Personalized medicine aims to match each patient with a treatment that uniquely fits their symptoms, biological markers, or other features like age and gender. It is only recently that we have research to guide us in this direction. In this article, we’ll look at ways to personalize the approach to antidepressant augmentation.

Anxious depression

When it comes to antidepressant augmentation, mirtazapine sits on the fence. Several large randomized controlled trials (RCTs) were negative, but a meta-analysis that included small but positive trials found an encouraging signal. This popular augmentation strategy may be most successful with a personalized approach. A signal in anxiety reduction in one of those RCTs prompted a second look at the evidence, which revealed benefits in both depression and anxiety among those with severe anxiety at baseline (number needed to treat [NNT]=5 for response) (Rifkin-Zybutz R et al, J Psychopharmacol Oxf Engl 2020;34(12):1342–1349). You could consider mirtazapine augmentation in anxious depression, as well as in depression with insomnia.

Quetiapine worked in augmentation for both anxious and depressive symptoms in two RCTs of major depression with comorbid anxiety disorders (average dose 200 mg QHS). This antipsychotic has a large effect in generalized anxiety disorder (GAD), and nearly earned FDA approval in GAD but for a drawback that also gives us pause—like other antipsychotics, quetiapine has serious side effects and should be reserved for severe anxiety.

Depression with suicidality

Lithium, along with clozapine and the ketamine formulations (ketamine and esketamine), is one of the only psychotropics with robust antisuicide effects. A couple of recent studies, however, have cast doubt on lithium’s antisuicide effects. One of these studies was a meta-analysis that excluded important older studies and instead focused on more recent, shorter studies that were likely not large or long enough to detect the relevant effect (Nabi Z et al, Epidemiol Psychiatr Sci 2022;16;31:e65). The other was an RCT that only looked at suicidal behaviors and attempts rather than death by suicide (Katz IR et al, JAMA Psychiatry 2022;79(1):24–32).

Rather than overturn the evidence that lithium reduces suicide risk, these studies helped to underscore that observing lithium’s antisuicide effect requires longer follow-up, and that lithium may not reduce all suicidal behaviors. In fact, decades of prospective and observational data support lithium’s role in patients with depression and suicidality. Lithium use requires monitoring of thyroid (10%–15% lifetime risk of hypothyroidism) and renal function. For depression augmentation, we start at 150–300 mg daily and titrate slowly every five days, aiming for a level between 0.6–0.8 mEq/L. The response takes two to six weeks.

Intranasal esketamine has emerged as another augmentation approach for suicidal patients. One common dosing practice is administering 84 mg twice a week for four weeks. The differentiator with esketamine (much like ketamine) is the speed of action—it works within hours, even faster than ECT (Ionescu DF et al, Int J Neuropsychopharmacol 2021;24(1):22–31). But just how long to continue treatment is still largely an open question. IV ketamine may work just as well with effects seen even after a single dose.

Depression with insomnia

Dozens of trials of benzodiazepines in augmentation of antidepressants and monotherapy have established their role not just in improving sleep, but in addressing certain core symptoms of depression. Most of these studies focused on relatively short-term use, and the benefits need to be weighed against known risks of long-term benzodiazepine therapy (eg, dependence, falls, cognitive impairment). The same antidepressant effect has not held up with most ­z-hypnotics, with the exception of eszopiclone (Lunesta). In two RCTs, eszopiclone 3 mg improved depressive symptoms even when sleep items were removed from the analysis (NNT=11 for remission) (Fava M et al, Biol Psychiatry 2006;59(11):1052–1160; McCall WV et al, J Clin Sleep Med 2010;6(4):322–329). Later controlled trials found benefits in GAD and chronic pain with eszopiclone.

Alternatively, some antidepressants like mirtazapine, trazodone, and quetiapine have evidence to improve sleep quality and initiation.

Depression with mixed features

Depression with mixed features is a newer specifier in the DSM-5, and it is used for patients who have depressed mood combined with at least three manic symptoms but do not have enough manic symptoms to meet criteria for bipolar disorder. These patients present as wired, restless, and irritable. In these patients, lurasidone is a good choice as it has robust evidence as monotherapy for mixed features. Aripiprazole is also a good choice as it worked as augmentation in depression with mixed features in a large VA trial (Zisook S et al, Am J Psychiatry 2019;176(5):348–357). Surprisingly, that trial also pointed to bupropion augmentation as a preferential treatment for mixed features. Among the antidepressants, bupropion has the lowest risk of inducing manic symptoms.

In some patients, antidepressants may cause mixed symptoms to emerge. If the timeline of mixed symptoms suggests this might be the case for your patient, for more rapid relief, it makes sense to augment with an antipsychotic like lurasidone while slowly tapering the antidepressant.

Winter depression

Light therapy has a medium effect size in winter depression, a common depressive subtype that affects up to 20% of people with major depressive disorder (MDD) (see “A Practical Guide to Light Therapy” in the November/December 2019 issue of TCPR). For full effect, the light needs to be white spectrum, ideally 10,000 lux, and should be used just after waking up, before 8 am. The best light boxes are at least 12 x 17 inches and should be angled at 30 degrees over the patient’s head for 30–60 minutes per day. Patients note some improvement within one to two weeks.

Vascular depression

Microvascular infarcts accumulate in the brain as vascular disease progresses, and this is speculated to be a common cause of depression in older adults. After age 50, one in five patients with depression have a vascular contribution, and this rises to one in two after age 65 and nearly 100% by age 75 (Taylor WD et al, Am J Psychiatry 2018;175(12):1169–1175). Patients with heart disease, diabetes, and hypertension are particularly at risk. Confirmation is found through white matter abnormalities in a brain MRI, even if patients are described as “normal for age.”

Antidepressant efficacy is greatly reduced in this condition, so augmentation is often necessary. One strategy is using nimodipine, an antihypertensive that improves cerebral blood flow and showed efficacy in two RCTs of vascular depression (remission NNT=5 and NNT=4) (Taragano FE et al, Int J Geriatr Psychiatry 2001;16(3):254–260; Taragano FE et al, Int Psychogeriatr 2005;17(3):487–498). The target dose is 90 mg TID, and it takes up to two months to see an effect. Start at 15 mg TID for patients who are already on blood pressure medicine, or 30 mg TID for other patients, and raise by 15 mg every 10 days.

Repetitive transcranial magnetic stimulation (rTMS) is another option for vascular depression. In one study, rTMS brought remission with an NNT of 5 (Jorge RE et al, Arch Gen Psychiatry 2008;65(3):268–276).

Inflammation and obesity

Inflammation, obesity, and depression are closely linked. A growing body of evidence points to specific antidepressant strategies for patients who are obese (BMI >30) or have inflammation, as measured by high-sensitivity C-reactive protein (hs-CRP ≥3).

Two augmentation strategies may be specifically effective in patients with both obesity and inflammation: L-methylfolate (15 mg/day) and bupropion (300 mg/day). Both worked preferentially in those populations in large RCTs (Shelton RC et al, J Clin Psychiatry 2015;76(12):1635–1641). Omega-3 fatty acids also may be effective in patients with elevated inflammatory markers (hs-CRP ≥3). They are usually dosed as 1,000–3,000 mg/day of combined EPA and DHA omega-3s, with the EPA ratio at least twice the DHA amount. However, higher doses (EPA >4,000 mg/day) were more effective in patients with obesity and inflammation in a recent study (Mischoulon D et al, J Clin Psychiatry 2022;83(5):21m14074).

Augmentation options with unique benefits in patients with inflammation include N-acetylcysteine and minocycline (Porcu M et al, Psychiatry Res 2018;263:268–274).

Insulin resistance and depression

Patients with depression and diabetes may benefit from augmentation with the antidiabetic medication pioglitazone. The research is preliminary, with one trial showing general benefits in MDD and another showing improvement only in those with insulin resistance (Lin KW et al, Psychiatry Res 2015;230(3):846–852). We recommend restricting pioglitazone to patients with comorbid diabetes and using it in consultation with their PCP (start 15 mg/day, target 30 mg/day). Pioglitazone is well tolerated but carries a black box warning about a small increased risk of bladder cancer.

Psychotic depression

For the psychotic subtype, ECT is the gold standard, bringing over 90% of cases to remission. If medication therapy is used, antipsychotic augmentation is usually necessary, but doses need to be higher than those used for general augmentation of MDD without psychosis (Farahani A and Correll CU, J Clin Psychiatry 2012;73(4):486–496). The STOP-PD II trial suggested that continuing the antipsychotic for six months reduces the risk of relapse (Flint AJ et al, JAMA 2019;322(7):622–631).

Depression with fatigue

Augmentation with modafinil has a limited role in treatment-resistant depression (NNT=10 for remission), but it might be useful for targeting residual fatigue. Modafinil (100–200 mg/day) and its isomeric cousin armodafinil (150–250 mg/day) are well tolerated and may boost overall adherence, as patients cite fatigue as a leading reason for antidepressant discontinuation.

For an overview of all the medications discussed here, see the table.

Carlat Verdict 

The are many types of depression, and specific signs and symptoms can point the way toward a more personalized augmentation strategy.