Brief Review of Major Depressive Disorder for Primary Care Providers
Medications
Given the realities of practice settings and patient preferences, medication is often the most practical first-line treatment choice. The newer antidepressant medications are the most likely choices in the primary care setting for treating depression, because they offer effective treatment with less severe adverse effects (AEs) and are much safer than the early tricyclic antidepressant and monoamine oxidase inhibitor medications. There are numerous metaanalyses comparing the effectiveness of the commonly prescribed newer antidepressants that consistently show there is no absolutely best choice antidepressant. A number of studies have tried to identify predictors of response for a particular antidepressant, but these have not yielded clinically significant results. Additionally, there is little difference between an antidepressant’s rate of response and tolerability on a population scale.13 Therefore, it is the AE profile and alternate uses that usually drive the choice of which to use for a particular patient.
Before discussing antidepressant medications with patients, it is important to note the FDA-required black box warning for increased risk of suicidal ideation in young people aged ≤ 24 years. The data that led to this warning did not show an increased risk of suicide.14 In patients aged > 24 years, there is no difference in risk of suicidal ideation, and in patients aged > 65 years, the risk of suicidal ideation decreases with the start of antidepressant medication.1
SSRIs
Selective serotonin reuptake inhibitors (SSRIs) are a common first-line treatment for MDD. Of interest, all SSRIs share the same mechanism of action (MOA), so failure of a single agent does not preclude a trial of a second agent of the same class, because the chance of response is essentially the same as switching the patient to another class. However, after a second failure, there is less chance of response to another SSRI.5 These agents are used for depression, anxiety (long term not acute), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder. The AEs include nausea, headache, insomnia, dry mouth, and loss of emotion. Other than feeling emotionally blunted, most of these AEs are usually temporary and resolve in days. Sexual dysfunction is often the AE of SSRIs that draws primary concern from patients. The most frequently experienced sexual AE is delayed orgasm. A review of FDA package inserts showed rates from 7% (sertraline) to as high as 28% (high-dose paroxetine).16,17 Impotence or decreased libido is often more concerning for patients and occurs at 3% to 6%. A common concern for patients is weight gain, and SSRIs are considered weight neutral. There has been no demonstrated benefit from combining these medications or using them with selective serotonin norepinephrine reuptake inhibitors (SNRIs), which only exposes patients to increased risk of AEs.
Other Medications
Often used as first-line medications for MDD, SNRIs are also useful for MDD, anxiety (long term not acute), and PTSD. Duloxetine also has indications for diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain. The SNRIs share the same AEs as SSRIs; however, some patients show an increase in blood pressure with venlafaxine. There has been no demonstrated benefit from combining these medications or with SSRIs. These are also considered weight neutral.
Mirtazapine, bupropion, and trazodone are medications with MOAs that do not fit within the abovementioned categories and differ from one another as well. These carry FDA indications for MDD. Bupropion also has indications of smoking cessation and seasonal affective disorder for the extended-release form. The AEs are varied and unique to each medication. Mirtazapine may show a rapid improvement in mood within 2 weeks and very low risk of sexual AEs.18 Associated with some weight gain and sedation, mirtazapine is useful for patients who have sleep problems or who are experiencing weight loss. It is noted in practice to be more sedating at lower doses.
Bupropion is considered an activating medication that can lead to jitteriness and increased anxiety for some patients. Bupropion also is associated with some weight loss and will disrupt sleep if taken later in the day. Therefore, bupropion can be useful for overweight patients or those with significant energy problems. It has few sexual AEs.
Although not widely used as a primary agent for MDD, trazodone is commonly used at low doses to treat insomnia. Sedation and dry mouth are the primary AEs with some sexual AEs. These medications can be used alone, in combination with SSRIs or SNRIs, or with one another in what is commonly called rational pharmacology.
Patient Response
There is a significant portion of patients who are treated for MDD who will not have an adequate response to their first medication, somewhat analogous to patients who are treated for hypertension or diabetes. If patients are showing a response at 6 to 8 weeks but not remission, the medication trial should continue for 12 or more weeks, increasing the dose as tolerated. If the dose has been raised to the maximum and if there are still significant depressive symptoms, some combination or augmentation strategy should be tried. If patients show no improvement at 6 to 8 weeks, it is appropriate to discontinue the current treatment and trial another medication.
There are no clear guidelines for the best way to switch medications. Some practitioners cross taper; some discontinue one medication prior to starting another; and some abruptly stop one and start another (ie, changing between SSRIs, or from a SSRI to a SNRI). In all cases, some caution is recommended to avoid discontinuation syndromes, which often drive the rate of discontinuation of the medication: Many people have no problem; others are very sensitive to dosage changes.
If a patient has achieved remission with the medication, the next step is easy—continue the medication. It is generally accepted that 6 to 12 months of medication treatment after remission is best, to avoid relapse to another episode of MDD. If a patient desires to stop medication after that period, it is best to slowly titrate off over a month or more, as the patient tolerates, to avoid the discontinuation syndrome and lessen the risk of relapse. Remission rates for a single trial of medication are 35% to 45% and up to 65% with repeated medication changes.19 Therefore, 35% of patients are inadequately relieved of illness, referred to as treatment-resistant illness.
In the patient who has experienced some benefit but not remission after taking the dose to the highest approved or tolerated dose, the question is whether to switch from a medication that has shown some efficacy to another that may be better or to add another medication to augment the efficacy of the first treatment. There are many opinions regarding these decisions and about how to proceed.
Augmentation and Combination Treatments
Augmentation is the use of a nonantidepressant medication in addition to the antidepressant to improve the efficacy of the antidepressant medication. Combination treatments use 2 antidepressant medications to improve efficacy. Although there is clear evidence of benefit from a number of augmentation strategies, including some that are FDA approved, combination treatments have conflicting
published evidence of efficacy.20,21
The FDA-approved medications for augmenting antidepressant medications in treatment-resistant MDD are aripiprazole and quetiapine XR. Both are atypical antipsychotic medications with the intrinsic class risks associated with them. Only psychiatrists usually use them, because most systems require the approval of a specialist to use these agents. Of particular concern is the longterm risks of tardive dyskinesia, neuroleptic malignant syndrome, weight gain, metabolic syndrome, diabetes, and sudden death in geriatric patients with dementia that warranted a black box warning. Other well-established augmentation strategies used by psychiatrists include the usage of lithium or T3 hormone. Using these agents requires collaborative monitoring with the PCP to prevent potential renal, cardiac, and thyroid abnormalities.
Conclusions
Successful treatment of depression in medical settings can have a positive impact on medical conditions, such as potentially improving outcomes in the treatment of diabetes, cardiovascular problems, and pain. Active screening for depression followed by a safe and well-tolerated antidepressant may relieve symptoms in 6 to 8 weeks in about half of treated patients.
Tracking responses with one of the aforementioned scales is an excellent way to guide treatment decisions. Lack of tolerability or response should not discourage physicians from trying a different antidepressant. The successful treatment of depression requires patience but can make a big difference in the patient’s quality of life.
