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This activity is supported by an unrestricted educational grant from Otsuka America Pharmaceuticals, Inc

Serotonin and Beyond: Optimizing Management of Major Depressive Disorder


Megan Maroney, PharmD, BCP

Clinical Assistant Professor
Ernest Mario School of Pharmacy
Rutgers, The State University of New Jersey
Clinical Psychiatric Pharmacist
Monmouth Medical Center
Long Branch, New Jersey

The following faculty, planners, and staff have no relevant financial relationships with commercial interests to disclose.

Pharmacy Times Office of Continuing Professional Education
Planning Staff—David Heckard, Steve Lin, PharmD, RPh, and Maryjo Dixon, RPh

Pharmacy Times
Editorial Staff
Kirk McKay

An anonymous peer reviewer was part of the content validation and conflict resolution process. The peer reviewer has no relevant financial relationships with commercial interests to disclose.

Educational Objectives
At the conclusion of this educational activity, participants should be able to complete the following:

  • Review the pathophysiology and risk factors related to major depressive disorder (MDD).
  • Discuss emerging data on remission, treatment response, and prognosis of MDD.
  • Explore the changes that have taken place with respect to the treatment approach for MDD.
  • Examine the new first-line treatment options for MDD.
  • Discuss the role of the pharmacist in addressing treatment challenges and optimizing outcomes in patients with MDD.

Target audience: Pharmacists
Type of activity: Knowledge
Release date: January 12, 2014
Expiration date: January 12, 2016
Estimated time to complete activity: 2 hours
Fee: Free

Description: Description: Description: Pharmacy Times/Ascend Media Office of Continuing Professional Education Pharmacy Times Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 2.0 contact hours (0.2 CEUs) under the ACPE universal activity number 0290-0000-14-001-H01-P. The activity is available for CE credit through  January 12, 2016.

Major depressive disorder (MDD) is the second-leading cause of disability and affects nearly 300 million people worldwide1. In the United States, approximately 6.7% of adults suffer from MDD annually, with 16.5% of US adults being affected by the disease at some point in their lifetimes2. MDD also contributes to the disease burden of several other illnesses, increasing the risk of developing ischemic heart disease and type 2 diabetes mellitus and increasing the risk of mortality following an acute myocardial infarction3. Depression occurs more commonly in females than in males and has a 3-fold higher prevalence among young adults 18 to 29 years of age compared with adults 60 years or older4.

Pathophysiology and Risk Factors
There is still much to learn about the pathophysiology behind MDD. Neuroimaging studies involving magnet-ic resonance imaging, positron emission tomography, and single photon emission computed tomography have shown that depression likely affects many different regions and circuits of the brain, such as the prefrontal cortex, amygdala, and hippocampus5. The majority of pharmacologic treatments currently available for MDD are thought to work by enhancing serotonin transmission, so it comes as no surprise that the serotonin (5-HT) hypothesis continues to be one of the most popular theories for the basis of MDD6,7. The serotonin hypothesis was developed in the 1960s and purports that a deficit in 5-HT is the primary cause of MDD7. Beyond serotonin, other monoamine neurotransmitters (eg, norepinephrine, dopamine) have also been consistently implicated in the biologic etiology of the disease8. It is generally accepted that a host of genetic, biologic, and environmental components are involved in MDD, and other neurobio-logic targets have since become the focus for antidepressant drug development, including cholinergic, glutamatergic, and opioid receptors9.

A variety of factors may increase the risk of developing MDD, including negative affectivity (ie, the tendency to experience negative emotions), adverse childhood experiences, stressful life events, chronic medical conditions (eg, diabetes mellitus, obesity, cardio-vascular disease [CVD]), and having a first-degree family member with MDD4. Heritability is thought to account for approximately 40% of MDD cases, and the risk for developing early onset or recurrent MDD is particularly high among individuals with a family history of the condition4.

According to the recently published 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, symptoms of depression must persist for at least 2 weeks and must represent a significant change from previous functioning to be classified as MDD. An individual must have either a depressed mood or loss of interest or pleasure (anhedonia) as one of the core symptoms of depression, and must experience at least 5 depressive symptoms in total, occurring nearly every day during that same 2-week period. These symptoms may include changes in appetite (ie, either a loss in appetite, with or without accompanying weight loss, or an increase in appetite), changes in sleep pattern (ie, insomnia or hypersomnia), psychomotor changes (eg, restlessness, irritability), fatigue or loss of energy, feelings of worthlessness or guilt, difficulty concentrating or indecisiveness, and recurrent thoughts of death or suicide. A depressive episode may further be classified as mild, moderate, or severe. A clinician may also choose to add “specifiers” that further describe a patient’s symptoms, such as “with anxious distress” if the patient displays prominent symptoms of anxiety that accompany the depression, or “with psychotic features” if features such as hallucinations or delusions are also present. Additional specifiers include mixed, melancholic, or atypical features, seasonal pattern, peripartum onset, and catatonia4.

Treatment Goals and Prognosis
The main goals of acute treatment for MDD are to induce disease remission, which may be defined as the virtual absence of depressive symptoms, and to return patients to their baseline level of functioning10. Patients with MDD who achieve remission experience improved functioning, a better prognosis, and increased long-term stability (ie, less risk of relapse) compared with patients who simply have a response to treatment, which is defined as a clinically significant degree of symptom reduc-tion11. Longer-term treatment goals focus on preventing the relapse and recurrence of depression10. A relapse is considered to be a return of symptoms following the onset of remission, and recurrence refers to the development of a new depressive episode following a period of recovery from depression11.

Treatment guidelines generally recommend that antidepressant medications should be tried for a minimum of 4 to 6 weeks to appropriately determine if a patient is having an adequate response to treatment, although some argue that alternative treatments should be attempted earlier in patients who do not demonstrate an early response12. Achieving disease remission may take even longer, as evidenced by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the largest randomized controlled trial conducted in patients with depression to date. In this study, achieving remission took an average of 6 to 8 weeks with antidepressant treatment, and some patients required 14 weeks or longer13. Risk factors that may be associated with a lack of response to treatment with antidepressants include the presence of psychiatric comorbidi-ties, particularly substance abuse, personality and anxiety disorders, having a medical comorbidity such as CVD or chronic pain, and having an early age of onset for depression14,15.

Pharmacologic Treatment
Antidepressant medication is recommended for moderate to severe episodes of MDD by most treatment guidelines and is further recommended in patients with mild depression by the American Psychiatric Association (APA)10,16,17. Although present evidence suggests that there is little difference in efficacy among the existing antidepressant medica-tions,18,19 there are still a number of differ-ent antidepressant drug options available to treat MDD (Table 120-22; Table 223-26). As such, selecting an antidepressant is usually based on other factors, including side effect potential, prior medication response, pharmacologic properties (eg, half-life, drug interactions), cost, and patient preference4.

First-line pharmacologic treatment for MDD typically consists of a selective serotonin reuptake inhibitor (SSRI), a selective norepinephrine reuptake inhibi-tor (SNRI), bupropion, or mirtazapine4. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are generally reserved for treatment refractory patients due to their side effect burden and many drug and food interactions. Patients who achieve sufficient response to treatment should be managed for at least 4 to 9 months to minimize the risk of symptom relapse, and those who have had 3 or more prior depressive episodes or a chronic course ofillness should receive long-term maintenance treatment with an antidepressant. Moreover, patients who experience significant residual symptoms, ongoing psychosocial stressors, have a family history of mood disorders, or had an early age of disease onset should also be considered for maintenance treatment4.

The 3 most recently approved antidepressant agents are vilazodone (Viibryd), levomilnacipran (Fetzima), and vortioxetine (Brintellix) (Table 1). Vilazodone, which was approved by the FDA in January 2011, acts as an SSRI and has additional activity as a partial agonist at 5-HT1A receptors. The most common side effects of vilazodone in clinical trials were nausea and headache, with rates of 28% and 23%, respectively. It is recommended that vilazodone be titrated up slowly to prevent these side effects. Additionally, vilazodone is a substrate of the CYP3A4 enzyme, so dosage adjustments are needed for patients concomitantly receiving strong CYP3A4 inhibitors20. Levomilnacipran and vortioxetine were approved by the FDA in July and September 2013, respectively. Levomilnacipran is an SNRI that is similar to venlafaxine, duloxetine, and desvenlafaxine, and is the active enantiomer of milnacipran, an SNRI that is currently approved for the treatment of fibromyalgia. Like other SNRIs, levomilnacipran has the potential to increase heart rate and blood pressure, and due to its relative potency for norepinephrine reuptake relative to other SNRIs, the risk of these noradrenergic side effects may be more of a concern27. Dosage adjustments with levomilnacipran should also be made for patients with renal dysfunction or on strong CYP3A4 inhibitors21. Similar to vilazodone, vortioxetine is an SSRI with additional serotonergic activity that acts as a partial agonist at 5-HT1A receptors and an antagonist at 5-HT3 and 5-HT7 receptors8. Also, similar to vilazodone, vortioxetine demonstrated high rates of nausea in clinical trials (up to 32%), with other com- mon adverse effects including constipation and vomiting. Vortioxetine is metabolized predominantly through CYP2D6, and dos- age adjustments are recommended for patients on strong CYP2D6 inhibitors or strong CYP inducers in general22.

The Role of the Pharmacist
Pharmacists play a key role in educating and managing patients with MDD, and treatment recommendations from APA emphasize counseling patients on appropriate dosage and administration for antidepressant medications, suggesting reminder systems (eg, pill boxes and alarms), discussing realistic treatment expectations (eg, how long before the medications are likely to take effect and what to do if side effects arise), continuing the medication regimen even after feeling better, and discussing concerns with their psychiatrist before discontinuing medications on their own4. Additionally, as vital members of the health care team, pharmacists help to monitor for drug interactions, symptom improvement, and adverse effects of medications, communicating any issues or updates to the treating physician.

The following is based on an interview with Dr. Christopher Fabian, an attending psychiatrist at Monmouth Medical Center in Long Branch, New Jersey.

Based on your experience, what are some of the relevant causative factors in treatment-resistant depression (TRD)?
Many of the patients who are classified as treatment resistant may actually be “pseudoresistant”; these patients may have been on many different antidepressants over the years, but it is hard to tell if they have ever had a fair trial on any one of those agents, especially if the patient is a poor historian. Patients may be falsely classified as resistant to an antidepressant medication if they had not been treated for an adequate amount of time with a therapeutic dose of a given drug. As many as 60% of patients with depression may fall into this “pseudoresistant” category19. Additionally, if a patient with depression was not fully adherent to a treatment regimen, physicians may falsely believe that the patient failed the medication, whereas the patient may have actually responded to treatment had he or she taken the medication(s) as prescribed. Unfortunately, up to 50% of patients with depression are non adherent to antidepressant therapy during the acute treatment phase, and even fewer remain adherent during the continuation phase28. Further, some patients may be very sensitive to the medication side effects, thereby causing premature discontinuation of treatment.

But the truth is antidepressants simply do not work all the time. Risk factors for resistance to antidepressant therapy include an early age of onset of depression, a severe and chronic course of illness, and comorbidities, such as substance abuse, anxiety or personality disorders, or medical illnesses, such as pain or CVD15.19. A misdiagnosis of MDD in a patient with bipolar disorder may also result in inadequate treatment, as the management of bipolar depression typically differs from unipolar depression, despite the similar presentation of symptoms in the depressed phase of bipolar disorder and MDD. In fact, it is estimated that bipolar I disorder remains undetected in 35% to 45% of patients with the condition19. A patient is generally considered treatment resistant after failing adequate trials of at least 2 different antidepressants from 2 distinct pharmaologic classes19. An antidepressant medication must be tried for a minimum of 4 to 8 weeks at a potentially effective dose to be considered an adequate trial10.

What are the current statistics related to the rates of response and remission with current antidepressants? How many patients with MDD are truly treatment resistant?
Even with the multitude of antidepressant treatment options that are available, between 30% and 40% of adequately treated depressive episodes are considered treatment resistant.15. In the landmark STAR*D trial, approximately 50% of patients with MDD who were initiated with the SSRI citalopram demonstrated positive responses to treatment, and roughly one third of patients achieved remission13. These figures are relatively consistent with the average response rate of 54% that is seen with the use of antidepressants in short-term placebo-controlled trials, and with the remission rates of 30% to 40% seen in recent trials5,19. As seen in the STAR*D trial, achieving remission is a key component to appropriately managing MDD, as patients who only responded to treatment were twice as likely to suffer a relapse during the following year as patients who had achieved remission29. Further, incomplete remission is associated with poor school and work functioning, as well as a persistent risk of relapse and recurrence long term4.

Has the prognosis of patients with MDD changed considerably in the past decade? If so, do you believe that the development of newer clas- ses of antidepressants (or improved use of existing antidepressants) has impacted this trend?
In my opinion, the prognosis of patients with MDD has not changed consider- ably in the past decade, but it certainly has since the introduction of the SSRI drug class. While TCAs and MAOIs generally worked, physicians just did not have many options to choose from prior to the newer medication classes. Fluoxetine was a blockbuster drug, mostly due to its tolerability, which played a major role in improving patient adherence to medication. Many patients did not want to take a TCA because of its side effect profile, and the MAOIs are associated with many dietary restrictions and drug interac- tions that make the medication class difficult to adhere to. As the SSRIs were introduced, TCAs and MAOIs quickly became last-line treatment options. Nowadays, we have even more treatment choices, such as bupropion and SNRIs. While I am not sure if there is much of a difference between having 5 or 6 different SSRIs as opposed to 1 or 2, it is better to have options in general.

Are there other factors that may play a more paramount role in the prognosis of MDD?
The health care community has become better at recognizing and diagnosing MDD. Unlike other mental health dis- orders, the diagnostic criteria for MDD have remained fairly consistent over the years, and there is also much more research available to help guide appropriate treatment. Psychotherapy has improved with its increased availability and use of cognitive behavioral therapy. Electroconvulsive therapy (ECT) has also been refined quite a bit, although it is not as readily available or often used as it should be. ECT may be a very effective treatment for patients with MDD, even for patients whose depression has been resistant to many medications. Overall, clinical trials involving patients with depression and TRD have demonstrated response rates of 70% to 90% and 50% to 60% following treatment with ECT, respectively4,30. Other nonpharmacologic strategies are used for the treatment of depression, such as transcranial magnetic stimulation (TMS), which was recently approved by the FDA for the treatment of MDD and appears to be quite effective, with response rates between 30% and 65% in patients with TRD30. Vagus nerve stimulation (FDA approved for TRD in 2005) and deep brain stimulation are also used for the treatment of depression, but these procedures are considered much more invasive than TMS.

How has the role of the SSRI changed or evolved?
SSRIs have a number of different indications now, including anxiety disorders, eating disorders, premenstrual dysphoric disorder, and hot flashes in perimenopause, among others31,32. SSRIs may also be used in combination with other antidepressants or augmenting agents for the treatment of MDD. For example, using an SSRI and bupropion in combination is beneficial for many patients with depression, as this strategy targets all 3 monoamines (serotonin is targeted by the SSRI; norepinephrine and dopamine are both affected by bupropion). These anti- depressants may also have beneficial, complementary side effect profiles. For example, if a patient is suffering from sexual dysfunction caused by an SSRI, which is a common side effect for both males and females, bupropion may sometimes counteract this effect while also providing additional depression symptom control33.

How should patients who either do not respond or respond inadequately to SSRIs be managed?
If the patient has not responded to treatment with an SSRI after 4 to 8 weeks at the maximum tolerated dose, the first step would usually be to try a second SSRI4. Patient response to these drugs is very heterogeneous, and some patients may respond well to one SSRI but not another. Other options may include switching to an SNRI, mirtazapine, or bupropion, and ECT should always be considered in patients with severe depression, especially if the risk for suicide is high4. Switching antidepressants is typically preferred when a patient has demonstrated little symptom improvement or if the patient has difficulty tolerating the side effects of the first medication (Table 313,29,38.)29.

If a patient demonstrates a partial response and residual symptoms remain, the next step would generally be to optimize the dose, while some clinicians may prefer to employ “watchful waiting.”29 In the first step of the STAR*D trial, the mean time to disease remission with citalopram was 6.7 weeks, with almost half of the remissions occurring after week 612. This result would indicate that optimal outcomes with SSRIs may require additional time, and clinicians should be careful not to abandon a treatment option prematurely. If the dose has been optimized and remission has still not been achieved, clinicians must confirm the diagnosis, recognize and treat any psychiatric and medical comorbidities, and assess treatment adherence4,29,34. Once these factors have been addressed, potential therapeutic options include either adding an augmenting agent, such as buspirone, thyroid hormone (T3), lithium, or an atypical anti psychotic, or combining the SSRI with an additional antidepressant, such as bupropion, trazodone, mirtazapine, or even a TCA4,13,29,35,36. Keep in mind, however, that psychotherapy should always be added if possible, as it is recommended most highly by APA treatment guidelines for depression34. Other pharmacologic options that have less supporting evidence but are sometimes used to augment the effects of antidepressants include stimulants, such as methylphenidate or modafinil, pindolol, folic acid, omega-3 fatty acids, estrogens, and l-methylfolate (Deplin)13,29,36.

With the introduction of the newer and emerging antidepressants, how do you see the current treatment approach for MDD evolving?
Most of the recently approved anti- depressants are either new dosage forms of older antidepressants, such as trazodone extended release tablets (Oleptro), selegiline transdermal patch (Emsam), or bupropion hydrobromide (Aplenzin), or slight variations on the monoamine approach, such as vilazodone (Viibryd), levomilnacipran (Fetzima), or vortioxetine (Brintellix). Trazodone extended release and selegiline transdermal patch should offer improved tolerability profiles, allowing for easier use and, hopefully, improved patient adherence. Bupropion hydrobromide may also improve treatment adherence among patients receiving the highest dosage. It is difficult to ascertain how the medications with new mechanisms of action will fit into clinical practice (levomilnacipran and vortioxetine were not yet available at the time of this writing), but those agents may be helpful for patients who have tried and failed other antidepressants, perhaps due to intolerance or lack of efficacy. Due to cost concerns, we will probably see those newer agents used more as second or third-line agents. Vilazodone has been available for several months now and that is mostly how I am seeing it used.

Some of the drugs currently in development may substantially impact how we treat MDD. It will be particularly interesting to see if the drugs that target glutamate will be able to produce a rapid improvement in depressive symptoms. In studies of the N-methyl-D- aspartate antagonist ketamine, patients were shown to have a significant improvement in depressive symptoms as early as 2 hours after receiving the medication, even among those who had a history of failing multiple antidepressants37. This would be a vast improvement over existing therapies, which generally take weeks to start working.

What are some major challenges associated with current approaches to treatment?
Even though the newer antidepressants are much better tolerated than the older TCAs and MAOIs, side effects are still a major concern for patients using antidepressants, which certainly impacts patient adherence with treatment. The fact that these medications often take a long time to work and that remission rates are still so low is discouraging for many patients with MDD. For some time, there had been a lack of truly novel antidepressants. This changed, but the progress seems to have leveled out over the past several years, with each new antidepressant showing only marginal improvements over existing therapies. Hopefully, the most recently approved antidepressants and agents still in development will also be able to put a bigger dent in the number of patients with TRD.

I also believe that ECT is probably underutilized. Many patients are sur- prised to hear that ECT is still used, and so many individuals have fears and misconceptions about the use of ECT. Increasing the availability and education regarding the potential benefits and safety of ECT would likely benefit many patients.

What is the role of approved antipsychotics in patients with TRD?
The atypical antipsychotics have some of the best evidence for use in augmentation for MDD (Table 438-40.) and are currently listed as a second-line augmentation strategy by APA4,13. The FDA approved both aripiprazole and quetiapine extended release for augmentation treatment of MDD in 2007 and 2009, respectively. A third agent, which combines olanzapine and fluoxetine, marketed as Symbyax, was also approved for TRD in 200938. The number needed to treat to achieve a good response with these agents ranges from 7 to 13, and for remission, 7 to 14; this means that we would need to treat anywhere from 7 to 13 patients to see 1 good response from an atypical antipsychotic that was not due to a placebo effect alone38. Similarly, a recent meta-analysis demonstrated that pooled response and remission rates with atypical antipsychotics compared with placebo were 57.2% and 47.4% versus 35.4% and 22.3%, respectively41.

Although atypical antipsychotics are effective in the treatment of MDD, these agents, like all medications, do have potential adverse effects, including weight gain, somnolence, orthostasis, dry mouth, and extrapyramidal symptoms such as akathisia39. In some cases, with aripiprazole for example, weight gain has been seen at a higher rate among patients with depression than what is typically seen in patients with schizophrenia39. The risk for longer-term side effects such as tardive dyskinesia (TD) and metabolic abnormalities, such as hyperlipidemia or diabetes, is unknown for patients with MDD at this time, but these effects should be monitored for all patients on antipsychotics. Because of the potential side effect burden, as well as cost related concerns, trying at least 1 other augmentation strategy before turning to an atypical antipsychotic is prudent4,39.

Another consideration regarding the use of atypical antipsychotics in patients with MDD is the appropriate duration of use for augmentation in depression. While studies with aripiprazole have lasted up to 1 year, some clinicians may recommend a maximum duration of treatment with atypical antipsychotics in MDD of only 6 months. A conservative approach to management is to taper the antipsychotic just after remission is achieved; however, without the necessary data or literature to assess long-term safety and efficacy, the proper duration of treatment with atypical antipsychotics remains unknown42. The optimal treatment strategy is to frequently reassess the safety and efficacy of a therapeutic regimen and to individualize the dosage for each patient39.

What are the implications for pharmacists?
Pharmacists should remain vigilant to ensure that these medications are being used appropriately and that the adverse effects are being monitored properly. (See references 43 and 44 for detailed antipsychotic metabolic monitoring guidelines.) Unfortunately, the long-term risks of using atypical antipsychotics in patients with MDD are unknown, but studies have shown that these types of patients may experience more adverse effects, such as weight gain and akathisia, than patients treated with the same medications for other conditions39. Pharmacists are in a key position to monitor patients for these long-term side effects, as pharmacists are easily accessible and often interact with patients on a frequent and consistent basis39. Catching these adverse effects and intervening early is important not only to minimize the long-term risk of developing permanent TD or metabolic complications but also to curtail the negative impact that these side effects may have on patient adherence.

Monitoring for drug interactions is another essential responsibility for phar-macists, and caution should be exercised when combining a strong CYP2D6 inhibitor (eg, fluoxetine or paroxetine) with an atypical antipsychotic (eg, aripiprazole or risperidone), as this combination may result in an increased risk of adverse effects39. Combining multiple medications that affect serotonin (eg, antidepressants and atypical antipsychotics) may also increase the risk of serotonin syndrome, which is a serious condition that all patients receiving antidepressants should be made aware of. Signs and symptoms of serotonin syndrome include gastrointestinal symptoms (eg, diarrhea and abdominal pain), neurologic symptoms (eg, lethargy, changes in mental status, tremor, myoclonus, hyperreflexia), and autonomic symptoms (eg, hyperthermia, flushing, sweating). If left untreated, patients may also suffer from rhabdomyolysis, renal failure, cardiovascular shock, and even death4.

What is the pharmacist’s role in addressing challenges that are commonly encountered in the management of MDD?
Pharmacists should be focused on ensuring that drug combinations are rational and that dosing is appropriate. It is especially important to maintain open lines of communication with the prescriber and to question when something looks strange or out of place. Some patients will eventually require complicated treatment regimens or high doses of medications when prescribers run out of options, but it is important for the pharmacist to inquire about the therapeutic rationale and to participate in the discussion of risks versus benefits.

Pharmacists must also be aware of the warning signs that may be indicative of adherence problems. If a patient is consistently late with his or her medication refills, the prescriber should be alerted. Making an effort to counsel patients regarding the importance of treatment adherence and asking about any challenges or obstacles that the patient may be experiencing are central to getting patients back on track. In some cases, for example, a patient may not be able to afford a certain medication, but a pharmacist’s simple recommendation for a less costly alternative may be all that is needed to make a difference for that patient.

What are some barriers to adherence that the pharmacist will face with patients on antidepressants?
People are often just afraid of taking medications; they worry about side effects that they hear about in the media or from friends who have had bad experiences, and some patients are afraid of developing addiction or dependence. It is imperative to educate patients with MDD about the potential risks and benefits of appropriate medication use in an effort to clarify potential misconceptions and popular myths. Patients who are depressed may not be motivated or optimistic about treatment and may also suffer from memory deficits that may impact their ability to adhere to treatment4. Other factors that have been associated with poor adherence to antidepressant treatment include having multiple comorbid medical conditions, lower socioeconomic status, alcohol and substance abuse, and a younger age28.

What are the risks of nonadherence that should be made known to all patients on antidepressants?
Patients should be aware of several risks—notably, the risk of disease relapse if their antidepressant treatment is discontinued prematurely4. Stopping an antidepressant therapy abruptly may also lead to discontinuation syndrome, particularly with antidepressants that have short half lives (eg, paroxetine, venlafaxine). Symptoms of antidepressant discontinuation syndrome may include flu like symptoms such as nausea, headache, body aches, lightheadedness, and chills, and neurologic symptoms such as paresthesias, insomnia, and electric shock–like sensations4. Another issue to consider is the impact on the relationship between the physician and the patient. A lack of communication between a patient and a physician leads to unaddressed concerns and an unknown status of treatment adherence, which complicates the physician’s ability to appropriately evaluate the patient’s response to treatment. A lack of clinical improvement in a patient’s depression may then be falsely attributed to nonresponse to an antidepressant, when in reality the patient may not have been taking the medication appropriately. While simple adjustments to the dose or timing of an antidepressant may improve adherence to treatment, health care providers involved in the care of patients with MDD are unable to offer solutions when they are unaware of the problems.

MDD is a highly prevalent and debilitat-ing disorder that is linked to increased morbidity and mortality. Fortunately, the expanding therapeutic pipeline for MDD in recent years has yielded several new antidepressants, including new dosage forms of previously approved drugs. Now, there are many more effective treat-ment options available for clinicians to choose from, including medications that can be used adjunctively with antidepressants to improve treatment outcomes. Pharmacists are instrumental in effectively managing patients with MDD, not only by helping physicians to select appropriate treatments and to monitor for medication effectiveness and safety, but also by recognizing and mitigating the potential barriers to treatment adherence. With a growing therapeutic armamentarium and evolving clinical practices, it is imperative for pharmacists to remain abreast of current treatment recommendations and optimal management strategies to ensure the best possible outcomes.

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Serotonin and Beyond: Optimizing Management of Major Depressive Disorder