Learning Objectives

After the webinar, clinicians should:

1. Summarize the role of primary care in the treatment of depression
2. Understand how to initiate depression treatment in the primary care setting 
3. Recognize when augmentation and combination therapies are appropriate 
4. Explain how to select antidepressant medications based on efficacy and side effect profiles

Transcript edited for clarity.

Hello everyone and welcome to another Carlat webinar episode titled Treating Depression Collaboratively. I am Dr. Garrett Rossi, an adult psychiatrist at AtlantiCare Regional Medical Center, specializing in consultation-liaison psychiatry and inpatient adult psychiatry. I have no conflicts of interest or disclosures to report for the recording of this webinar. 

Before we dive into the details about treating depression collaboratively, let's go over the learning objectives. After the webinar, clinicians should be able to summarize the role of primary care in the treatment of depression; understand how to initiate depression treatment in the primary care setting; recognize when augmentation and combination therapies are appropriate; and explain how to select antidepressant medications based on efficacy and side effect profile.

Why is depression such a problem?

To set the tone for this discussion, we must address the question: why is depression such a problem? An estimated 21 million adults in the United States had at least one major depressive episode in 2020. This represents 8.4% of all US adults, and of those individuals, only 28.7% received any type of treatment for their depression.

The prevalence of major depression was higher among women, 10.5% versus 6.2%. The prevalence of adults with a major depressive episode was highest among people aged 18 to 25 at 17%. Depression is a leading cause of disability worldwide and a major contributor to the overall global burden of disease.

In terms of numbers, the incremental economic burden of adults with major depression was estimated to be $326.2 billion in 2020 (Statistics provided by National Institute of Mental Health (NIMH). https://www.nimh.nih.gov/health/statistics/major-depression).

The role of primary care in depression 

So, what is the role of the primary care provider in depression? Most patients with depression are going to first seek treatment through their primary care provider.

Many patients will, in fact, do poorly with initial treatment. As few as 20% of those started on antidepressants in the primary care setting will show significant clinical improvement. By the time a referral is made to a psychiatrist, patients often face long waits and find it difficult to make it to their appointments and follow through with the referral.

In fact, 50% of those referred do not follow up with the psychiatrist (APA Collaborative Care Model: Fact Sheet. https://www.psychiatry.org/psychiatrists/practice/professional-interests/integrated-care/learn).

Case

An excellent way for us to begin discussing depression and its treatment in the primary care setting is to look at a case. This is Lori, a 42-year-old female who presented to her primary care provider with the following: she reports feeling stressed out due to childcare and work; she has had trouble sleeping and has lost interest in socializing with friends; she has a history of being on an antidepressant at the age of 18 but cannot remember which one she used. The question to us as clinicians is: what should our next steps be?

Next steps: Proper screening and evaluation 

The initial process of treating depression in the primary care setting involves proper screening and evaluation. This is crucial to ensuring that the right diagnosis is made and the most appropriate treatment is recommended. Here are some important steps to follow: 

1. Screen for depression: The Patient Health Questionnaire-9 (PHQ-9) is a widely used, effective, and brief self-report tool that can be administered to screen for depression. A score of 10 or higher is suggestive of depression and warrants further evaluation.
2. Assess severity: Use the PHQ-9 score to determine the severity of depression, which will guide treatment recommendations. The higher the score, the more severe the depression.
3. Rule out other causes: Before diagnosing a patient with depression, it is important to rule out other medical and psychiatric conditions that could be causing or contributing to the patient's symptoms, such as thyroid dysfunction, anemia, or substance use disorders.
4. Identify comorbid conditions: Assess for the presence of comorbid psychiatric conditions, such as anxiety disorders, bipolar disorder, or substance use disorders, as these can impact treatment recommendations.
5. Evaluate suicide risk: It is essential to assess for suicidal ideation, intent, or plan, as well as to evaluate protective factors and access to means. Depending on the level of risk, immediate intervention or referral to a higher level of care may be necessary.

Special considerations

Which patients need immediate referral to a psychiatrist or hospital? It is crucial to identify patients who may require immediate referral to a psychiatrist or hospital. Some situations that may warrant this include:

1. Active suicidal ideation with a plan and intent: This requires an immediate referral to the emergency department for evaluation.
2. Unclear diagnosis or suspected bipolar disorder: Bipolar disorder can be more challenging and nuanced to treat; therefore, referring to a psychiatrist may be necessary.
3. Presence of psychotic symptoms: These indicate a more severe form of depression, often requiring different treatment options and possibly immediate referral to a psychiatrist.
4. Severe functional impairment: If a patient is experiencing a rapid decline or severe impairment in daily functioning, a quick response may be needed, necessitating a referral.
5. Severe substance use disorder: In this case, you may want to consider inpatient rehabilitation or a dual-diagnosis unit that specializes in medication management for both substance use disorder and major depression.

You have established a diagnosis of MDD for Lori of moderate severity. How would you begin treatment?

After diagnosing Lori with moderate major depressive disorder (MDD), the first step in treatment is to establish a therapeutic alliance and educate her about MDD. A strong therapeutic alliance can significantly impact treatment outcomes, independent of medication or psychotherapy techniques. You can use empathetic statements and provide education about the diagnosis, prognosis, and treatment options for MDD.

Before discussing medications and psychotherapy, consider addressing lifestyle interventions that can help improve Lori's mood.

Lifestyle interventions

Encourage evidence-based lifestyle interventions for depression, including:

1. Exercise: A combination of aerobic and resistance training can help improve mood. Discuss duration and frequency with the patient and recommend starting right away.
2. Diet: Healthy eating can enhance mood. Recommend a Mediterranean-style diet and provide a handout with common foods involved in this type of diet.
3. Sleep hygiene: Discuss various techniques for improving sleep habits with the patient, as better sleep can significantly impact depression treatment outcomes. You may also consider recommending nutraceutical products such as melatonin if the patient prefers them.

Nutraceuticals

Patients who prefer natural products or are resistant to medication can consider nutraceuticals for depression treatment. Some options include:

1. S-adenosyl-L-methionine (SAMe): An over-the-counter product with established antidepressant effects.
2. St. John's Wort: Effective for mild to moderate depression, but be cautious due to potential drug interactions.

Be aware of the possible risks and side effects of these products, and allow their use as long as they do not interfere with the recommended treatment.

When should psychotherapy be the first-line option?

In every primary care encounter, brief supportive psychotherapy can be provided. Techniques such as behavioral goal setting, encouragement, positive reinforcement, and modeling can be implemented. According to the NICE guidelines, patients with mild to moderate depression should start with behavioral interventions, such as self-guided CBT, group CBT, or individual CBT, in combination with lifestyle modifications (Depression in adults: treatment and management (NG2022) https://www.ncbi.nlm.nih.gov/books/NBK583074/).

Clinical barriers in the United States include a lack of access to CBT groups and therapists and insufficient knowledge about making referrals. For moderate to severe depression, a combination of psychotherapy and medication is often indicated. Patients may also try other proven forms of psychotherapy, such as interpersonal therapy, behavioral therapy, or psychodynamic psychotherapy, based on personal preference or if CBT is not effective. Some patients may respond well to CBT alone, while others may require the addition of medication.

What are the next steps?

Let's return to our case briefly here. So back to our case, our 42-year-old female patient presented with excessive stress and sleep disturbance. We completed our PHQ-9, and she scored 16. She answered no to the questions regarding suicidal thoughts and yes to five out of nine SIGECAPS questions every day for the past two weeks.

We confirmed she meets criteria for major depressive disorder before making the diagnosis. She screened negative for bipolar disorder and substance use disorder, so we're not worried about those concerns.

Things to consider before prescribing medication

Before making a medication recommendation, rule out any medical causes of depression. Basic labs to order before prescribing medication include a BMP, CBC, and TSH. Order these tests if there isn't a baseline level available. For women, consider screening for symptoms around the premenstrual phase and remitting at the onset of menses. This may indicate premenstrual dysphoric disorder, requiring additional screening.

More advanced testing for autoimmune disease and brain imaging should be done on a case-by-case basis. If there are concerns for a potential medical cause based on the history or physical exam, consider referring the patient for psychotherapy and getting the necessary laboratory testing done before prescribing medication. Complete the full workup if you suspect a medical cause for depression before prescribing antidepressant medications. Consider close follow-up for these individuals, ideally within two weeks, to review labs and avoid delaying medication treatment if indicated.

Pharmacological treatments for major depression 

There are several options for treating depression, including:

1. Older medications, such as tricyclic antidepressants (e.g., nortriptyline), which are generally reserved for more difficult-to-treat depression.
2. Monoamine oxidase inhibitors (e.g., phenelzine), which are less likely to be first-line options due to dietary restrictions and side effects.
3. Selective serotonin reuptake inhibitors (e.g., escitalopram), which are often first-line options.
4. Serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), which are typically second-line options but can also serve as first-line treatments for major depression.

Serotonin modulators and atypical antidepressants (e.g., bupropion), which can be first-line options, but their cost and similar efficacy to SSRIs and SNRIs make them less favorable.

Antidepressant efficacy

Randomized, double-blind, placebo-controlled trials have demonstrated that all classes of antidepressants are equally effective in treating major depressive disorder. The NIMH-sponsored STAR*D study aimed to determine response and remission rates for a systematic approach to treating depression. Participants underwent up to four levels of treatment, characterized by switches or augmentation, until they reached remission. Remission rates at each level were 37% at the first stage, 56% at the second stage, 62% at the third stage, and 67% overall. This suggests that more aggressive treatment can result in higher rates of remission. In the absence of a clear difference between response and remission rates among antidepressants, we need a different approach to selecting medications (Sinyor M et al, Can J Psychiatry 2010;55(3):126-135).

Back to the case

Lori’s labs come back normal and there is nothing elicited on the physical exam that would indicate a need for further workup. She is still reporting symptoms of depression, and now we're considering medication. 

Best practices for medication selection

1. Prior use of medication that was effective for treating depression is a good indication.
2. Family history of a relative responding to a particular medication, since there is a genetic component to depression and response to medication.
3. Consider the side effect profile, taking into account which side effects the patient wants to avoid. 
4. Potential for drug interactions should be considered, as many psychiatric medications interfere with the cytochrome P450 enzymes in the liver.

5. Medical comorbidities should be taken into account when selecting medication.
6. Consider the risk in overdose, as some medications pose higher risks than others in the case of an overdose.
7. Take cost into consideration, as newer brand name medications not available as generic formulations may have a significant cost burden for the patient.

First-line options

Three medications that tend to be good first-line options, supported by evidence, are the selective serotonin reuptake inhibitor sertraline, the selective serotonin reuptake inhibitor escitalopram, and the atypical antidepressant bupropion.

In the next slide, we will discuss each of these medications in detail and go over why each one is a good first-line option.

Why sertraline?

Two meta-analyses of head-to-head and placebo-controlled trials of antidepressants found that sertraline and escitalopram had slightly superior efficacy and tolerability compared to other SSRIs. Sertraline has an advantage in safety, as it has the most favorable profile in cardiac disease, is safe in pregnancy and breastfeeding (when dosed below 150 mg/day), has minimal interactions with the cytochrome P450 enzyme system, and has efficacy that plateaus at 100 mg/day (Cipriani A et al, Lancet 2018;391(10128):1357–1366; Womersley K et al, Psychiatr Danub 2017;29(Suppl 3):629–644).

Why escitalopram? 

As mentioned in the slide on sertraline, two meta-analyses indicated a slight advantage for escitalopram in terms of efficacy and tolerability. The biggest benefit of escitalopram is its lack of drug interactions, as it does not inhibit or induce the cytochrome P450 enzyme system, making it an ideal choice for people on multiple medications (Rush AJ eat al, Am J Psychiatry 2011;168(7); 689-701).

What about bupropion? 

Bupropion is included in this presentation due to two important side effects: the lack of sexual dysfunction and the absence of antidepressant-induced weight gain. These factors can significantly impact a patient's adherence to treatment. Although bupropion may not be considered a first-line option by many, it should be given due to its minimal sexual side effects and reduced risk of weight gain.

Bupropion has been shown to improve anxiety with similar efficacy to other antidepressants and does not worsen insomnia, as previously believed. The studies that showed bupropion worsened anxiety were conducted in panic disorder, not depression or generalized anxiety disorder. In combination treatment, bupropion outperformed when added to the SSRI citalopram in the STAR*D study.

The risk for seizure associated with bupropion is often overstated. As long as doses remain 300 mg or less per day, the risk of seizure is comparable to that of SSRIs.

Using symptom profile and comorbidity to guide decisions

Consider the following strategies for specific patient presentations:

1. Severe anxiety: Brief course of benzodiazepines (2-4 weeks) alongside SSRI titration and psychotherapy initiation.
2. Tobacco use disorder: Consider starting Bupropion (FDA approved for tobacco use disorder treatment in sustained-release formulation).
3. Cognitive symptoms of depression or comorbid pain disorders: Use duloxetine as a first-line option.
4. Impaired sleep and poor appetite with weight loss: Consider mirtazapine, which can cause weight gain and sedation.

You started the medication. Now what? 

Two important components of an effective medication treatment are appropriate dosing and duration. Medications should be started at the lowest effective dose and titrated slowly to avoid side effects. Sensitive patients may require even lower starting doses. Common issues in primary care include starting a medication but failing to titrate to an effective dose. Continuously monitor symptoms and titrate as needed to achieve proper response or remission.

For sertraline, start at 25-50 mg per day and increase by 25-50 mg every week to a target dose of 100 mg per day. For escitalopram, start at 5 mg per day and increase to 10 mg after two weeks of treatment, with a maximum dose of 20 mg per day. For bupropion XL, start at 150 mg in the morning and increase to a target dose of 300 mg per day after one week.

Medication trials should continue for 4-6 weeks at the target dose before considering a switch to a different class of medication or an augmentation strategy. 

Let's return to our patient

Lori returns after two weeks on escitalopram 5 mg and reports no response to the medication. What should you do next? 

There are two important things to consider. First, the dose is relatively low, as 5 mg is below the minimal effective dose in adult patients, and she's only been taking it for two weeks. We will increase the dose of the medication. For example, if the patient is on sertraline, you can increase it up to 100 mg per day; citalopram can be increased up to 20 mg per day; and bupropion can be increased to 300 mg per day. 

Have the patient come back in two weeks and reassess depressive symptoms. The PHQ-9 can be used to follow treatment response if you want an objective measure. If the patient has a response, continue the medication at the previous dose and reassess after four weeks. If remission is reached, continue the treatment with monthly follow-ups. If there is a response but not remission, consider the titration recommendations listed above. 

No response to treatment

Lori returns after four weeks of treatment at an optimal dose of 20 mg per day of citalopram with a response to treatment but not remission. What can we do next? We have several options:

1. Switch medications: We could consider sertraline or bupropion as alternatives, or switch to an SNRI like venlafaxine or duloxetine. Mirtazapine may also be considered, especially in cases with insomnia and weight loss.
2. Try natural products: Dansyl-D-methionine, SAMe, or St. John's Wort could be considered, but be cautious of drug interactions and risk for serotonin syndrome.
3. Refer to a TMS provider: Repetitive transcranial magnetic stimulation may be a suitable option for some patients.
4. Augmentation strategies: Adding omega-3 fatty acids, L-methylfolate, bright light therapy, or bupropion to the initial SSRI or SNRI medication can be considered. Alternatively, augmenting with second-generation dopamine-blocking medications like aripiprazole, brexpiprazole, quetiapine, or risperidone may be effective. Thyroid hormone (T3) and lithium can also be used as augmentation strategies.

Why are we not recommending newer serotonin modulating antidepressants?

These medications include vortioxetine and vilazodone, both of which have failed to outperform other more cost-effective options. They are not recommended as first or second-line options in most cases. Vortioxetine may show benefits in treating cognitive effects associated with depression, but this is debatable and likely not a strong enough reason to favor it over other options.

Treatment-resistant depression

Treatment-resistant depression is defined as failing two or more adequate trials of antidepressant medication. At this point, you may need to reassess the diagnosis, consider referring the patient to a psychiatrist, or explore more advanced augmentation strategies like electroconvulsive therapy (ECT) or ketamine treatment, depending on the severity of the illness. 

ECT or ketamine may be recommended if there is an urgent need for depression improvement, such as active suicidal ideations, catatonia, a medical condition like pregnancy that prevents other treatment options, or the patient desires rapid relief of symptoms to return to work. Psychotic features or significant weight loss due to refusal to eat may also warrant consideration of ECT.

ECT has a remission rate of 75%, but patients may be reluctant to start treatment due to concerns about cognitive side effects and stigma surrounding the procedure. If a patient refuses ECT, ketamine infusions or intranasal ketamine may be offered. These options are likely beyond the scope of most primary care practices, but it's good to know when they should be considered. 

Summary

Primary care providers play a pivotal role in the treatment of depression. Having guidelines and algorithms can help guide treatment. Most patients will improve with initial treatment, switching, or augmentation. The extent of treatment as a primary care provider will depend on your comfort level. If a patient remains unimproved after these strategies, referral to a psychiatrist should be made.

Thank you for listening to this webinar. I hope it has been helpful and informative. We look forward to bringing you more topics in the future. 

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