Modafinil for Depression
Modafinil for depression? It’s not as crazy as you think. There are good reasons to consider modafinil as a potential treatment for depression.
Psychiatrists are getting increasingly creative with their pharmacologic choices due to poor remission rates with conventional antidepressants. Modern antidepressants have more tolerable side effects than their predecessors, but may have sacrificed some efficacy in the process.
Cognitive Symptoms of Depression
My interest in modafinil for depression stems from the fact that there are few medications on the market that address the cognitive symptoms of depression.
Researchers and health professionals like to talk a lot about cognitive symptoms of schizophrenia, which fall under “negative symptoms.” But the cognitive symptoms of depression gets less attention in the biomedical literature.
Some depressed patients experience:
- difficulty making decisions
- memory impairment
- mental sluggishness
There’s no question that these symptoms impair daily functioning. Finding a regimen that addresses both cognitive and emotional aspects of depression is a big challenge. Many patients in remission still experience mild cognitive impairment in spite of mood improvement.
Bupropion Normalizes Cognitive Deficits
A handful of antidepressants address the cognitive symptoms of depression. For example, bupropion (Wellbutrin) appears to normalize cognitive deficits in depressed patients.
Gualtieri and Johnson , in a previous paper, establish that:
depressed patients on modern antidepressants had, in spite of successful treatment, residual deficits in tests of effortful attention, executive function, and information processing speed
Therefore the authors asked whether some antidepressants might do a better job at mitigating the cognitive symptoms of depression than others.
So the authors conduct a naturalistic study of depressed patients that were treated with 7 different antidepressants. Their findings? Bupropion (Wellbutrin) succeeds in normalizing cognitive deficits in depressed patients.
What About Modafinil For Depression?
How are these data relevant to modafinil for depression?
Modafinil is a mood-brightening wakefulness enhancer that also seems to have nootropic effects in some people.
Modafinil is a good candidate for depressed patients because it improves motivation, attention, and reaction time while also elevating mood. Most conventional antidepressants actually increase apathy (particularly SSRIs) while stabilizing mood and making the lows more bearable.
SSRI-induced apathy is a well-known phenomenon. The cause is unknown, but some investigators have proposed some interesting hypotheses:
- Barnhart et al suggest that SSRI-induced apathy is caused by serotonergic effects in the frontal lobes or serotoninergic modulation of mid-brain dopamine
- Wongpakaran et al similarly point to frontal lobe dysfunction due to altered serotonin levels
The phenomenon of SSRI-induced apathy suggests that some antidepressants even contribute to the cognitive symptoms of depression despite improving mood.
Is Modafinil an Effective Antidepressant?
Most studies investigating modafinil for depression test modafinil as an augmentation agent. This means that modafinil is added on to another antidepressant to augment its effects. However, a few studies take a closer look at modafinil as monotherapy for depression.
Modafinil as Monotherapy: A Case Study
One case study described a 49-year old man who was initially diagnosed with depression in 1995.
He was successfully treated with 20 mg paroxetine, which became ineffective one year later. He was switched to bupropion 150 mg with only partial response followed by relapse. In 1998 his psychiatrist switched him to citalopram 40 mg, which did not resolve his symptoms.
When the patient was admitted to a clinic at Robert Wood Johnson, he was hypersomnolent with diminished energy, impaired memory, decreased libido, and had gained 70 lbs.
He agreed to a monotherapy trial of modafinil 200 mg. The patient reported a positive response to modafinil within the first week. Serial evaluations revealed improvement in HAMD-24 scores. The patient commented:
So this is what life is about—I was in the basement for 10 months, titrated on/off medications for 4 years for depression, and now I’m finally back in the gym working out and feeling normal.
What’s interesting about this case report is that the patient also had co-morbid panic disorder, but modafinil did not precipitate panic attacks. Instead, his panic disorder/agoraphobia was resolved with modafinil treatment.
The patient’s improvement in HAMD-24 scores also reflected improvement in the cognitive features associated with depression.
Goss et. al conducted a meta-analysis of modafinil in unipolar and bipolar depression.
The meta-analysis drew on data from 6 randomized clinical trials that enrolled a total of over 900 patients. Modafinil significantly improved depression scores and remission rates. Modafinil also alleviated fatigue, which is not surprising given that it’s FDA-approved to treat narcolepsy and obstructive sleep-apnea associated fatigue.
Moreover, the adverse events reported by patients taking modafinil did not differ from placebo, suggesting that modafinil was well-tolerated.
Atypical depression is the flavor of depression that’s characterized by:
- hyperphagia (excess hunger and eating)
- hypersomnolence (excess sleeping)
There are few good medications for atypical depression. Monoamine oxidase inhibitors are effective but have burdensome side effects like a potentially life-threatening hypertensive crisis.
Vaishnavi S and colleagues tested modafinil as monotherapy for atypical depression. It makes sense that modafinil would be re-purposed for this condition given its wakefulness enhancing effects.
Vaishnavi S reported that:
We found that modafinil significantly improved atypical depression symptoms during 12 weeks of open-label treatment (mean +/- SD Hamilton Depression Scale (29-item version) score changed from 34 +/- 8.2 at baseline to 9.7 +/- 9.3, P < 0.0001), and that benefits were maintained alike in both the continuation and placebo arms during the double-blind treatment phase (P = 0.92).
Can Modafinil Cause Depression?
There is little data on modafinil-induced depression. It seems at once strange that the same drug could both alleviate or induce depression depending on the context.
Genetic differences between patients and individual neurophysiology can account for these differing responses to modafinil’s effects.
I can’t cite any high-powered double-blind placebo-controlled trials. But my personal experience with modafinil and encounters with anecdotal reports suggests that modafinil can induce depressive symptoms. Modafinil can also exacerbate headaches, and there’s significant overlap between headaches and depression.
Some people become overstimulated or agitated on modafinil. Their sleep quality may erode over time if the drug lingers in their system at bed time.
I don’t know if you’ve heard of the Yerkes-Dodson law. It illustrates the idea that there’s an optimal level of arousal to facilitate performance.
Too much arousal leads to anxiety which impairs performance. Too little arousal also impairs performance by suppressing attention and engagement.
Some people are naturally anxious – maybe their sympathetic nervous system is more sensitive. Maybe they had an attachment disorder as a child. The possible biological and psychological explanations for a baseline state of heightened anxiety are endless.
But if you’re already prone to anxiety, modafinil can shift you further in this direction by bolstering arousal and wakefulness. This leads to agitation, diminished cognitive performance, and a generally unpleasant state of hyperarousal. Such hyperarousal can be depressogenic (precipitate depression).
Depression and Benzodiazepines
The situation with modafinil and depression is vaguely analogous to benzodiazepines and depression.
Some patients with depression actually improve when Xanax (alprazolam) is added to their regimen . Others worsen. You might expect patients with depression to worsen on Xanax because it’s a powerful central nervous system depressant. Depression is even in the name! But some depressed states (namely, mixed affective states) are characterized by:
- racing thoughts
- heightened irritability
- pressured activity
You can see that there are both manic and depressive features in this list of symptoms. But experiencing such states does not necessarily imply a manic depression. Some depressions have agitation and irritability as prominent features.
It’s not hard to see that benzodiazepines could be helpful for such mixed states. Benzodiazepines swiftly reduce irritability, agitation, and racing thoughts, which can take the edge off of a depression. Taking alprazolam is like being wrapped in a warm blanket.
This benzodiazepine example is to show apparent contradictions in how people respond to drugs. Similarly, modafinil can help banish depression – and is well-suited to treat the cognitive symptoms of depression. Yet some patients may nonetheless find modafinil agitating, anxiogenic, and all around depressogenic.
Until pharmacogenomics becomes mainstream, the only way to find out how you’ll respond is to trial the drug under the care of your physician.
1: Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatric Pract. 2004;10:196–199. [PubMed]
2: Wongpakaran N, van Reekum R, Wongpakaran T, Clarke D. Selective serotonin reuptake inhibitor use associates with apathy among depressed elderly: a case-controlled study. Ann Gen Psychiatry. 2007;6:7. [PMC free article] [PubMed]
3: Kaufman KR, Menza MA, Fitzsimmons A. Modafinil monotherapy in depression. Eur Psychiatry. 2002;17(3):167-9.
4: Yerkes, R. M. & Dodson, J. D. (1908). The Relation of Strength of Stimulus to Rapidity of Habit-Formation. Journal of Comparative Neurology and Psychology, 18, 459-482.
5: Dunlop BW, Davis PG. Combination treatment with benzodiazepines and SSRIs for comorbid anxiety and depression: a review. Prim Care Companion J Clin Psychiatry. 2008;10(3):222-8.
[^6]: Gualtieri CT, Johnson LG. Bupropion normalizes cognitive performance in patients with depression. MedGenMed. 2007;9(1):22.