.1016/j.jad.2021.04.033
3. Szukis H et al. Curr Med Res Opin. 2021;37(8):1393-1401. doi:10.1080/03007995.2021.1918073
4. Levey DF et al. Nat Neurosci. 2021;24(7):954-963. doi:10.1038/s41593-021-00860-2
5. Madore MR et al. J Affect Disord. 2022;297:671-678. doi:10.1016/j.jad.2021.10.025
6. Cheng CM et al. Adv Exp Med Biol. 2021;1305:333-349. doi:10.1007/978-981-33-6044-0_18
1. Moradi Y et al. BMC Psychiatry. 2021;21(1):510. doi:10.1186/s12888-021-03526-2
2. Ziobrowski HN et al. J Affect Disord. 2021;290:227-236. doi:10.1016/j.jad.2021.04.033
3. Szukis H et al. Curr Med Res Opin. 2021;37(8):1393-1401. doi:10.1080/03007995.2021.1918073
4. Levey DF et al. Nat Neurosci. 2021;24(7):954-963. doi:10.1038/s41593-021-00860-2
5. Madore MR et al. J Affect Disord. 2022;297:671-678. doi:10.1016/j.jad.2021.10.025
6. Cheng CM et al. Adv Exp Med Biol. 2021;1305:333-349. doi:10.1007/978-981-33-6044-0_18
Emotional blunting in patients taking antidepressants
When used to treat anxiety or depressive disorders, antidepressants can cause a variety of adverse effects, including emotional blunting. Emotional blunting has been described as emotional numbness, indifference, decreased responsiveness, or numbing. In a study of 669 patients who had been receiving antidepressants (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], or other antidepressants), 46% said they had experienced emotional blunting.1 A 2019 study found that approximately one-third of patients with unipolar depression or bipolar depression stopped taking their antidepressant due to emotional blunting.2
Historically, there has been difficulty parsing out emotional blunting (a general decrease of all range of emotions) from anhedonia (a restriction of positive emotions). Additionally, some researchers have questioned if the blunting of emotions is part of depressive symptomatology. In a study of 38 adults, most felt able to differentiate emotional blunting due to antidepressants by considering the resolution of other depressive symptoms and timeline of onset.3
A significant limitation has been how clinicians measure or assess emotional blunting. The Oxford Depression Questionnaire (ODQ), previously known as the Oxford Questionnaire on the Emotional Side-effects of Antidepressants, was created based on a qualitative survey of patients who endorsed emotional blunting.4 A validated scale, the ODQ divides emotional blunting into 4 dimensions:
- general reduction in emotions
- reduction in positive emotions
- emotional detachment from others
- not caring.4
The sections of ODQ focus on exploring specific aspects of patients’ emotional experiences, comparing experiences in the past week to before the development of illness/emotional blunting, and patients’ opinions about antidepressants. Example statements from the ODQ (Table4) may help clinicians better understand and explore emotional blunting with their patients.
There are 2 leading theories behind the mechanism of emotional blunting on antidepressants, both focused on serotonin. The first theory offers that SSRIs alter frontal lobe activity through serotonergic effects. The second theory is focused on the downward effects of serotonin on dopamine in reward pathways.5
Treatment options: Limited evidence
Data on how to address antidepressant-induced emotional blunting are limited and based largely on case reports. One open-label study (N = 143) found that patients experiencing emotional blunting while taking SSRIs and SNRIs who were switched to vortioxetine had a statistically significant decrease in ODQ total score; 50% reported no emotional blunting.6 Options to address emotional blunting include decreasing the antidepressant dose, augmenting with or switching to another agent, or considering other treatments such as neuromodulation.5 Further research is necessary to clarify which intervention is best.
Clinicians will encounter emotional blunting in patients who are taking antidepressants. It is important to recognize and address these symptoms to help improve patients’ adherence and overall quality of life.
1. Goodwin GM, Price J, De Bodinat C, et al. Emotional blunting with antidepressant treatments: a survey among depressed patients. J Affect Disord. 2017;221:31-35.
2. Rosenblat JD, Simon GE, Sachs GS, et al. Treatment effectiveness and tolerability outcomes that are most important to individuals with bipolar and unipolar depression. J Affect Disord. 2019;243:116-120.
3. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study. Br J Psychiatry. 2009;195(3):211-217.
4. Price J, Cole V, Doll H, et al. The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA): development, validity, reliability and sensitivity to change. J Affect Disord. 2012;140(1):66-74.
5. Ma H, Cai M, Wang H. Emotional blunting in patients with major depressive disorder: a brief non-systematic review of current research. Front Psychiatry. 2021;12:792960. doi:10.3389/fpsyt.2021.792960
6. Fagiolini A, Florea I, Loft H, et al. Effectiveness of vortioxetine on emotional blunting in patients with major depressive disorder with inadequate response to SSRI/SNRI treatment. J Affect Disord. 2021;283:472-479.
When used to treat anxiety or depressive disorders, antidepressants can cause a variety of adverse effects, including emotional blunting. Emotional blunting has been described as emotional numbness, indifference, decreased responsiveness, or numbing. In a study of 669 patients who had been receiving antidepressants (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], or other antidepressants), 46% said they had experienced emotional blunting.1 A 2019 study found that approximately one-third of patients with unipolar depression or bipolar depression stopped taking their antidepressant due to emotional blunting.2
Historically, there has been difficulty parsing out emotional blunting (a general decrease of all range of emotions) from anhedonia (a restriction of positive emotions). Additionally, some researchers have questioned if the blunting of emotions is part of depressive symptomatology. In a study of 38 adults, most felt able to differentiate emotional blunting due to antidepressants by considering the resolution of other depressive symptoms and timeline of onset.3
A significant limitation has been how clinicians measure or assess emotional blunting. The Oxford Depression Questionnaire (ODQ), previously known as the Oxford Questionnaire on the Emotional Side-effects of Antidepressants, was created based on a qualitative survey of patients who endorsed emotional blunting.4 A validated scale, the ODQ divides emotional blunting into 4 dimensions:
- general reduction in emotions
- reduction in positive emotions
- emotional detachment from others
- not caring.4
The sections of ODQ focus on exploring specific aspects of patients’ emotional experiences, comparing experiences in the past week to before the development of illness/emotional blunting, and patients’ opinions about antidepressants. Example statements from the ODQ (Table4) may help clinicians better understand and explore emotional blunting with their patients.
There are 2 leading theories behind the mechanism of emotional blunting on antidepressants, both focused on serotonin. The first theory offers that SSRIs alter frontal lobe activity through serotonergic effects. The second theory is focused on the downward effects of serotonin on dopamine in reward pathways.5
Treatment options: Limited evidence
Data on how to address antidepressant-induced emotional blunting are limited and based largely on case reports. One open-label study (N = 143) found that patients experiencing emotional blunting while taking SSRIs and SNRIs who were switched to vortioxetine had a statistically significant decrease in ODQ total score; 50% reported no emotional blunting.6 Options to address emotional blunting include decreasing the antidepressant dose, augmenting with or switching to another agent, or considering other treatments such as neuromodulation.5 Further research is necessary to clarify which intervention is best.
Clinicians will encounter emotional blunting in patients who are taking antidepressants. It is important to recognize and address these symptoms to help improve patients’ adherence and overall quality of life.
When used to treat anxiety or depressive disorders, antidepressants can cause a variety of adverse effects, including emotional blunting. Emotional blunting has been described as emotional numbness, indifference, decreased responsiveness, or numbing. In a study of 669 patients who had been receiving antidepressants (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], or other antidepressants), 46% said they had experienced emotional blunting.1 A 2019 study found that approximately one-third of patients with unipolar depression or bipolar depression stopped taking their antidepressant due to emotional blunting.2
Historically, there has been difficulty parsing out emotional blunting (a general decrease of all range of emotions) from anhedonia (a restriction of positive emotions). Additionally, some researchers have questioned if the blunting of emotions is part of depressive symptomatology. In a study of 38 adults, most felt able to differentiate emotional blunting due to antidepressants by considering the resolution of other depressive symptoms and timeline of onset.3
A significant limitation has been how clinicians measure or assess emotional blunting. The Oxford Depression Questionnaire (ODQ), previously known as the Oxford Questionnaire on the Emotional Side-effects of Antidepressants, was created based on a qualitative survey of patients who endorsed emotional blunting.4 A validated scale, the ODQ divides emotional blunting into 4 dimensions:
- general reduction in emotions
- reduction in positive emotions
- emotional detachment from others
- not caring.4
The sections of ODQ focus on exploring specific aspects of patients’ emotional experiences, comparing experiences in the past week to before the development of illness/emotional blunting, and patients’ opinions about antidepressants. Example statements from the ODQ (Table4) may help clinicians better understand and explore emotional blunting with their patients.
There are 2 leading theories behind the mechanism of emotional blunting on antidepressants, both focused on serotonin. The first theory offers that SSRIs alter frontal lobe activity through serotonergic effects. The second theory is focused on the downward effects of serotonin on dopamine in reward pathways.5
Treatment options: Limited evidence
Data on how to address antidepressant-induced emotional blunting are limited and based largely on case reports. One open-label study (N = 143) found that patients experiencing emotional blunting while taking SSRIs and SNRIs who were switched to vortioxetine had a statistically significant decrease in ODQ total score; 50% reported no emotional blunting.6 Options to address emotional blunting include decreasing the antidepressant dose, augmenting with or switching to another agent, or considering other treatments such as neuromodulation.5 Further research is necessary to clarify which intervention is best.
Clinicians will encounter emotional blunting in patients who are taking antidepressants. It is important to recognize and address these symptoms to help improve patients’ adherence and overall quality of life.
1. Goodwin GM, Price J, De Bodinat C, et al. Emotional blunting with antidepressant treatments: a survey among depressed patients. J Affect Disord. 2017;221:31-35.
2. Rosenblat JD, Simon GE, Sachs GS, et al. Treatment effectiveness and tolerability outcomes that are most important to individuals with bipolar and unipolar depression. J Affect Disord. 2019;243:116-120.
3. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study. Br J Psychiatry. 2009;195(3):211-217.
4. Price J, Cole V, Doll H, et al. The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA): development, validity, reliability and sensitivity to change. J Affect Disord. 2012;140(1):66-74.
5. Ma H, Cai M, Wang H. Emotional blunting in patients with major depressive disorder: a brief non-systematic review of current research. Front Psychiatry. 2021;12:792960. doi:10.3389/fpsyt.2021.792960
6. Fagiolini A, Florea I, Loft H, et al. Effectiveness of vortioxetine on emotional blunting in patients with major depressive disorder with inadequate response to SSRI/SNRI treatment. J Affect Disord. 2021;283:472-479.
1. Goodwin GM, Price J, De Bodinat C, et al. Emotional blunting with antidepressant treatments: a survey among depressed patients. J Affect Disord. 2017;221:31-35.
2. Rosenblat JD, Simon GE, Sachs GS, et al. Treatment effectiveness and tolerability outcomes that are most important to individuals with bipolar and unipolar depression. J Affect Disord. 2019;243:116-120.
3. Price J, Cole V, Goodwin GM. Emotional side-effects of selective serotonin reuptake inhibitors: qualitative study. Br J Psychiatry. 2009;195(3):211-217.
4. Price J, Cole V, Doll H, et al. The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA): development, validity, reliability and sensitivity to change. J Affect Disord. 2012;140(1):66-74.
5. Ma H, Cai M, Wang H. Emotional blunting in patients with major depressive disorder: a brief non-systematic review of current research. Front Psychiatry. 2021;12:792960. doi:10.3389/fpsyt.2021.792960
6. Fagiolini A, Florea I, Loft H, et al. Effectiveness of vortioxetine on emotional blunting in patients with major depressive disorder with inadequate response to SSRI/SNRI treatment. J Affect Disord. 2021;283:472-479.
Neuropsychiatric aspects of Parkinson’s disease: Practical considerations
Parkinson’s disease (PD) is a neurodegenerative condition diagnosed pathologically by alpha synuclein–containing Lewy bodies and dopaminergic cell loss in the substantia nigra pars compacta of the midbrain. Loss of dopaminergic input to the caudate and putamen disrupts the direct and indirect basal ganglia pathways for motor control and contributes to the motor symptoms of PD.1 According to the Movement Disorder Society criteria, PD is diagnosed clinically by bradykinesia (slowness of movement) plus resting tremor and/or rigidity in the presence of supportive criteria, such as levodopa responsiveness and hyposmia, and in the absence of exclusion criteria and red flags that would suggest atypical parkinsonism or an alternative diagnosis.2
Although the diagnosis and treatment of PD focus heavily on the motor symptoms, nonmotor symptoms can arise decades before the onset of motor symptoms and continue throughout the lifespan. Nonmotor symptoms affect patients from head (ie, cognition and mood) to toe (ie, striatal toe pain) and multiple organ systems in between, including the olfactory, integumentary, cardiovascular, gastrointestinal, genitourinary, and autonomic nervous systems. Thus, it is not surprising that nonmotor symptoms of PD impact health-related quality of life more substantially than motor symptoms.3 A helpful analogy is to consider the motor symptoms of PD as the tip of the iceberg and the nonmotor symptoms as the larger, submerged portions of the iceberg.4
Nonmotor symptoms can negatively impact the treatment of motor symptoms. For example, imagine a patient who is very rigid and dyscoordinated in the arms and legs, which limits their ability to dress and walk. If this patient also suffers from nonmotor symptoms of orthostatic hypotension and psychosis—both of which can be exacerbated by levodopa—dose escalation of levodopa for the rigidity and dyscoordination could be compromised, rendering the patient undertreated and less mobile.
In this review, we focus on identifying and managing nonmotor symptoms of PD that are relevant to psychiatric practice, including mood and motivational disorders, anxiety disorders, psychosis, cognitive disorders, and disorders related to the pharmacologic and surgical treatment of PD (Figure 1).
Mood and motivational disorders
Depression
Depression is a common symptom in PD that can occur in the prodromal period years to decades before the onset of motor symptoms, as well as throughout the disease course.5 The prevalence of depression in PD varies from 3% to 90%, depending on the methods of assessment, clinical setting of assessment, motor symptom severity, and other factors; clinically significant depression likely affects approximately 35% to 38% of patients.5,6 How depression in patients with PD differs from depression in the general population is not entirely understood, but there does seem to be less guilt and suicidal ideation and a substantial component of negative affect, including dysphoria and anxiety.7 Practically speaking, depression is treated similarly in PD and general populations, with a few considerations.
Despite limited randomized controlled trials (RCTs) for efficacy specifically in patients with PD, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are generally considered first-line treatments. There is also evidence for tricyclic antidepressants (TCAs), but due to potential worsening of orthostatic hypotension and cognition, TCAs may not be a favorable option for certain patients with PD.8,9 All antidepressants have the potential to worsen tremor. Theoretically, SNRIs, with noradrenergic activity, may be less tolerable than SSRIs in patients with PD. However, worsening tremor generally has not been a clinically significant adverse event reported in PD depression clinical trials, although it was seen in 17% of patients receiving paroxetine and 21% of patients receiving venlafaxine compared to 7% of patients receiving placebo.9-11 If tremor worsens, mirtazapine could be considered because it has been reported to cause less tremor than SSRIs or TCAs.12
Among medications for PD, pramipexole, a dopamine agonist, may have a beneficial effect on depression.13 Additionally, some evidence supports rasagiline, a monoamine oxidase type B inhibitor, as an adjunctive medication for depression in PD.14 Nevertheless, antidepressant medications remain the standard pharmacologic treatment for PD depression.
Continue to: In terms of nonpharmacologic options...
In terms of nonpharmacologic options, cognitive-behavioral therapy (CBT) is likely efficacious, exercise (especially yoga) is likely efficacious, and repetitive transcranial magnetic stimulation may be efficacious.15,16 While further high-quality trials are needed, these treatments are low-risk and can be considered, especially for patients who cannot tolerate medications.
Apathy
Apathy—a loss of motivation and goal-directed behavior—can occur in up to 30% of patients during the prodromal period of PD, and in up to 70% of patients throughout the disease course.17 Apathy can coexist with depression, which can make apathy difficult to diagnose.17 Given the time constraints of a clinic visit, a practical approach would be to first screen for depression and cognitive impairment. If there is continued suspicion of apathy, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale part I question (“In the past week have you felt indifferent to doing activities or being with people?”) can be used to screen for apathy, and more detailed scales, such as the Apathy Scale (AS) or Lille Apathy Rating Scale (LARS), could be used if indicated.18
There are limited high-quality positive trials of apathy-specific treatments in PD. In an RCT of patients with PD who did not have depression or dementia, rivastigmine improved LARS scores compared to placebo.15 Piribedil, a D2/D3 receptor agonist, improved apathy in patients who underwent subthalamic nucleus deep brain stimulation (STN DBS).15 Exercise such as individualized physical therapy programs, dance, and Nordic walking as well as mindfulness interventions were shown to significantly reduce apathy scale scores.19 SSRIs, SNRIs, and rotigotine showed a trend toward reducing AS scores in RCTs.10,20
Larger, high-quality studies are needed to clarify the treatment of apathy in PD. In the meantime, a reasonable approach is to first treat any comorbid psychiatric or cognitive disorders, since apathy can be associated with these conditions, and to optimize antiparkinsonian medications for motor symptoms, motor fluctuations, and nonmotor fluctuations. Then, the investigational apathy treatments described in this section could be considered on an individual basis.
Anxiety disorders
Anxiety is seen throughout the disease course of PD in approximately 30% to 50% of patients.21 It can manifest as generalized anxiety disorder, panic disorder, and other anxiety disorders. There are no high-quality RCTs of pharmacologic treatments of anxiety specifically in patients with PD, except for a negative safety and tolerability study of buspirone in which one-half of patients experienced worsening motor symptoms.15,22 Thus, the treatment of anxiety in patients with PD is similar to treatments in the general population. SSRIs and SNRIs are typically considered first-line, benzodiazepines are sometimes used with caution (although cognitive adverse effects and fall risk need to be considered), and nonpharmacologic treatments such as mindfulness yoga, exercise, CBT, and psychotherapy can be effective.16,21,23
Continue to: Because there is the lack...
Because there is the lack of evidence-based treatments for anxiety in PD, we highlight 2 PD-specific anxiety disorders: internal tremor, and nonmotor “off” anxiety.
Internal tremor
Internal tremor is a sense of vibration in the axial and/or appendicular muscles that cannot be seen externally by the patient or examiner. It is not yet fully understood if this phenomenon is sensory, anxiety-related, related to subclinical tremor, or the result of a combination of these factors (ie, sensory awareness of a subclinical tremor that triggers or is worsened by anxiety). There is some evidence for subclinical tremor on electromyography, but internal tremor does not respond to antiparkinsonian medications in 70% of patients.24 More electrophysiological research is needed to clarify this phenomenon. Internal tremor has been associated with anxiety in 64% of patients and often improves with anxiolytic therapies.24
Although poorly understood, internal tremor is a documented phenomenon in 33% to 44% of patients with PD, and in some cases, it may be an initial symptom that motivates a patient to seek medical attention for the first time.24,25 Internal tremor has also been reported in patients with essential tremor and multiple sclerosis.25 Therefore, physicians should be aware of internal tremor because this symptom could herald an underlying neurological disease.
Nonmotor ‘off’ anxiety
Patients with PD are commonly prescribed carbidopa-levodopa, a dopamine precursor, at least 3 times daily. Initially, this medication controls motor symptoms well from 1 dose to the next. However, as the disease progresses, some patients report motor fluctuations in which an individual dose of carbidopa-levodopa may wear off early, take longer than usual to take effect, or not take effect at all. Patients describe these periods as an “off” state in which they do not feel their medications are working. Such motor fluctuations can lead to anxiety and avoidance behaviors, because patients fear being in public at times when the medication does not adequately control their motor symptoms.
In addition to these motor symptom fluctuations and related anxiety, patients can also experience nonmotor symptom fluctuations. A wide variety of nonmotor symptoms, such as mood, cognitive, and behavioral symptoms, have been reported to fluctuate in parallel with motor symptoms.26,27 One study reported fluctuating restlessness in 39% of patients with PD, excessive worry in 17%, shortness of breath in 13%, excessive sweating and fear in 12%, and palpitations in 10%.27 A patient with fluctuating shortness of breath, sweating, and palpitations (for example) may repeatedly present to the emergency department with a negative cardiac workup and eventually be diagnosed with panic disorder, whereas the patient is truly experiencing nonmotor “off” symptoms. Thus, it is important to be aware of nonmotor fluctuations so this diagnosis can be made and the symptoms appropriately treated. The first step in treating nonmotor fluctuations is to optimize the antiparkinsonian regimen to minimize fluctuations. If “off” anxiety symptoms persist, anxiolytic medications can be prescribed.21
Continue to: Psychosis
Psychosis
Psychosis can occur in prodromal and early PD but is most common in advanced PD.28 One study reported that 60% of patients developed hallucinations or delusions after 12 years of follow-up.29 Disease duration, disease severity, dementia, and rapid eye movement sleep behavior disorder are significant risk factors for psychosis in PD.30 Well-formed visual hallucinations are the most common manifestation of psychosis in patients with PD. Auditory hallucinations and delusions are less common. Delusions are usually seen in patients with dementia and are often paranoid delusions, such as of spousal infidelity.30 Sensory hallucinations can occur, but should not be mistaken with formication, a central pain syndrome in PD that can represent a nonmotor “off” symptom that may respond to dopaminergic medication.31 Other more mild psychotic symptoms include illusions or misinterpretation of stimuli, false sense of presence, and passage hallucinations of fleeting figures in the peripheral vision.30
The pathophysiology of PD psychosis is not entirely understood but differs from psychosis in other disorders. It can occur in the absence of antiparkinsonian medication exposure and is thought to be a consequence of the underlying disease process of PD involving neurodegeneration in certain brain regions and aberrant neurotransmission of not only dopamine but also serotonin, acetylcholine, and glutamate.30
Figure 2 outlines the management of psychosis in PD. After addressing medical and medication-related causes, it is important to determine if the psychotic symptom is sufficiently bothersome to and/or potentially dangerous for the patient to warrant treatment. If treatment is indicated, pimavanserin and clozapine are efficacious for psychosis in PD without worsening motor symptoms, and quetiapine is possibly efficacious with a low risk of worsening motor symptoms.15 Other antipsychotics, such as olanzapine, risperidone, and haloperidol, can substantially worsen motor symptoms.15 Both second-generation antipsychotics and pimavanserin have an FDA black-box warning for a higher risk of all-cause mortality in older patients with dementia; however, because psychosis is associated with early mortality in PD, the risk/benefit ratio should be discussed with the patient and family for shared decision-making.30 If the patient also has dementia, rivastigmine—which is FDA-approved for PD dementia (PDD)—may also improve hallucinations.32
Cognitive disorders
This section focuses on PD mild cognitive impairment (PD-MCI) and PDD. When a patient with PD reports cognitive concerns, the approach outlined in Figure 3 can be used to diagnose the cognitive disorder. A detailed history, medication review, and physical examination can identify any medical or psychiatric conditions that could affect cognition. The American Academy of Neurology recommends screening for depression, obtaining blood levels of vitamin B12 and thyroid-stimulating hormone, and obtaining a CT or MRI of the brain to rule out reversible causes of dementia.33 A validated screening test such as the Montreal Cognitive Assessment, which has higher sensitivity for PD-MCI than the Mini-Mental State Examination, is used to identify and quantify cognitive impairment.34 Neuropsychological testing is the gold standard and can be used to confirm and/or better quantify the degree and domains of cognitive impairment.35 Typically, cognitive deficits in PD affect executive function, attention, and/or visuospatial domains more than memory and language early on, and deficits in visuospatial and language domains have the highest sensitivity for predicting progression to PDD.36
Once reversible causes of dementia are addressed or ruled out and cognitive testing is completed, the Movement Disorder Society (MDS) criteria for PD-MCI and PDD summarized in Figure 3 can be used to diagnose the cognitive disorder.37,38 The MDS criteria for PDD require a diagnosis of PD for ≥1 year prior to the onset of dementia to differentiate PDD from dementia with Lewy bodies (DLB). If the dementia starts within 1 year of the onset of parkinsonism, the diagnosis would be DLB. PDD and DLB are on the spectrum of Lewy body dementia, with the same Lewy body pathology in different temporal and spatial distributions in the brain.38
Continue to: PD-MCI is present in...
PD-MCI is present in approximately 25% of patients.35 PD-MCI does not always progress to dementia but increases the risk of dementia 6-fold. The prevalence of PDD increases with disease duration; it is present in approximately 50% of patients at 10 years and 80% of patients at 20 years of disease.35 Rivastigmine is the only FDA-approved medication to slow progression of PDD. There is insufficient evidence for other acetylcholinesterase inhibitors and memantine.15 Unfortunately, RCTs of pharmacotherapy for PD-MCI have failed to show efficacy. However, exercise, cognitive rehabilitation, and neuromodulation are being studied. In the meantime, addressing modifiable risk factors (such as vascular risk factors and alcohol consumption) and treating comorbid orthostatic hypotension, obstructive sleep apnea, and depression may improve cognition.35,39
Treatment-related disorders
Impulse control disorders
Impulse control disorders (ICDs) are an important medication-related consideration in patients with PD. The ICDs seen in PD include pathological gambling, binge eating, excessive shopping, hypersexual behaviors, and dopamine dysregulation syndrome (Table). These disorders are more common in younger patients with a history of impulsive personality traits and addictive behaviors (eg, history of tobacco or alcohol abuse), and are most strongly associated with dopaminergic therapies, particularly the dopamine agonists.40,41 In the DOMINION study, the odds of ICDs were 2- to 3.5-fold higher in patients taking dopamine agonists.42 This is mainly thought to be due to stimulation of D2/D3 receptors in the mesolimbic system.40 High doses of levodopa, monoamine oxidase inhibitors, and amantadine are also associated with ICDs.40-42
The first step in managing ICDs is diagnosing them, which can be difficult because patients often are not forthcoming about these problems due to embarrassment or failure to recognize that the ICD is related to PD medications. If a family member accompanies the patient at the visit, the patient may not want to disclose the amount of money they spend or the extent to which the behavior is a problem. Thus, a screening questionnaire, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) can be a helpful way for patients to alert the clinician to the issue.41 Education for the patient and family is crucial before the ICD causes significant financial, health, or relationship problems.
The mainstay of treatment is to reduce or taper off the dopamine agonist or other offending agent while monitoring for worsening motor symptoms and dopamine withdrawal syndrome. If this is unsuccessful, there is very limited evidence for further treatment strategies (Table), including antidepressants, antipsychotics, and mood stabilizers.40,43,44 There is insufficient evidence for naltrexone based on an RCT that failed to meet its primary endpoint, although naltrexone did significantly reduce QUIP scores.15,44 There is also insufficient evidence for amantadine, which showed benefit in some studies but was associated with ICDs in the DOMINION study.15,40,42 In terms of nonpharmacologic treatments, CBT is likely efficacious.15,40 There are mixed results for STN DBS. Some studies showed improvement in the ICD, due at least in part to dopaminergic medication reduction postoperatively, but this treatment has also been reported to increase impulsivity.40,45
Deep brain stimulation–related disorders
For patients with PD, the ideal lead location for STN DBS is the dorsolateral aspect of the STN, as this is the motor region of the nucleus. The STN functions in indirect and hyperdirect pathways to put the brake on certain motor programs so only the desired movement can be executed. Its function is clinically demonstrated by patients with STN stroke who develop excessive ballistic movements. Adjacent to the motor region of the STN is a centrally located associative region and a medially located limbic region. Thus, when stimulating the dorsolateral STN, current can spread to those regions as well, and the STN’s ability to put the brake on behavioral and emotional programs can be affected.46 Stimulation of the STN has been associated with mania, euphoria, new-onset ICDs, decreased verbal fluency, and executive dysfunction. Depression, apathy, and anxiety can also occur, but more commonly result from rapid withdrawal of antiparkinsonian medications after DBS surgery.46,47 Therefore, for PD patients with DBS with new or worsening psychiatric or cognitive symptoms, it is important to inquire about any recent programming sessions with neurology as well as recent self-increases in stimulation by the patient using their controller. Collaboration with neurology is important to troubleshoot whether stimulation could be contributing to the patient’s psychiatric or cognitive symptoms.
Continue to: Bottom Line
Bottom Line
Mood, anxiety, psychotic, and cognitive symptoms and disorders are common psychiatric manifestations associated with Parkinson’s disease (PD). In addition, patients with PD may experience impulsive control disorders and other symptoms related to treatments they receive for PD. Careful assessment and collaboration with neurology is crucial to alleviating the effects of these conditions.
Related Resources
- Weintraub D, Aarsland D, Chaudhuri KR, et al. The neuropsychiatry of Parkinson’s disease: advances and challenges. Lancet Neurology. 2022;21(1):89-102. doi:10.1016/S1474-4422(21)00330-6
- Goldman JG, Guerra CM. Treatment of nonmotor symptoms associated with Parkinson disease. Neurologic Clinics. 2020;38(2):269-292. doi:10.1016/j.ncl.2019.12.003
- Castrioto A, Lhommee E, Moro E et al. Mood and behavioral effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurology. 2014;13(3):287-305. doi:10.1016/ S1474-4422(13)70294-1
Drug Brand Names
Amantadine • Gocovri
Carbidopa-levodopa • Sinemet
Clozapine • Clozaril
Haloperidol • Haldol
Memantine • Namenda
Mirtazapine • Remeron
Naltrexone • Vivitrol
Olanzapine • Zyprexa
Paroxetine • Paxil
Pimavanserin • Nuplazid
Piribedil • Pronoran
Pramipexole • Mirapex
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Rivastigmine • Exelon
Ropinirole • Requip
Rotigotine • Neupro
Venlafaxine • Effexor
Zonisamide • Zonegran
1. Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet Neurology. 2021;397(10291):2284-2303.
2. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Movement Disorders. 2015;30(12):1591-1601.
3. Martinez-Martin P, Rodriguez-Blazquez C, Kurtiz MM, et al. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov Disord. 2011;26(3):399-406.
4. Langston WJ. The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol. 2006;59(4):591-596.
5. Cong S, Xiang C, Zhang S, et al. Prevalence and clinical aspects of depression in Parkinson’s disease: a systematic review and meta‑analysis of 129 studies. Neurosci Biobehav Rev. 2022;141:104749. doi:10.1016/j.neubiorev.2022.104749
6. Reijnders JS, Ehrt U, Weber WE, et al. A systematic review of prevalence studies in depression in Parkinson’s disease. Mov Disord. 2008;23(2):183-189.
7. Zahodne LB, Marsiske M, Okun MS, et al. Components of depression in Parkinson disease. J Geriatr Psychiatry Neurol. 2012;25(3):131-137.
8. Skapinakis P, Bakola E, Salanti G, et al. Efficacy and acceptability of selective serotonin reuptake inhibitors for the treatment of depression in Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials. BMC Neurology. 2010;10:49. doi:10.1186/1471-2377-10-49
9. Richard IH, McDermott MP, Kurlan R, et al; SAD-PD Study Group. A randomized, double-blind placebo-controlled trial of antidepressants in Parkinson’s disease. Neurology. 2012;78(16):1229-1236.
10. Takahashi M, Tabu H, Ozaki A, et al. Antidepressants for depression, apathy, and gait instability in Parkinson’s disease: a multicenter randomized study. Intern Med. 2019;58(3):361-368.
11. Bonuccelli U, Mecco G, Fabrini G, et al. A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson’s disease. Expert Opin Pharmacother. 2012;13(16):2269-2280.
12. Wantanabe N, Omorio IM, Nakagawa A, et al; MANGA (Meta-Analysis of New Generation Antidepressants) Study Group. Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression. CNS Drugs. 2010;24(1):35-53.
13. Barone P, Scarzella L, Marconi R, et al; Depression/Parkinson Italian Study Group. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-group randomized study. J Neurol. 2006;253(5):601-607.
14. Smith KM, Eyal E, Weintraub D, et al; ADAGIO Investigators. Combined rasagiline and anti-depressant use in Parkinson’s disease in the ADAGIO study: effects on non-motor symptoms and tolerability. JAMA Neurology. 2015;72(1):88-95.
15. Seppi K, Chaudhuri R, Coelho M, et al; the collaborators of the Parkinson’s Disease Update on Non-Motor Symptoms Study Group on behalf of the Movement Disorders Society Evidence-Based Medicine Committee. Update on treatments for nonmotor symptoms of Parkinson’s disease--an evidence-based medicine review. Mov Disord. 2019;34(2):180-198.
16. Kwok JYY, Kwan JCY, Auyeung M, et al. Effects of mindfulness yoga vs stretching and resistance training exercises on anxiety and depression for people with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2019;76(7):755-763.
17. De Waele S, Cras P, Crosiers D. Apathy in Parkinson’s disease: defining the Park apathy subtype. Brain Sci. 2022;12(7):923.
18. Mele B, Van S, Holroyd-Leduc J, et al. Diagnosis, treatment and management of apathy in Parkinson’s disease: a scoping review. BMJ Open. 2020;10(9):037632. doi:10.1136/bmjopen-2020-037632
19. Mele B, Ismail Z, Goodarzi Z, et al. Non-pharmacological interventions to treat apathy in Parkinson’s disease: a realist review. Clin Park Relat Disord. 2021;4:100096. doi:10.1016/j.prdoa.2021.100096
20. Chung SJ, Asgharnejad M, Bauer L, et al. Evaluation of rotigotine transdermal patch for the treatment of depressive symptoms in patients with Parkinson’s disease. Expert Opin Pharmacother. 2016;(17)11:1453-1461.
21. Goldman JG, Guerra CM. Treatment of nonmotor symptoms associated with Parkinson disease. Neurol Clin. 2020;38(2):269-292.
22. Schneider RB, Auinger P, Tarolli CG, et al. A trial of buspirone for anxiety in Parkinson’s disease: safety and tolerability. Parkinsonism Relat Disord. 2020;81:69-74.
23. Moonen AJH, Mulders AEP, Defebvre L, et al. Cognitive behavioral therapy for anxiety in Parkinson’s disease: a randomized controlled trial. Mov Disord. 2021;36(11):2539-2548.
24. Shulman LM, Singer C, Bean JA, et al. Internal tremor in patient with Parkinson’s disease. Mov Disord. 1996;11(1):3-7.
25. Cochrane GD, Rizvi S, Abrantes A, et al. Internal tremor in Parkinson’s disease, multiple sclerosis, and essential tremor. Parkinsonism Relat Disord. 2015;21(10):1145-1147.
26. Del Prete E, Schmitt E, Meoni S, et al. Do neuropsychiatric fluctuations temporally match motor fluctuations in Parkinson’s disease? Neurol Sci. 2022;43(6):3641-3647.
27. Kleiner G, Fernandez HH, Chou KL, et al. Non-motor fluctuations in Parkinson’s disease: validation of the non-motor fluctuation assessment questionnaire. Mov Disord. 2021;36(6):1392-1400.
28. Pachi I, Maraki MI, Giagkou N, et al. Late life psychotic features in prodromal Parkinson’s disease. Parkinsonism Relat Disord. 2021;86:67-73.
29. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson’s disease. Arch Neurol. 2010;67(8):996-1001.
30. Chang A, Fox SH. Psychosis in Parkinson’s disease: epidemiology, pathophysiology, and management. Drugs. 2016;76(11):1093-1118.
31. Kasunich A, Kilbane C, Wiggins R. Movement disorders moment: pain and palliative care in movement disorders. Practical Neurology. 2021;20(4):63-67.
32. Burn D, Emre M, McKeith I, et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord. 2006;21(11):1899-1907.
33. Tripathi M, Vibha D. Reversible dementias. Indian J Psychiatry. 2009; 51 Suppl 1(Suppl 1): S52-S55.
34. Dalrymple-Alford JC, MacAskill MR, Nakas CT, et al. The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology. 2010;75(19):1717-1725.
35. Goldman J, Sieg, E. Cognitive impairment and dementia in Parkinson disease. Clin Geriatr Med. 2020;36(2):365-377.
36. Gonzalez-Latapi P, Bayram E, Litvan I, et al. Cognitive impairment in Parkinson’s disease: epidemiology, clinical profile, protective and risk factors. Behav Sci (Basel). 2021;11(5):74.
37. Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society Task Force Guidelines. Mov Disord. 2012;27(3):349-356.
38. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22(16):2314-2324.
39. Aarsland D, Batzu L, Halliday GM, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers. 2021;7(1):47. doi:10.1038/s41572-021-00280-3
40. Weintraub D, Claassen DO. Impulse control and related disorders in Parkinson’s disease. Int Rev Neurobiol. 2017;133:679-717.
41. Vilas D, Pont-Sunyer C, Tolosa E. Impulse control disorders in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18 Suppl 1:S80-S84.
42. Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010;67(5):589-595.
43. Faouzi J, Corvol JC, Mariani LL. Impulse control disorders and related behaviors in Parkinson’s disease: risk factors, clinical and genetic aspects, and management. Curr Opin Neurol. 2021;34(4):547-555.
44. Samuel M, Rodriguez-Oroz M, Antonini A, et al. Impulse control disorders in Parkinson’s disease: management, controversies, and potential approaches. Mov Disord. 2015;30(2):150-159.
45. Frank MJ, Samanta J, Moustafa AA, et al. Hold your horses: impulsivity, deep brain stimulation and medication in Parkinsonism. Science. 2007;318(5854):1309-1312.
46. Jahanshahi M, Obeso I, Baunez C, et al. Parkinson’s disease, the subthalamic nucleus, inhibition, and impulsivity. Mov Disord. 2015;30(2):128-140.
47. Castrioto A, Lhommée E, Moro E, et al. Mood and behavioral effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurol. 2014;13(3):287-305.
Parkinson’s disease (PD) is a neurodegenerative condition diagnosed pathologically by alpha synuclein–containing Lewy bodies and dopaminergic cell loss in the substantia nigra pars compacta of the midbrain. Loss of dopaminergic input to the caudate and putamen disrupts the direct and indirect basal ganglia pathways for motor control and contributes to the motor symptoms of PD.1 According to the Movement Disorder Society criteria, PD is diagnosed clinically by bradykinesia (slowness of movement) plus resting tremor and/or rigidity in the presence of supportive criteria, such as levodopa responsiveness and hyposmia, and in the absence of exclusion criteria and red flags that would suggest atypical parkinsonism or an alternative diagnosis.2
Although the diagnosis and treatment of PD focus heavily on the motor symptoms, nonmotor symptoms can arise decades before the onset of motor symptoms and continue throughout the lifespan. Nonmotor symptoms affect patients from head (ie, cognition and mood) to toe (ie, striatal toe pain) and multiple organ systems in between, including the olfactory, integumentary, cardiovascular, gastrointestinal, genitourinary, and autonomic nervous systems. Thus, it is not surprising that nonmotor symptoms of PD impact health-related quality of life more substantially than motor symptoms.3 A helpful analogy is to consider the motor symptoms of PD as the tip of the iceberg and the nonmotor symptoms as the larger, submerged portions of the iceberg.4
Nonmotor symptoms can negatively impact the treatment of motor symptoms. For example, imagine a patient who is very rigid and dyscoordinated in the arms and legs, which limits their ability to dress and walk. If this patient also suffers from nonmotor symptoms of orthostatic hypotension and psychosis—both of which can be exacerbated by levodopa—dose escalation of levodopa for the rigidity and dyscoordination could be compromised, rendering the patient undertreated and less mobile.
In this review, we focus on identifying and managing nonmotor symptoms of PD that are relevant to psychiatric practice, including mood and motivational disorders, anxiety disorders, psychosis, cognitive disorders, and disorders related to the pharmacologic and surgical treatment of PD (Figure 1).
Mood and motivational disorders
Depression
Depression is a common symptom in PD that can occur in the prodromal period years to decades before the onset of motor symptoms, as well as throughout the disease course.5 The prevalence of depression in PD varies from 3% to 90%, depending on the methods of assessment, clinical setting of assessment, motor symptom severity, and other factors; clinically significant depression likely affects approximately 35% to 38% of patients.5,6 How depression in patients with PD differs from depression in the general population is not entirely understood, but there does seem to be less guilt and suicidal ideation and a substantial component of negative affect, including dysphoria and anxiety.7 Practically speaking, depression is treated similarly in PD and general populations, with a few considerations.
Despite limited randomized controlled trials (RCTs) for efficacy specifically in patients with PD, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are generally considered first-line treatments. There is also evidence for tricyclic antidepressants (TCAs), but due to potential worsening of orthostatic hypotension and cognition, TCAs may not be a favorable option for certain patients with PD.8,9 All antidepressants have the potential to worsen tremor. Theoretically, SNRIs, with noradrenergic activity, may be less tolerable than SSRIs in patients with PD. However, worsening tremor generally has not been a clinically significant adverse event reported in PD depression clinical trials, although it was seen in 17% of patients receiving paroxetine and 21% of patients receiving venlafaxine compared to 7% of patients receiving placebo.9-11 If tremor worsens, mirtazapine could be considered because it has been reported to cause less tremor than SSRIs or TCAs.12
Among medications for PD, pramipexole, a dopamine agonist, may have a beneficial effect on depression.13 Additionally, some evidence supports rasagiline, a monoamine oxidase type B inhibitor, as an adjunctive medication for depression in PD.14 Nevertheless, antidepressant medications remain the standard pharmacologic treatment for PD depression.
Continue to: In terms of nonpharmacologic options...
In terms of nonpharmacologic options, cognitive-behavioral therapy (CBT) is likely efficacious, exercise (especially yoga) is likely efficacious, and repetitive transcranial magnetic stimulation may be efficacious.15,16 While further high-quality trials are needed, these treatments are low-risk and can be considered, especially for patients who cannot tolerate medications.
Apathy
Apathy—a loss of motivation and goal-directed behavior—can occur in up to 30% of patients during the prodromal period of PD, and in up to 70% of patients throughout the disease course.17 Apathy can coexist with depression, which can make apathy difficult to diagnose.17 Given the time constraints of a clinic visit, a practical approach would be to first screen for depression and cognitive impairment. If there is continued suspicion of apathy, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale part I question (“In the past week have you felt indifferent to doing activities or being with people?”) can be used to screen for apathy, and more detailed scales, such as the Apathy Scale (AS) or Lille Apathy Rating Scale (LARS), could be used if indicated.18
There are limited high-quality positive trials of apathy-specific treatments in PD. In an RCT of patients with PD who did not have depression or dementia, rivastigmine improved LARS scores compared to placebo.15 Piribedil, a D2/D3 receptor agonist, improved apathy in patients who underwent subthalamic nucleus deep brain stimulation (STN DBS).15 Exercise such as individualized physical therapy programs, dance, and Nordic walking as well as mindfulness interventions were shown to significantly reduce apathy scale scores.19 SSRIs, SNRIs, and rotigotine showed a trend toward reducing AS scores in RCTs.10,20
Larger, high-quality studies are needed to clarify the treatment of apathy in PD. In the meantime, a reasonable approach is to first treat any comorbid psychiatric or cognitive disorders, since apathy can be associated with these conditions, and to optimize antiparkinsonian medications for motor symptoms, motor fluctuations, and nonmotor fluctuations. Then, the investigational apathy treatments described in this section could be considered on an individual basis.
Anxiety disorders
Anxiety is seen throughout the disease course of PD in approximately 30% to 50% of patients.21 It can manifest as generalized anxiety disorder, panic disorder, and other anxiety disorders. There are no high-quality RCTs of pharmacologic treatments of anxiety specifically in patients with PD, except for a negative safety and tolerability study of buspirone in which one-half of patients experienced worsening motor symptoms.15,22 Thus, the treatment of anxiety in patients with PD is similar to treatments in the general population. SSRIs and SNRIs are typically considered first-line, benzodiazepines are sometimes used with caution (although cognitive adverse effects and fall risk need to be considered), and nonpharmacologic treatments such as mindfulness yoga, exercise, CBT, and psychotherapy can be effective.16,21,23
Continue to: Because there is the lack...
Because there is the lack of evidence-based treatments for anxiety in PD, we highlight 2 PD-specific anxiety disorders: internal tremor, and nonmotor “off” anxiety.
Internal tremor
Internal tremor is a sense of vibration in the axial and/or appendicular muscles that cannot be seen externally by the patient or examiner. It is not yet fully understood if this phenomenon is sensory, anxiety-related, related to subclinical tremor, or the result of a combination of these factors (ie, sensory awareness of a subclinical tremor that triggers or is worsened by anxiety). There is some evidence for subclinical tremor on electromyography, but internal tremor does not respond to antiparkinsonian medications in 70% of patients.24 More electrophysiological research is needed to clarify this phenomenon. Internal tremor has been associated with anxiety in 64% of patients and often improves with anxiolytic therapies.24
Although poorly understood, internal tremor is a documented phenomenon in 33% to 44% of patients with PD, and in some cases, it may be an initial symptom that motivates a patient to seek medical attention for the first time.24,25 Internal tremor has also been reported in patients with essential tremor and multiple sclerosis.25 Therefore, physicians should be aware of internal tremor because this symptom could herald an underlying neurological disease.
Nonmotor ‘off’ anxiety
Patients with PD are commonly prescribed carbidopa-levodopa, a dopamine precursor, at least 3 times daily. Initially, this medication controls motor symptoms well from 1 dose to the next. However, as the disease progresses, some patients report motor fluctuations in which an individual dose of carbidopa-levodopa may wear off early, take longer than usual to take effect, or not take effect at all. Patients describe these periods as an “off” state in which they do not feel their medications are working. Such motor fluctuations can lead to anxiety and avoidance behaviors, because patients fear being in public at times when the medication does not adequately control their motor symptoms.
In addition to these motor symptom fluctuations and related anxiety, patients can also experience nonmotor symptom fluctuations. A wide variety of nonmotor symptoms, such as mood, cognitive, and behavioral symptoms, have been reported to fluctuate in parallel with motor symptoms.26,27 One study reported fluctuating restlessness in 39% of patients with PD, excessive worry in 17%, shortness of breath in 13%, excessive sweating and fear in 12%, and palpitations in 10%.27 A patient with fluctuating shortness of breath, sweating, and palpitations (for example) may repeatedly present to the emergency department with a negative cardiac workup and eventually be diagnosed with panic disorder, whereas the patient is truly experiencing nonmotor “off” symptoms. Thus, it is important to be aware of nonmotor fluctuations so this diagnosis can be made and the symptoms appropriately treated. The first step in treating nonmotor fluctuations is to optimize the antiparkinsonian regimen to minimize fluctuations. If “off” anxiety symptoms persist, anxiolytic medications can be prescribed.21
Continue to: Psychosis
Psychosis
Psychosis can occur in prodromal and early PD but is most common in advanced PD.28 One study reported that 60% of patients developed hallucinations or delusions after 12 years of follow-up.29 Disease duration, disease severity, dementia, and rapid eye movement sleep behavior disorder are significant risk factors for psychosis in PD.30 Well-formed visual hallucinations are the most common manifestation of psychosis in patients with PD. Auditory hallucinations and delusions are less common. Delusions are usually seen in patients with dementia and are often paranoid delusions, such as of spousal infidelity.30 Sensory hallucinations can occur, but should not be mistaken with formication, a central pain syndrome in PD that can represent a nonmotor “off” symptom that may respond to dopaminergic medication.31 Other more mild psychotic symptoms include illusions or misinterpretation of stimuli, false sense of presence, and passage hallucinations of fleeting figures in the peripheral vision.30
The pathophysiology of PD psychosis is not entirely understood but differs from psychosis in other disorders. It can occur in the absence of antiparkinsonian medication exposure and is thought to be a consequence of the underlying disease process of PD involving neurodegeneration in certain brain regions and aberrant neurotransmission of not only dopamine but also serotonin, acetylcholine, and glutamate.30
Figure 2 outlines the management of psychosis in PD. After addressing medical and medication-related causes, it is important to determine if the psychotic symptom is sufficiently bothersome to and/or potentially dangerous for the patient to warrant treatment. If treatment is indicated, pimavanserin and clozapine are efficacious for psychosis in PD without worsening motor symptoms, and quetiapine is possibly efficacious with a low risk of worsening motor symptoms.15 Other antipsychotics, such as olanzapine, risperidone, and haloperidol, can substantially worsen motor symptoms.15 Both second-generation antipsychotics and pimavanserin have an FDA black-box warning for a higher risk of all-cause mortality in older patients with dementia; however, because psychosis is associated with early mortality in PD, the risk/benefit ratio should be discussed with the patient and family for shared decision-making.30 If the patient also has dementia, rivastigmine—which is FDA-approved for PD dementia (PDD)—may also improve hallucinations.32
Cognitive disorders
This section focuses on PD mild cognitive impairment (PD-MCI) and PDD. When a patient with PD reports cognitive concerns, the approach outlined in Figure 3 can be used to diagnose the cognitive disorder. A detailed history, medication review, and physical examination can identify any medical or psychiatric conditions that could affect cognition. The American Academy of Neurology recommends screening for depression, obtaining blood levels of vitamin B12 and thyroid-stimulating hormone, and obtaining a CT or MRI of the brain to rule out reversible causes of dementia.33 A validated screening test such as the Montreal Cognitive Assessment, which has higher sensitivity for PD-MCI than the Mini-Mental State Examination, is used to identify and quantify cognitive impairment.34 Neuropsychological testing is the gold standard and can be used to confirm and/or better quantify the degree and domains of cognitive impairment.35 Typically, cognitive deficits in PD affect executive function, attention, and/or visuospatial domains more than memory and language early on, and deficits in visuospatial and language domains have the highest sensitivity for predicting progression to PDD.36
Once reversible causes of dementia are addressed or ruled out and cognitive testing is completed, the Movement Disorder Society (MDS) criteria for PD-MCI and PDD summarized in Figure 3 can be used to diagnose the cognitive disorder.37,38 The MDS criteria for PDD require a diagnosis of PD for ≥1 year prior to the onset of dementia to differentiate PDD from dementia with Lewy bodies (DLB). If the dementia starts within 1 year of the onset of parkinsonism, the diagnosis would be DLB. PDD and DLB are on the spectrum of Lewy body dementia, with the same Lewy body pathology in different temporal and spatial distributions in the brain.38
Continue to: PD-MCI is present in...
PD-MCI is present in approximately 25% of patients.35 PD-MCI does not always progress to dementia but increases the risk of dementia 6-fold. The prevalence of PDD increases with disease duration; it is present in approximately 50% of patients at 10 years and 80% of patients at 20 years of disease.35 Rivastigmine is the only FDA-approved medication to slow progression of PDD. There is insufficient evidence for other acetylcholinesterase inhibitors and memantine.15 Unfortunately, RCTs of pharmacotherapy for PD-MCI have failed to show efficacy. However, exercise, cognitive rehabilitation, and neuromodulation are being studied. In the meantime, addressing modifiable risk factors (such as vascular risk factors and alcohol consumption) and treating comorbid orthostatic hypotension, obstructive sleep apnea, and depression may improve cognition.35,39
Treatment-related disorders
Impulse control disorders
Impulse control disorders (ICDs) are an important medication-related consideration in patients with PD. The ICDs seen in PD include pathological gambling, binge eating, excessive shopping, hypersexual behaviors, and dopamine dysregulation syndrome (Table). These disorders are more common in younger patients with a history of impulsive personality traits and addictive behaviors (eg, history of tobacco or alcohol abuse), and are most strongly associated with dopaminergic therapies, particularly the dopamine agonists.40,41 In the DOMINION study, the odds of ICDs were 2- to 3.5-fold higher in patients taking dopamine agonists.42 This is mainly thought to be due to stimulation of D2/D3 receptors in the mesolimbic system.40 High doses of levodopa, monoamine oxidase inhibitors, and amantadine are also associated with ICDs.40-42
The first step in managing ICDs is diagnosing them, which can be difficult because patients often are not forthcoming about these problems due to embarrassment or failure to recognize that the ICD is related to PD medications. If a family member accompanies the patient at the visit, the patient may not want to disclose the amount of money they spend or the extent to which the behavior is a problem. Thus, a screening questionnaire, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) can be a helpful way for patients to alert the clinician to the issue.41 Education for the patient and family is crucial before the ICD causes significant financial, health, or relationship problems.
The mainstay of treatment is to reduce or taper off the dopamine agonist or other offending agent while monitoring for worsening motor symptoms and dopamine withdrawal syndrome. If this is unsuccessful, there is very limited evidence for further treatment strategies (Table), including antidepressants, antipsychotics, and mood stabilizers.40,43,44 There is insufficient evidence for naltrexone based on an RCT that failed to meet its primary endpoint, although naltrexone did significantly reduce QUIP scores.15,44 There is also insufficient evidence for amantadine, which showed benefit in some studies but was associated with ICDs in the DOMINION study.15,40,42 In terms of nonpharmacologic treatments, CBT is likely efficacious.15,40 There are mixed results for STN DBS. Some studies showed improvement in the ICD, due at least in part to dopaminergic medication reduction postoperatively, but this treatment has also been reported to increase impulsivity.40,45
Deep brain stimulation–related disorders
For patients with PD, the ideal lead location for STN DBS is the dorsolateral aspect of the STN, as this is the motor region of the nucleus. The STN functions in indirect and hyperdirect pathways to put the brake on certain motor programs so only the desired movement can be executed. Its function is clinically demonstrated by patients with STN stroke who develop excessive ballistic movements. Adjacent to the motor region of the STN is a centrally located associative region and a medially located limbic region. Thus, when stimulating the dorsolateral STN, current can spread to those regions as well, and the STN’s ability to put the brake on behavioral and emotional programs can be affected.46 Stimulation of the STN has been associated with mania, euphoria, new-onset ICDs, decreased verbal fluency, and executive dysfunction. Depression, apathy, and anxiety can also occur, but more commonly result from rapid withdrawal of antiparkinsonian medications after DBS surgery.46,47 Therefore, for PD patients with DBS with new or worsening psychiatric or cognitive symptoms, it is important to inquire about any recent programming sessions with neurology as well as recent self-increases in stimulation by the patient using their controller. Collaboration with neurology is important to troubleshoot whether stimulation could be contributing to the patient’s psychiatric or cognitive symptoms.
Continue to: Bottom Line
Bottom Line
Mood, anxiety, psychotic, and cognitive symptoms and disorders are common psychiatric manifestations associated with Parkinson’s disease (PD). In addition, patients with PD may experience impulsive control disorders and other symptoms related to treatments they receive for PD. Careful assessment and collaboration with neurology is crucial to alleviating the effects of these conditions.
Related Resources
- Weintraub D, Aarsland D, Chaudhuri KR, et al. The neuropsychiatry of Parkinson’s disease: advances and challenges. Lancet Neurology. 2022;21(1):89-102. doi:10.1016/S1474-4422(21)00330-6
- Goldman JG, Guerra CM. Treatment of nonmotor symptoms associated with Parkinson disease. Neurologic Clinics. 2020;38(2):269-292. doi:10.1016/j.ncl.2019.12.003
- Castrioto A, Lhommee E, Moro E et al. Mood and behavioral effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurology. 2014;13(3):287-305. doi:10.1016/ S1474-4422(13)70294-1
Drug Brand Names
Amantadine • Gocovri
Carbidopa-levodopa • Sinemet
Clozapine • Clozaril
Haloperidol • Haldol
Memantine • Namenda
Mirtazapine • Remeron
Naltrexone • Vivitrol
Olanzapine • Zyprexa
Paroxetine • Paxil
Pimavanserin • Nuplazid
Piribedil • Pronoran
Pramipexole • Mirapex
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Rivastigmine • Exelon
Ropinirole • Requip
Rotigotine • Neupro
Venlafaxine • Effexor
Zonisamide • Zonegran
Parkinson’s disease (PD) is a neurodegenerative condition diagnosed pathologically by alpha synuclein–containing Lewy bodies and dopaminergic cell loss in the substantia nigra pars compacta of the midbrain. Loss of dopaminergic input to the caudate and putamen disrupts the direct and indirect basal ganglia pathways for motor control and contributes to the motor symptoms of PD.1 According to the Movement Disorder Society criteria, PD is diagnosed clinically by bradykinesia (slowness of movement) plus resting tremor and/or rigidity in the presence of supportive criteria, such as levodopa responsiveness and hyposmia, and in the absence of exclusion criteria and red flags that would suggest atypical parkinsonism or an alternative diagnosis.2
Although the diagnosis and treatment of PD focus heavily on the motor symptoms, nonmotor symptoms can arise decades before the onset of motor symptoms and continue throughout the lifespan. Nonmotor symptoms affect patients from head (ie, cognition and mood) to toe (ie, striatal toe pain) and multiple organ systems in between, including the olfactory, integumentary, cardiovascular, gastrointestinal, genitourinary, and autonomic nervous systems. Thus, it is not surprising that nonmotor symptoms of PD impact health-related quality of life more substantially than motor symptoms.3 A helpful analogy is to consider the motor symptoms of PD as the tip of the iceberg and the nonmotor symptoms as the larger, submerged portions of the iceberg.4
Nonmotor symptoms can negatively impact the treatment of motor symptoms. For example, imagine a patient who is very rigid and dyscoordinated in the arms and legs, which limits their ability to dress and walk. If this patient also suffers from nonmotor symptoms of orthostatic hypotension and psychosis—both of which can be exacerbated by levodopa—dose escalation of levodopa for the rigidity and dyscoordination could be compromised, rendering the patient undertreated and less mobile.
In this review, we focus on identifying and managing nonmotor symptoms of PD that are relevant to psychiatric practice, including mood and motivational disorders, anxiety disorders, psychosis, cognitive disorders, and disorders related to the pharmacologic and surgical treatment of PD (Figure 1).
Mood and motivational disorders
Depression
Depression is a common symptom in PD that can occur in the prodromal period years to decades before the onset of motor symptoms, as well as throughout the disease course.5 The prevalence of depression in PD varies from 3% to 90%, depending on the methods of assessment, clinical setting of assessment, motor symptom severity, and other factors; clinically significant depression likely affects approximately 35% to 38% of patients.5,6 How depression in patients with PD differs from depression in the general population is not entirely understood, but there does seem to be less guilt and suicidal ideation and a substantial component of negative affect, including dysphoria and anxiety.7 Practically speaking, depression is treated similarly in PD and general populations, with a few considerations.
Despite limited randomized controlled trials (RCTs) for efficacy specifically in patients with PD, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are generally considered first-line treatments. There is also evidence for tricyclic antidepressants (TCAs), but due to potential worsening of orthostatic hypotension and cognition, TCAs may not be a favorable option for certain patients with PD.8,9 All antidepressants have the potential to worsen tremor. Theoretically, SNRIs, with noradrenergic activity, may be less tolerable than SSRIs in patients with PD. However, worsening tremor generally has not been a clinically significant adverse event reported in PD depression clinical trials, although it was seen in 17% of patients receiving paroxetine and 21% of patients receiving venlafaxine compared to 7% of patients receiving placebo.9-11 If tremor worsens, mirtazapine could be considered because it has been reported to cause less tremor than SSRIs or TCAs.12
Among medications for PD, pramipexole, a dopamine agonist, may have a beneficial effect on depression.13 Additionally, some evidence supports rasagiline, a monoamine oxidase type B inhibitor, as an adjunctive medication for depression in PD.14 Nevertheless, antidepressant medications remain the standard pharmacologic treatment for PD depression.
Continue to: In terms of nonpharmacologic options...
In terms of nonpharmacologic options, cognitive-behavioral therapy (CBT) is likely efficacious, exercise (especially yoga) is likely efficacious, and repetitive transcranial magnetic stimulation may be efficacious.15,16 While further high-quality trials are needed, these treatments are low-risk and can be considered, especially for patients who cannot tolerate medications.
Apathy
Apathy—a loss of motivation and goal-directed behavior—can occur in up to 30% of patients during the prodromal period of PD, and in up to 70% of patients throughout the disease course.17 Apathy can coexist with depression, which can make apathy difficult to diagnose.17 Given the time constraints of a clinic visit, a practical approach would be to first screen for depression and cognitive impairment. If there is continued suspicion of apathy, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale part I question (“In the past week have you felt indifferent to doing activities or being with people?”) can be used to screen for apathy, and more detailed scales, such as the Apathy Scale (AS) or Lille Apathy Rating Scale (LARS), could be used if indicated.18
There are limited high-quality positive trials of apathy-specific treatments in PD. In an RCT of patients with PD who did not have depression or dementia, rivastigmine improved LARS scores compared to placebo.15 Piribedil, a D2/D3 receptor agonist, improved apathy in patients who underwent subthalamic nucleus deep brain stimulation (STN DBS).15 Exercise such as individualized physical therapy programs, dance, and Nordic walking as well as mindfulness interventions were shown to significantly reduce apathy scale scores.19 SSRIs, SNRIs, and rotigotine showed a trend toward reducing AS scores in RCTs.10,20
Larger, high-quality studies are needed to clarify the treatment of apathy in PD. In the meantime, a reasonable approach is to first treat any comorbid psychiatric or cognitive disorders, since apathy can be associated with these conditions, and to optimize antiparkinsonian medications for motor symptoms, motor fluctuations, and nonmotor fluctuations. Then, the investigational apathy treatments described in this section could be considered on an individual basis.
Anxiety disorders
Anxiety is seen throughout the disease course of PD in approximately 30% to 50% of patients.21 It can manifest as generalized anxiety disorder, panic disorder, and other anxiety disorders. There are no high-quality RCTs of pharmacologic treatments of anxiety specifically in patients with PD, except for a negative safety and tolerability study of buspirone in which one-half of patients experienced worsening motor symptoms.15,22 Thus, the treatment of anxiety in patients with PD is similar to treatments in the general population. SSRIs and SNRIs are typically considered first-line, benzodiazepines are sometimes used with caution (although cognitive adverse effects and fall risk need to be considered), and nonpharmacologic treatments such as mindfulness yoga, exercise, CBT, and psychotherapy can be effective.16,21,23
Continue to: Because there is the lack...
Because there is the lack of evidence-based treatments for anxiety in PD, we highlight 2 PD-specific anxiety disorders: internal tremor, and nonmotor “off” anxiety.
Internal tremor
Internal tremor is a sense of vibration in the axial and/or appendicular muscles that cannot be seen externally by the patient or examiner. It is not yet fully understood if this phenomenon is sensory, anxiety-related, related to subclinical tremor, or the result of a combination of these factors (ie, sensory awareness of a subclinical tremor that triggers or is worsened by anxiety). There is some evidence for subclinical tremor on electromyography, but internal tremor does not respond to antiparkinsonian medications in 70% of patients.24 More electrophysiological research is needed to clarify this phenomenon. Internal tremor has been associated with anxiety in 64% of patients and often improves with anxiolytic therapies.24
Although poorly understood, internal tremor is a documented phenomenon in 33% to 44% of patients with PD, and in some cases, it may be an initial symptom that motivates a patient to seek medical attention for the first time.24,25 Internal tremor has also been reported in patients with essential tremor and multiple sclerosis.25 Therefore, physicians should be aware of internal tremor because this symptom could herald an underlying neurological disease.
Nonmotor ‘off’ anxiety
Patients with PD are commonly prescribed carbidopa-levodopa, a dopamine precursor, at least 3 times daily. Initially, this medication controls motor symptoms well from 1 dose to the next. However, as the disease progresses, some patients report motor fluctuations in which an individual dose of carbidopa-levodopa may wear off early, take longer than usual to take effect, or not take effect at all. Patients describe these periods as an “off” state in which they do not feel their medications are working. Such motor fluctuations can lead to anxiety and avoidance behaviors, because patients fear being in public at times when the medication does not adequately control their motor symptoms.
In addition to these motor symptom fluctuations and related anxiety, patients can also experience nonmotor symptom fluctuations. A wide variety of nonmotor symptoms, such as mood, cognitive, and behavioral symptoms, have been reported to fluctuate in parallel with motor symptoms.26,27 One study reported fluctuating restlessness in 39% of patients with PD, excessive worry in 17%, shortness of breath in 13%, excessive sweating and fear in 12%, and palpitations in 10%.27 A patient with fluctuating shortness of breath, sweating, and palpitations (for example) may repeatedly present to the emergency department with a negative cardiac workup and eventually be diagnosed with panic disorder, whereas the patient is truly experiencing nonmotor “off” symptoms. Thus, it is important to be aware of nonmotor fluctuations so this diagnosis can be made and the symptoms appropriately treated. The first step in treating nonmotor fluctuations is to optimize the antiparkinsonian regimen to minimize fluctuations. If “off” anxiety symptoms persist, anxiolytic medications can be prescribed.21
Continue to: Psychosis
Psychosis
Psychosis can occur in prodromal and early PD but is most common in advanced PD.28 One study reported that 60% of patients developed hallucinations or delusions after 12 years of follow-up.29 Disease duration, disease severity, dementia, and rapid eye movement sleep behavior disorder are significant risk factors for psychosis in PD.30 Well-formed visual hallucinations are the most common manifestation of psychosis in patients with PD. Auditory hallucinations and delusions are less common. Delusions are usually seen in patients with dementia and are often paranoid delusions, such as of spousal infidelity.30 Sensory hallucinations can occur, but should not be mistaken with formication, a central pain syndrome in PD that can represent a nonmotor “off” symptom that may respond to dopaminergic medication.31 Other more mild psychotic symptoms include illusions or misinterpretation of stimuli, false sense of presence, and passage hallucinations of fleeting figures in the peripheral vision.30
The pathophysiology of PD psychosis is not entirely understood but differs from psychosis in other disorders. It can occur in the absence of antiparkinsonian medication exposure and is thought to be a consequence of the underlying disease process of PD involving neurodegeneration in certain brain regions and aberrant neurotransmission of not only dopamine but also serotonin, acetylcholine, and glutamate.30
Figure 2 outlines the management of psychosis in PD. After addressing medical and medication-related causes, it is important to determine if the psychotic symptom is sufficiently bothersome to and/or potentially dangerous for the patient to warrant treatment. If treatment is indicated, pimavanserin and clozapine are efficacious for psychosis in PD without worsening motor symptoms, and quetiapine is possibly efficacious with a low risk of worsening motor symptoms.15 Other antipsychotics, such as olanzapine, risperidone, and haloperidol, can substantially worsen motor symptoms.15 Both second-generation antipsychotics and pimavanserin have an FDA black-box warning for a higher risk of all-cause mortality in older patients with dementia; however, because psychosis is associated with early mortality in PD, the risk/benefit ratio should be discussed with the patient and family for shared decision-making.30 If the patient also has dementia, rivastigmine—which is FDA-approved for PD dementia (PDD)—may also improve hallucinations.32
Cognitive disorders
This section focuses on PD mild cognitive impairment (PD-MCI) and PDD. When a patient with PD reports cognitive concerns, the approach outlined in Figure 3 can be used to diagnose the cognitive disorder. A detailed history, medication review, and physical examination can identify any medical or psychiatric conditions that could affect cognition. The American Academy of Neurology recommends screening for depression, obtaining blood levels of vitamin B12 and thyroid-stimulating hormone, and obtaining a CT or MRI of the brain to rule out reversible causes of dementia.33 A validated screening test such as the Montreal Cognitive Assessment, which has higher sensitivity for PD-MCI than the Mini-Mental State Examination, is used to identify and quantify cognitive impairment.34 Neuropsychological testing is the gold standard and can be used to confirm and/or better quantify the degree and domains of cognitive impairment.35 Typically, cognitive deficits in PD affect executive function, attention, and/or visuospatial domains more than memory and language early on, and deficits in visuospatial and language domains have the highest sensitivity for predicting progression to PDD.36
Once reversible causes of dementia are addressed or ruled out and cognitive testing is completed, the Movement Disorder Society (MDS) criteria for PD-MCI and PDD summarized in Figure 3 can be used to diagnose the cognitive disorder.37,38 The MDS criteria for PDD require a diagnosis of PD for ≥1 year prior to the onset of dementia to differentiate PDD from dementia with Lewy bodies (DLB). If the dementia starts within 1 year of the onset of parkinsonism, the diagnosis would be DLB. PDD and DLB are on the spectrum of Lewy body dementia, with the same Lewy body pathology in different temporal and spatial distributions in the brain.38
Continue to: PD-MCI is present in...
PD-MCI is present in approximately 25% of patients.35 PD-MCI does not always progress to dementia but increases the risk of dementia 6-fold. The prevalence of PDD increases with disease duration; it is present in approximately 50% of patients at 10 years and 80% of patients at 20 years of disease.35 Rivastigmine is the only FDA-approved medication to slow progression of PDD. There is insufficient evidence for other acetylcholinesterase inhibitors and memantine.15 Unfortunately, RCTs of pharmacotherapy for PD-MCI have failed to show efficacy. However, exercise, cognitive rehabilitation, and neuromodulation are being studied. In the meantime, addressing modifiable risk factors (such as vascular risk factors and alcohol consumption) and treating comorbid orthostatic hypotension, obstructive sleep apnea, and depression may improve cognition.35,39
Treatment-related disorders
Impulse control disorders
Impulse control disorders (ICDs) are an important medication-related consideration in patients with PD. The ICDs seen in PD include pathological gambling, binge eating, excessive shopping, hypersexual behaviors, and dopamine dysregulation syndrome (Table). These disorders are more common in younger patients with a history of impulsive personality traits and addictive behaviors (eg, history of tobacco or alcohol abuse), and are most strongly associated with dopaminergic therapies, particularly the dopamine agonists.40,41 In the DOMINION study, the odds of ICDs were 2- to 3.5-fold higher in patients taking dopamine agonists.42 This is mainly thought to be due to stimulation of D2/D3 receptors in the mesolimbic system.40 High doses of levodopa, monoamine oxidase inhibitors, and amantadine are also associated with ICDs.40-42
The first step in managing ICDs is diagnosing them, which can be difficult because patients often are not forthcoming about these problems due to embarrassment or failure to recognize that the ICD is related to PD medications. If a family member accompanies the patient at the visit, the patient may not want to disclose the amount of money they spend or the extent to which the behavior is a problem. Thus, a screening questionnaire, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) can be a helpful way for patients to alert the clinician to the issue.41 Education for the patient and family is crucial before the ICD causes significant financial, health, or relationship problems.
The mainstay of treatment is to reduce or taper off the dopamine agonist or other offending agent while monitoring for worsening motor symptoms and dopamine withdrawal syndrome. If this is unsuccessful, there is very limited evidence for further treatment strategies (Table), including antidepressants, antipsychotics, and mood stabilizers.40,43,44 There is insufficient evidence for naltrexone based on an RCT that failed to meet its primary endpoint, although naltrexone did significantly reduce QUIP scores.15,44 There is also insufficient evidence for amantadine, which showed benefit in some studies but was associated with ICDs in the DOMINION study.15,40,42 In terms of nonpharmacologic treatments, CBT is likely efficacious.15,40 There are mixed results for STN DBS. Some studies showed improvement in the ICD, due at least in part to dopaminergic medication reduction postoperatively, but this treatment has also been reported to increase impulsivity.40,45
Deep brain stimulation–related disorders
For patients with PD, the ideal lead location for STN DBS is the dorsolateral aspect of the STN, as this is the motor region of the nucleus. The STN functions in indirect and hyperdirect pathways to put the brake on certain motor programs so only the desired movement can be executed. Its function is clinically demonstrated by patients with STN stroke who develop excessive ballistic movements. Adjacent to the motor region of the STN is a centrally located associative region and a medially located limbic region. Thus, when stimulating the dorsolateral STN, current can spread to those regions as well, and the STN’s ability to put the brake on behavioral and emotional programs can be affected.46 Stimulation of the STN has been associated with mania, euphoria, new-onset ICDs, decreased verbal fluency, and executive dysfunction. Depression, apathy, and anxiety can also occur, but more commonly result from rapid withdrawal of antiparkinsonian medications after DBS surgery.46,47 Therefore, for PD patients with DBS with new or worsening psychiatric or cognitive symptoms, it is important to inquire about any recent programming sessions with neurology as well as recent self-increases in stimulation by the patient using their controller. Collaboration with neurology is important to troubleshoot whether stimulation could be contributing to the patient’s psychiatric or cognitive symptoms.
Continue to: Bottom Line
Bottom Line
Mood, anxiety, psychotic, and cognitive symptoms and disorders are common psychiatric manifestations associated with Parkinson’s disease (PD). In addition, patients with PD may experience impulsive control disorders and other symptoms related to treatments they receive for PD. Careful assessment and collaboration with neurology is crucial to alleviating the effects of these conditions.
Related Resources
- Weintraub D, Aarsland D, Chaudhuri KR, et al. The neuropsychiatry of Parkinson’s disease: advances and challenges. Lancet Neurology. 2022;21(1):89-102. doi:10.1016/S1474-4422(21)00330-6
- Goldman JG, Guerra CM. Treatment of nonmotor symptoms associated with Parkinson disease. Neurologic Clinics. 2020;38(2):269-292. doi:10.1016/j.ncl.2019.12.003
- Castrioto A, Lhommee E, Moro E et al. Mood and behavioral effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurology. 2014;13(3):287-305. doi:10.1016/ S1474-4422(13)70294-1
Drug Brand Names
Amantadine • Gocovri
Carbidopa-levodopa • Sinemet
Clozapine • Clozaril
Haloperidol • Haldol
Memantine • Namenda
Mirtazapine • Remeron
Naltrexone • Vivitrol
Olanzapine • Zyprexa
Paroxetine • Paxil
Pimavanserin • Nuplazid
Piribedil • Pronoran
Pramipexole • Mirapex
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Rivastigmine • Exelon
Ropinirole • Requip
Rotigotine • Neupro
Venlafaxine • Effexor
Zonisamide • Zonegran
1. Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet Neurology. 2021;397(10291):2284-2303.
2. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Movement Disorders. 2015;30(12):1591-1601.
3. Martinez-Martin P, Rodriguez-Blazquez C, Kurtiz MM, et al. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov Disord. 2011;26(3):399-406.
4. Langston WJ. The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol. 2006;59(4):591-596.
5. Cong S, Xiang C, Zhang S, et al. Prevalence and clinical aspects of depression in Parkinson’s disease: a systematic review and meta‑analysis of 129 studies. Neurosci Biobehav Rev. 2022;141:104749. doi:10.1016/j.neubiorev.2022.104749
6. Reijnders JS, Ehrt U, Weber WE, et al. A systematic review of prevalence studies in depression in Parkinson’s disease. Mov Disord. 2008;23(2):183-189.
7. Zahodne LB, Marsiske M, Okun MS, et al. Components of depression in Parkinson disease. J Geriatr Psychiatry Neurol. 2012;25(3):131-137.
8. Skapinakis P, Bakola E, Salanti G, et al. Efficacy and acceptability of selective serotonin reuptake inhibitors for the treatment of depression in Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials. BMC Neurology. 2010;10:49. doi:10.1186/1471-2377-10-49
9. Richard IH, McDermott MP, Kurlan R, et al; SAD-PD Study Group. A randomized, double-blind placebo-controlled trial of antidepressants in Parkinson’s disease. Neurology. 2012;78(16):1229-1236.
10. Takahashi M, Tabu H, Ozaki A, et al. Antidepressants for depression, apathy, and gait instability in Parkinson’s disease: a multicenter randomized study. Intern Med. 2019;58(3):361-368.
11. Bonuccelli U, Mecco G, Fabrini G, et al. A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson’s disease. Expert Opin Pharmacother. 2012;13(16):2269-2280.
12. Wantanabe N, Omorio IM, Nakagawa A, et al; MANGA (Meta-Analysis of New Generation Antidepressants) Study Group. Safety reporting and adverse-event profile of mirtazapine described in randomized controlled trials in comparison with other classes of antidepressants in the acute-phase treatment of adults with depression. CNS Drugs. 2010;24(1):35-53.
13. Barone P, Scarzella L, Marconi R, et al; Depression/Parkinson Italian Study Group. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-group randomized study. J Neurol. 2006;253(5):601-607.
14. Smith KM, Eyal E, Weintraub D, et al; ADAGIO Investigators. Combined rasagiline and anti-depressant use in Parkinson’s disease in the ADAGIO study: effects on non-motor symptoms and tolerability. JAMA Neurology. 2015;72(1):88-95.
15. Seppi K, Chaudhuri R, Coelho M, et al; the collaborators of the Parkinson’s Disease Update on Non-Motor Symptoms Study Group on behalf of the Movement Disorders Society Evidence-Based Medicine Committee. Update on treatments for nonmotor symptoms of Parkinson’s disease--an evidence-based medicine review. Mov Disord. 2019;34(2):180-198.
16. Kwok JYY, Kwan JCY, Auyeung M, et al. Effects of mindfulness yoga vs stretching and resistance training exercises on anxiety and depression for people with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2019;76(7):755-763.
17. De Waele S, Cras P, Crosiers D. Apathy in Parkinson’s disease: defining the Park apathy subtype. Brain Sci. 2022;12(7):923.
18. Mele B, Van S, Holroyd-Leduc J, et al. Diagnosis, treatment and management of apathy in Parkinson’s disease: a scoping review. BMJ Open. 2020;10(9):037632. doi:10.1136/bmjopen-2020-037632
19. Mele B, Ismail Z, Goodarzi Z, et al. Non-pharmacological interventions to treat apathy in Parkinson’s disease: a realist review. Clin Park Relat Disord. 2021;4:100096. doi:10.1016/j.prdoa.2021.100096
20. Chung SJ, Asgharnejad M, Bauer L, et al. Evaluation of rotigotine transdermal patch for the treatment of depressive symptoms in patients with Parkinson’s disease. Expert Opin Pharmacother. 2016;(17)11:1453-1461.
21. Goldman JG, Guerra CM. Treatment of nonmotor symptoms associated with Parkinson disease. Neurol Clin. 2020;38(2):269-292.
22. Schneider RB, Auinger P, Tarolli CG, et al. A trial of buspirone for anxiety in Parkinson’s disease: safety and tolerability. Parkinsonism Relat Disord. 2020;81:69-74.
23. Moonen AJH, Mulders AEP, Defebvre L, et al. Cognitive behavioral therapy for anxiety in Parkinson’s disease: a randomized controlled trial. Mov Disord. 2021;36(11):2539-2548.
24. Shulman LM, Singer C, Bean JA, et al. Internal tremor in patient with Parkinson’s disease. Mov Disord. 1996;11(1):3-7.
25. Cochrane GD, Rizvi S, Abrantes A, et al. Internal tremor in Parkinson’s disease, multiple sclerosis, and essential tremor. Parkinsonism Relat Disord. 2015;21(10):1145-1147.
26. Del Prete E, Schmitt E, Meoni S, et al. Do neuropsychiatric fluctuations temporally match motor fluctuations in Parkinson’s disease? Neurol Sci. 2022;43(6):3641-3647.
27. Kleiner G, Fernandez HH, Chou KL, et al. Non-motor fluctuations in Parkinson’s disease: validation of the non-motor fluctuation assessment questionnaire. Mov Disord. 2021;36(6):1392-1400.
28. Pachi I, Maraki MI, Giagkou N, et al. Late life psychotic features in prodromal Parkinson’s disease. Parkinsonism Relat Disord. 2021;86:67-73.
29. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson’s disease. Arch Neurol. 2010;67(8):996-1001.
30. Chang A, Fox SH. Psychosis in Parkinson’s disease: epidemiology, pathophysiology, and management. Drugs. 2016;76(11):1093-1118.
31. Kasunich A, Kilbane C, Wiggins R. Movement disorders moment: pain and palliative care in movement disorders. Practical Neurology. 2021;20(4):63-67.
32. Burn D, Emre M, McKeith I, et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord. 2006;21(11):1899-1907.
33. Tripathi M, Vibha D. Reversible dementias. Indian J Psychiatry. 2009; 51 Suppl 1(Suppl 1): S52-S55.
34. Dalrymple-Alford JC, MacAskill MR, Nakas CT, et al. The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology. 2010;75(19):1717-1725.
35. Goldman J, Sieg, E. Cognitive impairment and dementia in Parkinson disease. Clin Geriatr Med. 2020;36(2):365-377.
36. Gonzalez-Latapi P, Bayram E, Litvan I, et al. Cognitive impairment in Parkinson’s disease: epidemiology, clinical profile, protective and risk factors. Behav Sci (Basel). 2021;11(5):74.
37. Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society Task Force Guidelines. Mov Disord. 2012;27(3):349-356.
38. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22(16):2314-2324.
39. Aarsland D, Batzu L, Halliday GM, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers. 2021;7(1):47. doi:10.1038/s41572-021-00280-3
40. Weintraub D, Claassen DO. Impulse control and related disorders in Parkinson’s disease. Int Rev Neurobiol. 2017;133:679-717.
41. Vilas D, Pont-Sunyer C, Tolosa E. Impulse control disorders in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18 Suppl 1:S80-S84.
42. Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010;67(5):589-595.
43. Faouzi J, Corvol JC, Mariani LL. Impulse control disorders and related behaviors in Parkinson’s disease: risk factors, clinical and genetic aspects, and management. Curr Opin Neurol. 2021;34(4):547-555.
44. Samuel M, Rodriguez-Oroz M, Antonini A, et al. Impulse control disorders in Parkinson’s disease: management, controversies, and potential approaches. Mov Disord. 2015;30(2):150-159.
45. Frank MJ, Samanta J, Moustafa AA, et al. Hold your horses: impulsivity, deep brain stimulation and medication in Parkinsonism. Science. 2007;318(5854):1309-1312.
46. Jahanshahi M, Obeso I, Baunez C, et al. Parkinson’s disease, the subthalamic nucleus, inhibition, and impulsivity. Mov Disord. 2015;30(2):128-140.
47. Castrioto A, Lhommée E, Moro E, et al. Mood and behavioral effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurol. 2014;13(3):287-305.
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16. Kwok JYY, Kwan JCY, Auyeung M, et al. Effects of mindfulness yoga vs stretching and resistance training exercises on anxiety and depression for people with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2019;76(7):755-763.
17. De Waele S, Cras P, Crosiers D. Apathy in Parkinson’s disease: defining the Park apathy subtype. Brain Sci. 2022;12(7):923.
18. Mele B, Van S, Holroyd-Leduc J, et al. Diagnosis, treatment and management of apathy in Parkinson’s disease: a scoping review. BMJ Open. 2020;10(9):037632. doi:10.1136/bmjopen-2020-037632
19. Mele B, Ismail Z, Goodarzi Z, et al. Non-pharmacological interventions to treat apathy in Parkinson’s disease: a realist review. Clin Park Relat Disord. 2021;4:100096. doi:10.1016/j.prdoa.2021.100096
20. Chung SJ, Asgharnejad M, Bauer L, et al. Evaluation of rotigotine transdermal patch for the treatment of depressive symptoms in patients with Parkinson’s disease. Expert Opin Pharmacother. 2016;(17)11:1453-1461.
21. Goldman JG, Guerra CM. Treatment of nonmotor symptoms associated with Parkinson disease. Neurol Clin. 2020;38(2):269-292.
22. Schneider RB, Auinger P, Tarolli CG, et al. A trial of buspirone for anxiety in Parkinson’s disease: safety and tolerability. Parkinsonism Relat Disord. 2020;81:69-74.
23. Moonen AJH, Mulders AEP, Defebvre L, et al. Cognitive behavioral therapy for anxiety in Parkinson’s disease: a randomized controlled trial. Mov Disord. 2021;36(11):2539-2548.
24. Shulman LM, Singer C, Bean JA, et al. Internal tremor in patient with Parkinson’s disease. Mov Disord. 1996;11(1):3-7.
25. Cochrane GD, Rizvi S, Abrantes A, et al. Internal tremor in Parkinson’s disease, multiple sclerosis, and essential tremor. Parkinsonism Relat Disord. 2015;21(10):1145-1147.
26. Del Prete E, Schmitt E, Meoni S, et al. Do neuropsychiatric fluctuations temporally match motor fluctuations in Parkinson’s disease? Neurol Sci. 2022;43(6):3641-3647.
27. Kleiner G, Fernandez HH, Chou KL, et al. Non-motor fluctuations in Parkinson’s disease: validation of the non-motor fluctuation assessment questionnaire. Mov Disord. 2021;36(6):1392-1400.
28. Pachi I, Maraki MI, Giagkou N, et al. Late life psychotic features in prodromal Parkinson’s disease. Parkinsonism Relat Disord. 2021;86:67-73.
29. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson’s disease. Arch Neurol. 2010;67(8):996-1001.
30. Chang A, Fox SH. Psychosis in Parkinson’s disease: epidemiology, pathophysiology, and management. Drugs. 2016;76(11):1093-1118.
31. Kasunich A, Kilbane C, Wiggins R. Movement disorders moment: pain and palliative care in movement disorders. Practical Neurology. 2021;20(4):63-67.
32. Burn D, Emre M, McKeith I, et al. Effects of rivastigmine in patients with and without visual hallucinations in dementia associated with Parkinson’s disease. Mov Disord. 2006;21(11):1899-1907.
33. Tripathi M, Vibha D. Reversible dementias. Indian J Psychiatry. 2009; 51 Suppl 1(Suppl 1): S52-S55.
34. Dalrymple-Alford JC, MacAskill MR, Nakas CT, et al. The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology. 2010;75(19):1717-1725.
35. Goldman J, Sieg, E. Cognitive impairment and dementia in Parkinson disease. Clin Geriatr Med. 2020;36(2):365-377.
36. Gonzalez-Latapi P, Bayram E, Litvan I, et al. Cognitive impairment in Parkinson’s disease: epidemiology, clinical profile, protective and risk factors. Behav Sci (Basel). 2021;11(5):74.
37. Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society Task Force Guidelines. Mov Disord. 2012;27(3):349-356.
38. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22(16):2314-2324.
39. Aarsland D, Batzu L, Halliday GM, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers. 2021;7(1):47. doi:10.1038/s41572-021-00280-3
40. Weintraub D, Claassen DO. Impulse control and related disorders in Parkinson’s disease. Int Rev Neurobiol. 2017;133:679-717.
41. Vilas D, Pont-Sunyer C, Tolosa E. Impulse control disorders in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18 Suppl 1:S80-S84.
42. Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010;67(5):589-595.
43. Faouzi J, Corvol JC, Mariani LL. Impulse control disorders and related behaviors in Parkinson’s disease: risk factors, clinical and genetic aspects, and management. Curr Opin Neurol. 2021;34(4):547-555.
44. Samuel M, Rodriguez-Oroz M, Antonini A, et al. Impulse control disorders in Parkinson’s disease: management, controversies, and potential approaches. Mov Disord. 2015;30(2):150-159.
45. Frank MJ, Samanta J, Moustafa AA, et al. Hold your horses: impulsivity, deep brain stimulation and medication in Parkinsonism. Science. 2007;318(5854):1309-1312.
46. Jahanshahi M, Obeso I, Baunez C, et al. Parkinson’s disease, the subthalamic nucleus, inhibition, and impulsivity. Mov Disord. 2015;30(2):128-140.
47. Castrioto A, Lhommée E, Moro E, et al. Mood and behavioral effects of subthalamic stimulation in Parkinson’s disease. Lancet Neurol. 2014;13(3):287-305.
