notes: fatigue in depression

I'm so enjoying Stahl's lectures on NEI that I will share my notes along the way. The following are a few notes from his talk on psychopharmacology of fatigue. Please note that this is NOT a comprehensive discussion of fatigue or of the medications mentioned! I'm just sharing a few notes from a fascinating talk:

• Fatigue might be the most common symptom in depression other than depressed mood its self.
• Fatigue must be fully treated to achieve full remission from depression.
• Fatigue can cause poor outcome even if mood is better -- so treat it!
• Interestingly, antidepressants may have an easier time treating mood than fatigue.
• Mental fatigue can be linked to dysregulation of norepinephrine, dopamine and histamine in projections to dorsolateral pre-frontal cortex (DLPFC).
• Physical fatigue may be more related to depleted serotonin and norepinephrine in descending spinal cord.
• Histamine helps keep you awake. Histamine cell bodies live in TMN (wake promotor nucleus) and project to DLPFC, amongst other things.
• Thus, anti-histamines make you tired while boosting histamine wakes you up -- decreasing mental and physical fatigue.

• What medications can help?

Any antidepressant can cause at least 1/3 of patients to go into remission with a lifting of fatigue. This is the easy and obvious way to manage fatigue associated with depression.

The other 2/3 might require further medications to address fatigue though.

Not tons of studies RE best options so all of these approaches could benefit from studies! However reasonable approaches may include:

1. Switch antidepressants. Second antidepressant could be more effective.

2. Give buproprion (Wellbutrin) a norepinephrine and dopamine reuptake inhibitor (NDRI) as switch or as augmentation. Buproprion is a nice choice as people usually don't get wired from this medicine. As a bonus, it can boost mood further. Downsides is that its onset is usually delayed.

3. Add modafinil (Provigil). Modafinil offers a novel way to increase output from histamine pathway. By boosting histamine output, it decreases fatigue. It turns on the TMN pathways. Modafinil is not approved for fatigue in depression either. The drug is approved for helping sleepiness in narcolepsy or sleepiness in other sleep disorders. Sometimes less is more so dose slowly.

4. Add stimulants. These also, of course, boost delivery of norepinephrine and dopamine. Downside of stimulants is that it is easy to over do and then one can feel wired. Further shortcomings include possibility of abuse and cardiac effects.

5. Atomoxetine (Stratterra) a norepinephrine reuptake blocker offers another intriguing option.

6. Other drugs that blocks norepinephrine reuptake should likewise help. So, the antidepressants effexor or duloxetine may be of use for fatigue.