Learning Objectives

After taking this webinar, clinicians should be able to:

1. Providers will be able to apply the findings of the meta-analysis to weigh the benefits and risks of long-term antidepressant use and make informed decisions about the appropriate duration of treatment for their patients with MDD.
1. 2. Providers will understand the key findings from the clinical trials that demonstrated failures, including cariprazine in preventing new episodes of bipolar disorder, levomilnacipran in pediatric depression, and the Rejoyn app for depression.

In this episode:

• Antidepressants: When to stop?
• Lumateperone and Lavender in Depression
• Lavender Matches Setraline in First Depression Foray
• Most Long-Term Benzos Avoid Escalating to High Doses
• Clonidine Patch Outperforms Placebo in Tourette'sClonidine in Tourette's
• Treatment Resistant Smoking
• Weight Loss Surgeries May Increase Subs
• Trial Failures: Cariprazine in bipolar, levomilnacipran in pediatric depression, and an app for depression

[Transcript edited for clarity]

Chris Aiken, MD: I'm Dr. Chris Akin.

Greg Malzberg, MD: I'm Dr. Greg Malzberg.

Kellie Newsome, PMHNP: And I'm Kelly Newsome, a psychiatric NP, and we'll bring you the top psychiatric stories from the past month, free of industry support.

Greg Malzberg, MD: Highlights from this month include Lumateperone, Lavender, treatment resistant smoking, and Clonidine patches and Tourettes. A new meta analysis published in Psychiatry Research sheds light on a critical question.

The Optimal Duration of Antidepressant Treatment: Finding the Balance

Greg Malzberg, MD: A new meta-analysis published in Psychiatry Research sheds light on a critical question: How long should patients continue taking an antidepressant after recovery from depression?

The study, led by researchers from Southeast University in China, analyzed data from 35 randomized controlled trials involving over 9,000 patients with MDD. They found that the risk of relapse after stopping antidepressants was significantly related to the duration of initial treatment.

What were the key findings? 

• On average, 34.8% of patients relapsed within 6 months of discontinuing antidepressants, and 45.1% relapsed within a year.
• The risk of relapse was relatively high when antidepressants were taken for less than 3 months. This risk decreased after 3 months of treatment.
• There didn’t appear to be any additional reduction in relapse risk when antidepressants were continued beyond 6 months.
• Younger age was associated with a higher likelihood of relapse after discontinuation.

The results support current guidelines recommending that antidepressants be continued for at least 4-9 months after acute treatment response. However, they question the added benefit of longer durations. 

There were some limitations: there was a lack of trials examining treatment beyond 9 months and inability to fully account for differences between studies. However, the findings provide important insight to help clinicians and patients weigh the benefits and risks of long-term antidepressant use.

This study suggests targeting a "sweet spot" of around 6 months may optimize relapse prevention while avoiding unnecessarily prolonged treatment for many patients with MDD. For now, the results confirms the findings of earlier studies, that at least 6 months of anti-depressants is helpful, but also reassure that indefinite continuation may not be necessary for all.

Lumateperone in Major Depression

Chris Aiken, MD: Lumateperone (Caplyta) is FDA approved in bipolar depression, but until this next study came out we didn’t know whether this antipsychotic could also augment antidepressants in major depressive disorder. Technically, this study hasn’t come out – it’s available in abstract form – so we can only skim the surface of what they found:

https://ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-positive-phase-3-topline

The industry sponsored trial was large - 485 patients – and lasted 6 weeks. Like most antipsychotic studies, it tested the drug in patients who had failed 1-2 antidepressant trials – so not the level of true treatment resistance which requires 2 or more failed trials. 

Lumateperone still has no trials in bipolar mania. To its credit, lumateperone separated from placebo with a medium effect size: effect size (0.6). That’s consistent with its robust effects in bipolar depression, and bigger than the effects we’ve seen with competitors like brexpiprazole and cariprazine. But whether this holds up in a second study is yet to be seen, and we expect that to come out soon as the company will need that to earn the FDA approval they are aiming for.

Lavender in Depression

Kellie Newsome, PMHNP: This next depression trial is the same size as the lumateperone one, but the medication they tested is of a very different nature. Siegfried Kasper and colleagues tested a branded extract of the lavender plant – Silexan – in 489 patients with mild to moderate depression. They tested it against a placebo and an active antidepressant – sertraline 50mg. After 8 weeks, lavender equaled sertraline and both drugs surpassed placebo.

Silexan has regulatory approval for generalized anxiety disorder in 12 European countries, but this is its first foray into major depression. Although it is a prescription in Europe, it is available over the counter in the US as CalmAid, which is made by the pharmaceutical company that produces the prescription form. That separates it from other natural products in the US, many of which suffer from inconsistent manufacturing and are supported by only small clinical trials. Lavender’s anxiety trials are also large, and there it has a large effect size, even surpassing paroxetine and equaling lorazepam in head-to-head comparisons. In anxiety, the dose is 160mg per day, and we suspect the drug was underdosed in this depression study, at only 80 mg per day.

Long-Term Benzodiazepine Use Rarely Leads to Dose Escalation, Danish Study Finds

Gregory Malzberg, MD: Amid concerns about the addictive potential of benzodiazepines, a large cohort study from Denmark published in the American Journal of Psychiatry suggests that long-term use of these medications may be less problematic than often believed. Researchers found that doses rose to high levels in only a small proportion of patients prescribed benzodiazepines and Z-drugs over time.

The study followed nearly 4.3 million adults in Denmark from 2000 to 2020 and looked at the over 900,000 who initiated benzos and z-hypnotics like zolpidem. 

What were the key findings?     

• First, long-term use was rare. Only 15% continued use for more than 1 year, and 3% for more than 7 years.
• Only 5% of patients with at least 3 years of continuous use escalated to doses higher than recommended guidelines. How high is that? You have to convert to diazepam equivalents, and the max they used was 40mg diazepam for patients under 65, or 20mg if 65 or older.
• Substance use disorders, particularly with alcohol, were associated with greater risk of both long-term use and dose escalation.

The findings suggest the risk of dose escalation on benzodiazepine related drugs is relatively low. We have to keep in mind this was an observational study, and only looked at a Danish Cohort (which is a country with strict prescribing regulations), so it’s unclear if this generalizes to countries with different healthcare systems. However, the findings provide reassurance that with appropriate safeguards, these drugs can be used safely for extended periods in many patients.

The authors caution that the results do not negate the need for careful patient selection and monitoring. Patients with psychiatric comorbidities, especially substance use disorders, should be prescribed benzodiazepine related drugs judiciously and receive close follow-up to prevent misuse. This study suggests that fears of inevitable dose escalation with long-term benzodiazepine related drugs use may be overblown. With judicious prescribing and monitoring, these medications can be a valuable tool for managing appropriately selected patients. 

Clonidine Patch Shows Promise for Tourette Syndrome with ADHD

Gregory Malzberg, MD: A recent study published in Psychiatry Investigation offers new hope for children and adolescents with Tourette syndrome and comorbid ADHD. Researchers from China found that clonidine adhesive patches can safely and effectively reduce tic symptoms in this population, with potential benefits for ADHD as well.

The multicenter, randomized, double-blind, placebo-controlled trial included 127 patients aged 6-18 years with Tourette syndrome and ADHD. Participants were randomly assigned to receive clonidine patches at doses of 1.0 mg/week, 1.5 mg/week, 2.0 mg/week, or placebo for 8 weeks.

What were the key findings? 

• First, clonidine worked better than placebo, with an impressive number needed to treat of 2. All 3 doses doses worked equally at improving tics. 
• Although clonidine is FDA approved for ADHD, in this study clonidine brought no significant difference in ADHD symptoms. 
• Only 9 mild to moderate skin-related adverse reactions occurred, all resolving spontaneously. Clonidine patches were well-tolerated at all doses.

Clonidine is already recommended first-line in treatment guidelines for Tourette’s, so what does this study add?  Compared to earlier trials this one has a better design, with a larger sample size and a placebo control. Earlier studies – most of which were from the 1980’s - used an active comparator or a cross-over design. This trial also expands the range of clonidine formulations to transdermal patch. The patch is applied weekly and may be better tolerated for some. In studies of hypertension, clonidine patch caused less fatigue and dry mouth than the oral version.

Treatment Resistant Smoking

Gregory Malzberg, MD: Smokers who don't succeed in quitting with first-line treatments varenicline (Chantix) or combined nicotine replacement therapy (CNRT) may benefit from increasing the dosage or switching medications, according to a new randomized clinical trial published in JAMA.

In this double-blind, placebo-controlled trial, 490 smokers were randomized to receive varenicline (2 mg/day) or combined-NRT (21-mg patch plus 2-mg lozenges) for 6 weeks. Those who hadn't quit at that point were then rerandomized to either continue their initial therapy, switch to the other treatment, or increase the dosage (to 3 mg/day varenicline or 42-mg patch plus lozenges) for another 6 weeks.

What were the key findings?     

• Among varenicline nonresponders, increasing the dosage led to a 20% abstinence rate at end of treatment, compared to 3% with continued initial dosing and 0% after switching to CNRT.
• For CNRT nonresponders, both increasing the dosage and switching to varenicline resulted in 14% abstinence rates, versus 8% with continued CNRT.
• Only the increased dosages of varenicline and CNRT produced better long-term (6-month) quit rates than continuing initial dosages.

The results support increasing varenicline to 3 mg/day in smokers who don't quit on the standard 2 mg/day dose. For CNRT nonresponders, either raising the nicotine patch dose or switching to varenicline appear to be reasonable strategies, with some evidence favoring the dosage increase approach.

Overall, the findings provide much-needed evidence to guide treatment adjustments following an unsuccessful quit attempt on two first-line smoking cessation aids. To recap:

> If your patient is taking varenicline and doesn’t respond, raise the dose from 2 to 3 mg/day

> If they are using a nicotine replacement patch and don’t respond, you can either raise the dose of the patch, like from 21 to 42 mg/day, or switch to varenicline.

By identifying tactics to improve outcomes in this challenging group, this research may help more smokers achieve abstinence despite initial treatment failure. Clinicians should consider these dosage increase and switching strategies to enhance success rates.

Bariatric Surgery Linked to Increased Risk of New-Onset Substance Use Disorders

Gregory Malzberg, MD: A recent meta-analysis published in Obesity Surgery raises concerns about the development of new-onset substance use disorders following bariatric surgery. Researchers from Italy and Canada found that patients who undergo weight-loss surgery may be at heightened risk for substance abuse, particularly opioid use.

The study analyzed data from 7 cohort studies involving over 116,000 patients who underwent bariatric procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy. 

What were the key findings? 

• 1 in 28 patients developed a new stubstance use disorder after bariatric surgery.
• Chronic opioid use was the most common type of new-onset substance abuse disorders, reported in 22.3% to 100% of affected patients.
• Risk factors for developing new-onset substance abuse disorders included pre-existing mental health disorders, public health insurance, higher pre-surgical BMI, and postoperative complications or chronic pain.

This is a serious concern, but why does it happen? The intuitive explanation is that people are replacing food addiction with another addiction. The authors point out some similarities between highly processed foods and drugs of abuse, like rapid absorption, concentrated dose, dopaminergic effects. Both are known to cause cravings and continuous use despite negative consequences. Patients agree – in one study, 83% of people who developed addictions after bariatric surgery felt they had substituted one addiction for another. These explanations make sense, but we’ll keep an open mind – so far the cause is unknown and unproven.

The findings highlight the importance of careful patient selection, thorough pre-surgical assessment, and ongoing multidisciplinary support to identify and manage risk factors for substance abuse. Monitoring for signs of new-onset substance abuse should be a key aspect of postoperative care.

Clinicians should educate patients about the possibility of developing substance use disorders and work closely with them to create personalized prevention and treatment strategies, both before and after surgery. Refining patient selection criteria and optimizing postoperative support may help mitigate this concerning complication of weight-loss procedures.

Failed Trials

Chris Aiken, MD: It’s important to know what works, but just as important to know what does not work. So we close with a few failures: Cariprazine in bipolar, Levomilnacipran in pediatric depression, and an app for depression.

In an industry funded trial, cariprazine (Vraylar) failed to prevent new episodes of bipolar, despite earlier success in treating acute bipolar depression and mania. The study was large, placebo-controlled, and tested the antipsychotic as monotherapy. The drug failed despite several factors that would have favored it, like an enriched design in which only people who responded to cariprazine were included, and early discontinuation after only 2 months of recovery. Clinically, we recommend waiting for at least 6 months of recovery before coming off an antipsychotic in mood disorders.

Next, the SNRI levomilnacipran (Fetzima) failed in 2 new industry funded trials of pediatric depression, joining over a dozen other antidepressants that failed in this population. That leaves only fluoxetine with a strong track record in pediatric depression. Next in line would be escitalopram and citalopram, which have a mix or positive and negative trials despite escitalopram holding FDA approval down to age X. 

Why do so many antidepressants fail in children? The usual answer is that the placebo response is high in this age group, suggesting that a general supportive approach is helpful enough and antidepressants aren’t able to augment that. But that explanation assumes that the meds must be effective – something that hasn’t been proven. Childhood depression may be a different disorder. This population has high rates of conversion to bipolar disorder, and for reasons that appear to be separate from any issues of bipolarity, antidepressants carry a risk of suicidality in children and young adults under age 25, coincidentally, the age where the brain is considered fully matured.

The next one is different kind of failure. It’s an app for depression – Rejoin – and if you haven’t heard of it yet you’ll probably will soon because this app was recently cleared by the FDA. But FDA clearance is a much lower bar to pass than FDA approval, and Rejoin illustrates that point. The approval was based on a large clinical trial where Rejoin failed to make a difference on the primary outcome, although it did succeed on secondary outcomes. We see the same thing with genetic testing – which consistently fails to make a difference on primary outcomes but improves a few secondary measures. The problem is that secondary outcomes are prone to all the random errors that make us long for more scientific studies in the first place, so they confirm little while suggesting a lot.

References: 

Chen, Yanhui et al. “Clonidine Patch for Tourette Syndrome With Attention-Deficit/Hyperactivity Disorder.” Psychiatry investigation vol. 21,4 (2024): 387-395. doi:10.30773/pi.2023.0262

Hu, Yuhua et al. “Association between duration of antidepressant treatment for major depressive disorder and relapse rate after discontinuation: A meta-analysis.” Psychiatry research vol. 337 (2024): 115926. doi:10.1016/j.psychres.2024.115926

Kasper, Siegfried et al. “Lavender oil preparation Silexan is effective in mild-to-moderate major depression: a randomized, placebo- and reference-controlled trial.” European archives of psychiatry and clinical neuroscience, 10.1007/s00406-024-01783-2. 1 Apr. 2024, doi:10.1007/s00406-024-01783-2

Martinelli, Silvia et al. “Bariatric Surgery and New-Onset Substance Use Disorders: A Systematic review and Meta-analysis.” Obesity surgery vol. 34,4 (2024): 1366-1375. doi:10.1007/s11695-024-07130-7

McIntyre, Roger S et al. “Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder.” Bipolar disorders, 10.1111/bdi.13421. 12 Apr. 2024, doi:10.1111/bdi.13421

Radecki, Daniel T et al. “Safety and Efficacy of Levomilnacipran Extended Release in Pediatric Patients Aged 7-17 Years with Major Depressive Disorder: Results of Two Phase 3, Randomized, Double-Blind Studies.” Journal of child and adolescent psychopharmacology, 10.1089/cap.2023.0080. 3 May. 2024, doi:10.1089/cap.2023.0080

Rosenqvist, Thomas Wolff et al. “Long-Term Use of Benzodiazepines and Benzodiazepine-Related Drugs: A Register-Based Danish Cohort Study on Determinants and Risk of Dose Escalation.” The American journal of psychiatry vol. 181,3 (2024): 246-254. doi:10.1176/appi.ajp.20230075

__________

The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one half (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.