Augmentation Strategies for Treatment-Resistant Depression

An Evidence-Based Approach to Augmentation and Combination Strategies for Treatment-Resistant Depression – free full-text /PMC2958866/Psychiatry (Edgmont). 2006 Jul;

This long paper explores all kinds of other medications that can be used in addition to the usual antidepressants. I experimented with countless medications over several decades and now operate on a cocktail of antidepressants (SNRI’s and tricyclics), mood stabilizers, and supplementary hormones (estrogen, thyroid, neurosteroids).

I’m still depressed at least half the time, but the suicidal impulses have quieted since I got my anxiety under better control using pregnenolone (and Lyrica, which also has anti-anxiety properties).

This paper is a review article that collects and synthesizes up-to-date information about the practice of augmenting and combining medications in regards to treatment-resistant major depressive disorder. 

 A thorough MEDLINE search was utilized to collect many papers dedicated to this area of study spanning 1989-2005.  


Treatment-resistant depression (TRD) is, unfortunately, a common variant of major depressive disorder (MDD). 

Despite initial adequate antidepressant monotherapy of appropriate trial duration and dose optimization many patients will not fully respond or remit into a wellness state,

In fact, the longer a depressive episode lasts, as complicating factors increase, more treatments are failed, then resistance tends to increase and prognosis decreases.

a failure to obtain remission of depressive symptoms may neurophysiologically predispose an individual to an increase in relapses with a worsening of symptoms in future major depressive episodes, making the initial treatment of a TRD patient an important one.

As the term augmentation suggests, an agent is prescribed and utilized simultaneously and in conjunction with an already therapeutically dosed, FDA-approved antidepressant.

We have written this article in order to describe the existing evidence base in regards to augmentation and combination strategies employed in the treatment of TRD.

Augmentation Strategies


The seminal work of De Montigny, et al., in the 1980s described the rapid antidepressant effects when lithium (Li) was added to tricyclic antidepressants in treatment-resistant patients and laid the path for augmentation research

Li as an augmentation agent continues to be the focus of much research and clinical application in TRD, and the literature continues to support its use in this capacity.

A narrative review of 27 studies and 803 patients, completed by Bauer, noted an average response rate of 45 percent, in the Li group, versus 18 percent placebo, in acute-treatment trials.

The pooled data indicated that 50 percent of patients responded to Li augmentation within 2 to 6 weeks, corresponding with blood levels of 0.5–1.0mmol/liter.

In 33 studies, 37.0 percent of patients responded within two days, 36.5 percent of patients responded from two days to two weeks, 27.5 percent of patients responded after two weeks.

On the basis of such data, Bauer and Rouillon both recommend the continuation of Li augmentation for a minimum of 12 months in Li augmentation responders despite the suggestion by Nierenberg that long-term efficacy may be a function of acute response to Li augmentation versus duration of treatment augmentation.

Unfortunately, only a few placebo-controlled trials in these meta-analyses examined lithium’s efficacy with SSRIs or SNRIs,

Randomized studies evaluating lithium’s efficacy with SSRIs in TRD, such as those conducted by Baumann, et al. and Katona, et al., using citalopram and fluoxetine, and lofepramine, respectively, have yielded similar effectiveness data versus placebo


Lithium remains a first-line augmentation strategy best supported by double-blind, randomized, placebo-controlled data.

It is effective as both a response modulator and accelerant, often effecting a treatment response within two weeks of beginning treatment at doses between 750mg and 1500mg/day corresponding to serum levels >0.5mEq/L. Follow-up studies have shown Li augmentation of antidepressants to be efficacious with good tolerability when evaluated over three years later.


While never considered suitable monotherapy agents for the treatment of pure mood symptoms, such neuroleptics were often utilized in the treatment of affective disorders with psychotic or agitated features.

the focus of recent research has shifted to augmentation using the newer, ‘second generation’ antipsychotics. This newer, or atypical, class of antipsychotics that differ from the strictly D2 receptor antagonism of the predecessors theoretically lack the “cognitive blunting” effect of older antipsychotics, such as thioridazine.

It is postulated that these atypical antipsychotics have significantly more potent antagonism of the 5-HT2A serotonin receptor than the D2 receptor antagonism of their predecessors

Mesocortical dopmanine pathways may also be optimized and help the usual hypofrontality noted in depressed patients. Thus, the atypical antipsychotics appear to show much promise as potential augmentation agents, due to this serotonin antagonism.


What data does exist appears to support the use of olanzapine and, to a limited extent, risperidone as augmentation agents while remaining mindful of the metabolic, endocrine, and cardiovascular risks.

Dosing may also be important in that low to moderate doses may be best suited for offlabel use in depression.

Thyroid hormone.

Prange, et al., conducted the first of several studies in 1969, and similar to the research in lithium (Li) augmentation, this original study was conducted with TCA non-responders.

In this pioneering study for thyroid hormone augmentation, the researchers demonstrated an “enhanced and accelerated recovery” when the more biologically active triiodo-thyronine (T3) was added to imipramine monotherapy.

While the exact mechanisms of action are still debated, it has been postulated that thyroid hormone acts in a number of ways including interacting with norepinephrine, acting directly on the pituitary-thyroid axis, modulating the T3 effect on thyroxine, or enhancing central beta-adrenergic receptor function.

Limited by a paucity of data pertaining to thyroid hormone augmentation of SSRIs, Joffe published three cases in 1993 in which triiodothyronine (T3) was used to successfully augment an antidepressant response to fluoxetine.

These cases were similar in that the patient experienced improvement in depressive symptoms when given either a tricyclic or MAOI antidepressant as well.

However, residual dysthymia and lack of energy persisted similar to fluoxetine used as a monotherapy. These symptoms dissipated within weeks of adding T3 to augment fluoxetine, with no adverse effects noted.


Based on pooled data and randomized controlled trials, thyroid hormone has been found to be an effective augmenter in TCA non-responders.


Similar to pindolol, buspirone likely exerts its effects as a partial 5HT1A receptor agonist.

The addition of buspirone to an SSRI or TCA may result in an enhanced serotinergic effect and improvement of depressive symptoms.


In addition, the STAR*D randomized study and multiple smaller open-label trials have supported the efficacy of buspirone 20 to 30mg/day as an augmentation agent.


The data for steroid augmentation of antidepressants is founded in interrelationships between gonadal steroids and their modulation of central nervous system serotinergic function,.

steroids, such as prednisone, may function to suppress a dysregulation of the hypothalamic-pituitary-adrenal axis that is believed to occur in depression. This postulated dysregulation results in the hypersecretion of cortisol


At the end-point, sertraline-treated women taking estrogen replacement therapy (ERT) with a mean dose of 0.625mg/day had significantly greater global improvement (79% vs. 58%) and improved quality of life than those not receiving ERT.

Patients received either citalopram monotherapy for 12 weeks (n=22) or citalopram plus 100mcg/day-estrogen therapy for eight weeks (n=13). Of the 92.3 percent of the patients who completed the adjunctive treatment trial, 91.6 percent achieved full remission with ERT.

Symptoms that had persisted after an initial four-week treatment with estrogen alone (tension, anxiety, tiredness, and difficulty concentrating) improved significantly.

Anxiety and somatic complaints had significant improvement (p<0.05)


Efficacy analysis revealed that the testosterone-treated patients had a significantly greater rate of decrease in scores on both the HAM-D and CGI than the placebo-treated patients. There were no significant differences between the placebo and testosterone with regard to changes in body fat or muscle mass.


In 2000, Bouwer, et al., completed a nonplacebo-controlled, naturalistic, retrospective study of six patients with TRD with severe fatigue and low cortisol levels. Prednisone 7.5mg/day was added to their antidepressant regimens for four weeks.

Significant improvement in depression was seen in 83.3 percent of the patients treated with predisone augmentation, and 66.6 percent demonstrated a greater than 50-percent reduction in HAM-D scores.

Prednisone augmentation resulted in weight gain in all six patients


The available data suggests a possible role of adjunctive estrogen in the treatment of peri- and post-menopausal depression in woman with and without vasomotor symptoms.

With limited data at this point, one should be mindful of the positive efficacy and tolerability data and weigh it against potential long-term risks of uterine and breast cancer and thromboembolism

Similarly, studies suggest a possible role for adjunctive testosterone and prednisone in TRD patients who are testosterone and cortisol deficient, respectively.

However, the clinician and patient must weigh the potential risks when evaluating the limited steroid-TRD data.

While still in college, I had taken prednisone for a brutal attack of poison oak and noticed how energetic it made me feel. So I tried a low dose of 5mg prednisone for my chronic pain, mainly as an anti-inflammatory to ease my pain but also to increase my energy.

Unfortunately for me, the low dose doesn’t have the effects of higher ones and I had only a little pain relief and a little more energy – not enough to risk the long-term side effects of this medication.

I still keep it around in case of predictable pain flares after I’ve done something I know will cause me agony the next day (like a walk on concrete sidewalks or shopping trips, also on concrete flooring).

Then I take 5-10mg right before bed because it takes about 5-7 hours for me to feel an effect, after which I can’t sleep for a while. But I only take it sporadically less than once a month, so I’m not worried about side effects.


The structural homology of the β-blocker pindolol to serotonin is likely to underlie its capacity to act as an antidepressant-augmenting agent at the level of the serotonin receptor.

pindolol likely exerts its effect by acting on the 5-HT1A serotonin receptor.


The effectiveness story is similar to the busprione data presented above, and both medications may use the same mechanism of antidepressant action.

little is known about pindolol’s longer-term tolerability.

Omega-3 fatty acids.

There is some evidence that omega-3 acids may have an effect on human CSF serotonin metabolites, a property that may be utilized to augment the effects of an antidepressant agent.


With limited research, that suggests efficacy as an augmentation agent dosed at 1 to 2g/day, the innocuousness of nutriceuticals, such as omega 3 fatty acids, warrants further investigation


Despite its need for an intact dopamine reuptake carrier side, this “stimulant” exerts much of its wakefulness effects in a manner completely unlike stimulants or dopamine agonists.

Modafinil appears to increase histamine activity in the tuberomammilary nucleus with its projections to the frontal cortex. In addition, it is believed that some of modafinil’s augmentation effects may be ascribed to its reduction of alpha-aminobutyric acid release.


Certain study results support the idea that modafinil dosed at 100 to 400mg/day is a reasonable antidepressant accelerant or adjunct used to treat target symptoms of depression, such as fatigue, rather than the core mood and anhedonia components of the disease.

Recent studies suggest that modafinil, with its benign side effect profile (some reported jitteriness and nausea), might be more appropriately considered an augmentation agent in the treatment antidepressant partial responders with excessive fatigue.

I’ve tried Modafinil but could hardly discern any effect except that I stayed awake past 8pm. The problem is its cost. Otherwise, I’d much prefer this to the Adderall I’m taking.


Psychostimulants, such as methylphenidate, are typically utilized in the treatment of attention disorders, most notably in the pediatric and adolescent patient population.

The efficacy of stimulants is based in their actions as either inhibitors of dopamine/norepinephrine reuptake, or release of these monoamines into the synaptic cleft.

This dopaminergic boost acting on the level of mesolimbic dopaminergic projections is believed to contribute to an enhanced and rapid antidepressant effect and possibly addictive potential.


multiple open-label trials have suggested that methylphenidate at doses between 5 to 20mg/day and other stimulants are efficacious antidepressant augments and treatment accelerators, notably in depressed elderly patients.

Unfortunately, well-documented adverse effects, such as anxiety, insomnia, dose-dependent hypertension, abuse potential, and exacerbation of psychosis and mania, could continue to limit their use in the absence of more robust data regarding both long-term efficacy and tolerability.

I’m lucky to have a doctor who also prescribes me Adderall for my previously diagnosed ADHD. I keep hearing how people absolutely fall in love with this medication, but unfortunately, it has no mood effects on me. I use it to stay awake during the day when all I want to do is sleep.


it has been suggested that α2-antagonists, such as yohimbine, may further disinhibit norepinephrine autoreceptors and serotonin heteroreceptors resulting in a net release of both monoamines. This effect would augment the serotonin effect of long-term SSRI or TCA treatment.


Despite positive data, yohimbine’s efficacy as an augmentation agent is still questionable given the limited power of the studies.


The utility of anti-anxiety sedative agents like the benzodiazepines as augmentation agents in TRD may be most beneficial for atypical depression accompanied by significant anxiety, mood reactivity/lability, and hyperactivity versus vegetative symptoms.

Based on intent-to-treat analysis, the benzodiazepine-augmented antidepressant group was more likely (63% vs. 38%) to show response in four weeks.

There were no reported differences in adverse events.


Similar to modafinil targeting a specific set of vegetative depressive symptoms, the sedatives may preferentially target the spectrum of hyperarousal symptoms of depression.


There is a growing body of evidence that dopamine agonists, such as pergolide, as well as others drugs currently being used in the treatment of Parkinson’s disease may have utility as adjuncts in the treatment of depression

new data based on RCTs have supported the concept that optimizing dopamine, like other monoamines, is important in the treatment of patient’s with TRD.


Based on conflicting negative data from a double-blind study and marginally positive data from two open-label studies, further efficacy and tolerability data from randomized trials is needed before pergolide should be reasonably considered for antidepressant augmentation.


One proposed neurophysiogical mechanism of depressive processes involves the cytotoxic effects of glutamate on the central nervous system.

Thus, it has been speculated that a final pathway for efficacious antidepressant effect is the modulation or dampening of glutamate and its NMDA receptor.

To this end, anticonvulsants that inhibit glutamate release, such as lamotrigine, may be effective augmentation agents.


The results of such trials suggest that anticonvulsants, such as lamotrigine, may be efficacious as augmentation agents, especially in patients with shorter duration depression and fewer antidepressant trials.

I started trialing this with the lowest dose, 25mg,  and felt an immediate difference in my wildly swinging moods (bipolar II).

Lamotrigine seems to prevent those quick dips into depression that “came out of nowhere”. I’d be plunged into tearful misery for a few hours almost daily, and that stopped when I started this medication.

I trialed up to 100mg lamotrigine/day, but never felt anything more as I titrated up, so I’m staying on what they call a “sub-clinical dose” (meaning there should be no noticeable effect) to get the benefit without having to take huge amounts of this drug.

Combination Strategies

As discussed earlier, a “combination” strategy utilizes two FDA approved antidepressants added together (usually in sequence) to obtain better symptom remission in a depressed patient. Combination therapy is widely popular, as highlighted by a study in which approximately 25 percent of discharged patients from a psychiatric hospital were on more than one antidepressant.

The article goes on to describe the effects of

  • heterocyclic antidepressants (Mirtazapine, Trazodone, Nefazodone), 
  • Tricyclic antidepressants, Bupropion, and
  • SNRIs (Venlafaxine, Duloxetine).


There is a wide range of literature available in regards to treating resistant major depression by way of augmentation or combination strategies.

The heterogeneity exists in regards to type of agents used and the scientific merit behind the evidence base that is currently available. It appears to be the standard of care that psychiatrists will often add medications together in order to better treat major depressive disorder to full remission.

Interestingly, the large literature base briefly reviewed above often demonstrates that, “the most common augmentation strategies in depression are those with the least controlled evidence.”

The best studied approaches, i.e., Li augmentation, may be the least used due to adverse effects such as end organ damage risk.

much of psychopharmacology is also an “art” in which clinicians prescribe based on anecdotal experience of positive patient responses based on particular depressive symptoms.

Similar to the idea of nature and nurture, where both are necessary to adequately explain human processes, a consideration of both the clinician’s subjective experience and more objective evidence-based data is necessary.

Weighing all of these issues and with the goal of gaining depressive remission in our patients, clinicians may then make well-rounded decisions when prescribing for their patients with resistant major depressive disorder.

Another study from Oct 2007 reaffirms these findings:

Augmentation strategies for treatment-resistant depression: a literature review. – PubMed – NCBI – J Clin Pharm Ther. 2007 Oct


Treatment-resistant depression (TRD) is a therapeutic challenge for the clinician. Augmentation pharmacotherapy refers to the addition of drugs that are not standard antidepressants in order to enhance the effect of a classical antidepressant drug. The aim of this paper was to review the available evidence on the various augmenting agents that have been tested for efficacy in TRD.


Although augmentation strategies have been tested with various pharmacological agents, there are few controlled studies published.

Lithium, triiodothyronine (T3), buspirone and pindolol have been most widely studied.

Other agents include

  • dopaminergic agents,
  • atypical antipsychotics,
  • psychostimulants,
  • benzodiazepines/hypnotics,
  • hormones and
  • anticonvulsants.


The augmentation therapy with the best evidence was the lithium-antidepressant combination, especially in patients not responding to tricyclic agents.

However, good results have also been reported with augmentation strategies involving T3 [thyroid] and buspirone [Buspar].


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