CGPR: Can you speak about the challenges in diagnosing and recognizing anxiety in older adults?

Dr. Andreescu: Anxiety in older adults is often overlooked or minimized due to stigma, especially in primary care settings. Older adults may downplay their symptoms or use terms like ‘stress’ instead of ‘anxiety’ or ‘worry.’ Clinicians might assume that anxiety is a normal part of aging and thus fail to provide appropriate treatment. Or they may provide inappropriate care (eg, by prescribing benzodiazepines or sleep aids). However, when psychiatrists are involved, as seen in collaborative care models, anxiety outcomes improve significantly across various settings when compared to usual care (Reynolds CF 3rd et al, World Psychiatry 2022;21(3):336–363). Adults with anxiety often present with comorbid late-life depression, which requires a different treatment approach. 

CGPR: Tell us about the long-term effects of anxiety.

Dr. Andreescu: There is growing evidence suggesting that long-term anxiety can have negative effects on the aging brain and body (Perna G et al, Neural Plast 2016;2016:8457612). We have new data from our lab showing that anxiety has an effect on the age of brain gray matter. People who have severe worry lose about 1.3 months of brain age with each 1-point increase in a 70-point scale that measures severe worry (Karim HT et al, Neurobiol Aging 2021;101:13–21). You can imagine that many years of anxiety will have an impact on brain regions like the prefrontal cortex or the hippocampus—regions that are involved in emotion regulation and emotion reactivity. So far, we have managed to map out these factors, but we still need to understand their association to treatment resistance. While more research is needed to fully understand the association between anxiety and cognitive decline or dementia, there is evidence suggesting that chronic anxiety may increase the risk of cognitive decline over time (Santabárbara J et al, J Clin Med 2020;9(6):1791).

CGPR: Can you tell us more about this relationship?

Dr. Andreescu: We are increasingly seeing a link between long-term anxiety and cognitive decline, though the direction of the causality is unclear. Chronic anxiety might lead to brain changes, reducing cognitive reserve and raising dementia risk. Alternatively, early dementia, which progresses slowly, might first present with what we call mild behavioral symptoms (eg, anxiety or worry). Few studies have explored this, but existing evidence suggests that chronic anxiety over decades increases the risk of cognitive decline. Both causal paths are thus likely, making treatment more challenging (Santabárbara et al 2020). 

CGPR: What are the primary factors contributing to treatment-resistant anxiety among older adults?

Dr. Andreescu: Anxiety is a vague term, and there is a lot of heterogeneity among anxiety disorders (Garakani A et al, Front Psychiatry 2020;11:595584). Under the umbrella of anxiety disorders, we find very different clinical experiences—from panic to obsessive-compulsive disorder. Treatment resistance is generally recognized after two or more adequate treatment trials fail to yield significant improvement (Domschke K et al, World Psychiatry 2024;23(1):113-123). It can be due to different anxiety disorders requiring different treatments. For instance, panic responds to treatment differently than generalized anxiety disorder (GAD). It’s also important to consider the appropriateness of the medication dose. Anxiety often requires higher doses than depression, and many older adults do not receive a dose that can keep them well. Additionally, some older adults may be taking medications that are less suitable for their age group, such as benzodiazepines or antihistamines, which can increase the risk of confusion, falls, and cognitive decline. Furthermore, there are multiple medical conditions associated with increased anxiety in older adults, such as chronic obstructive pulmonary disease (COPD) and Parkinson’s disease, and the medications used to treat these conditions can also contribute to treatment resistance.

CGPR: Can you tell us about the different types of anxiety phenotypes and how they respond to treatment?

Dr. Andreescu: Absolutely. Panic symptoms or obsessive-compulsive symptoms may be carried over from mid-life or younger years and may not be as prominent in older adults. These types of anxiety symptoms often respond well to antidepressants like SSRIs and low-dose benzodiazepines. On the other hand, GAD has two peaks of incidence—one in teenagers and another in older adults (DeGeorge KC et al, Am Fam Physician 2022;106(2):157–164). Treating severe worry and GAD in older adults can be particularly challenging because standard antidepressants may not have a dramatic effect on these late-onset cases. Individuals with severe worry also often have concerns about medication side effects, which can lead to treatment dropout. Among psychological treatments in older adults, cognitive behavioral therapy (CBT) can effectively reduce anxiety severity immediately following treatment compared to minimal management, but this reduction in anxiety may not be maintained over time (Hendriks GJ et al, Cochrane Database Syst Rev 2024; 7(7):CD007674). 

CGPR: In your experience, what are the most effective techniques for distinguishing between different anxiety phenotypes during clinical assessment?

Dr. Andreescu: The key to distinguishing among anxiety phenotypes is to focus on the unique characteristics of each disorder. For GAD, the emphasis is on persistent and excessive worry about a variety of topics. In contrast, panic disorder is identified by spontaneous panic attacks and ongoing worry about additional attacks or their consequences. Social anxiety disorder is marked by intense fear and avoidance of social situations due to the fear of scrutiny and negative evaluation by others. Specific phobias are easier to pinpoint because they relate to an irrational fear of a specific object or situation that leads to avoidance behavior. 

CGPR: Any theories on why treatment-resistant anxiety might develop in older adults?

Dr. Andreescu: One hypothesis is that there is an increased burden of cerebrovascular disease, what we see as white matter hyperintensities in the brain (Gerlach AR et al, Am J Geriatr Psychiatry 2024;32(1):83–97). Cerebrovascular disease leads to changes in white matter tract connectivity between various brain regions involved in emotion regulation, such as reappraisal—emotional regulation that is standardly used in CBT. Once this dysconnectivity syndrome appears, it’s harder for people to respond to treatments such as CBT.

CGPR: Let’s talk about strategies for managing treatment-resistant anxiety. What are your recommendations?

Dr. Andreescu: Lifestyle interventions, such as getting enough sleep, engaging in physical activities, and participating in social activities, have been found to be beneficial in improving mental well-being of older adults (Reynolds et al, 2022). Traditional CBT, the gold standard for middle-aged adults, doesn’t work as well for older adults, particularly those with severe anxiety. This is why newer therapies tailored for older adults focus less on cognitive restructuring and more on behavioral interventions like relaxation, which are more effective. While there are data indicating the effectiveness of other types of therapy beyond CBT, such as acceptance and commitment therapy and mindful meditation, a therapist specializing in these treatments is harder to find (Delhom I et al, Front Psychiatry 2022;13:976363). 

CGPR: When do you consider therapy vs medications in treating late-life anxiety?

Dr. Andreescu: Older adults with anxiety often prefer therapy over medications due to fewer side effects and the human connection it offers. However, a meta-analysis shows that while therapy works slightly better for depression in older adults, the opposite is true in anxiety—medications tend to be more effective (Pinquart M and Duberstein PR, Am J Geriatr Psychiatry 2007;15(8):639–651). A combination approach may offer the most benefits. Starting treatment with a modified form of CBT or mindful meditation, both validated approaches for addressing anxiety in older adults, can help. Once the patient feels less overwhelmed by their emotions, medication can be introduced, followed by another layer of therapy, possibly incorporating cognitive restructuring or lifestyle interventions. This sequential treatment approach may be more effective, as it allows cognitive interventions to work better when the patient is not in the middle of an emotional crisis.

CGPR: Tell us how you think through your first medication trial for late-life anxiety.

Dr. Andreescu: First, I assess previous medication trials, considering dosage, duration, and any side effects. I often start with antidepressants such as sertraline or escitalopram. I usually start at a low dose—about a quarter of the standard adult dose—and gradually increase the dose over several weeks to minimize side effects. For example, I might start sertraline at 12.5 mg daily and increase by 12.5 mg every two weeks, assessing the patient’s response and side effects at each step, until reaching a therapeutic dose that ranges from 50 to 100 mg per day. After reaching a therapeutic dose, I will wait a few weeks to assess response before titrating further—patients with anxiety disorder often require higher dosages for full resolution of symptoms. This cautious approach has been effective in my practice. 

CGPR: Where do buspirone, gabapentin, and benzodiazepines fit in?

Dr. Andreescu: In healthy older adults with mild anxiety, I might consider buspirone as an alternative if patients are worried about the sexual side effects of SSRIs (Chen A et al, J Geriatr Psychiatry Neurol 2024;8919887241289533). Gabapentin does not have randomized trials supporting its use in GAD in either older or younger adults, but there are studies demonstrating efficacy in social anxiety disorder, preoperative anxiety, and anxiety in breast cancer survivors (Chen A et al 2024). While I don’t avoid benzodiazepines, I ensure their use is carefully controlled, with clear guidelines to avoid dependency and abuse, such as limiting use to no more than twice a week and regularly reviewing the necessity of the medication. I might prescribe lorazepam 0.25 mg, to be taken only as needed for acute anxiety symptoms. 

CGPR: Tell us more about your next steps if your first few medication trials are ineffective.

Dr. Andreescu: I couple medication use with lifestyle interventions—often underestimated but important—and at least one form of therapy, such as mindful meditation, if accessible. When standard antidepressants are ineffective, I might consider augmentation with mirtazapine (by itself, mirtazapine’s effects are modest). I consider low-dose quetiapine as a fourth-line treatment, as patients who are otherwise restless appreciate the sedation. I use it cautiously at low doses to avoid akathisia and over-sedation and to minimize potential anticholinergic effects. It’s important not to dismiss an entire class of medication based on one failed response and to explore all treatment stages before labeling a patient as treatment-resistant. Sometimes what we diagnose as treatment-resistant anxiety in older adults is not actually treatment-resistant, just poorly explored. I’ve seen patients not respond to venlafaxine, but they respond to duloxetine. Venlafaxine is more anxiogenic if titrated too fast, in contrast to duloxetine, which has a much more sedating effect in older patients.

CGPR: Can you discuss some of the unique challenges of using medications in older adults with late-life anxiety?

Dr. Andreescu: One concern with older adults is whether their dosages are appropriate, as anxiety often requires higher doses of antidepressants than depression. Older adults also need prolonged treatment due to a higher risk of relapse. Unfortunately, two-thirds of older adults do not receive effective, sustained treatment, often relying on quick fixes that can be harmful in the long run (Andreescu C et al, JAMA Psychiatry 2023;80(3):197–198). As patients age, treating them with benzodiazepines becomes increasingly problematic due to the higher risk of cognitive decline, falls, and tolerance. Many older adults turn to over-the-counter medications like diphenhydramine, which are not ideal for older adults due to increased confusion and cognitive decline. This can lead to a cycle of increased anxiety and medication use, as patients believe something is wrong with their brains, exacerbating the problem. To combat this, we can prioritize nonpharmacologic strategies like CBT, exercise, mindfulness, and dietary changes (Aucoin M et al, Nutrients 2021;13(12):4418). Educating patients and caregivers about the dangers of inappropriate medication use and the benefits of regular therapy can help break the cycle of inadequate treatment and dependency on harmful quick fixes.

CGPR: How does comorbid cognitive impairment influence treatment choices?

Dr. Andreescu: CBT becomes harder, so it’s better to focus on relaxation strategies or mindful meditation, which remain effective longer, rather than on cognitive restructuring. When considering pharmacological options, avoid medications with anticholinergic effects. In later stages, patients can become more agitated, and I’ve often seen excessive use of antipsychotics, which not only have anticholinergic effects but also cause akathisia, leading to increased anxiety and difficulty in treatment. It’s important to manage polypharmacy in these patients, the first step of which is to avoid making the situation worse, so select medications with the best possible side effect profiles to support these patients effectively. 

CGPR: What’s the relationship between late-life anxiety, medical comorbidities, and treatments?

Dr. Andreescu: There are multiple medical conditions that are associated with increased anxiety. COPD is one of the classic ones—people with COPD are 85% more likely to develop anxiety disorders than the general population (Yohannes AM et al, J Fam Pract 2018;67(2 Suppl):S11–S18). Parkinson’s disease is another one—about half of people with Parkinson’s disease experience anxiety. Medications can also increase the risk of anxiety, or they can give patients side effects that make them more anxious—for example, SSRIs can cause hyponatremia or GI bleeding. When patients are given an antidepressant, they may get a “dirty antidepressant” like paroxetine, which has its own side effect profile that’s not ideal for older adults. Then there are interactions between their antidepressant and the medications for their medical illnesses. When side effects start to appear, it is more difficult to keep patients in treatment.

CGPR: Can you share insights about emerging research in treatment-resistant anxiety in older adults?

Dr. Andreescu: There have been many attempts at new molecules because SSRIs and SNRIs didn’t really live up to their promise. Molecules like pregabalin did not get too far. One area of emerging research is focused on understanding the neural circuits involved in maintaining pathologic worry in older adults with anxiety. By mapping these circuits, we hope to develop targeted interventions using techniques like transcranial magnetic stimulation to modify brain activity and break the cycle of chronic worry. Additionally, there is ongoing research into modifying existing therapies like CBT to better suit the needs of older adults with severe worry. This may involve emphasizing behavioral interventions like relaxation techniques rather than cognitive restructuring. Another trend is combining different treatment approaches sequentially, such as starting with therapy or mindful meditation followed by medication and then another round of therapy focusing on cognitive restructuring.

CGPR: Thank you for your time, Dr. Andreescu.