Posted by jrbecker on May 29, 2003, at 16:13:19
In reply to HPA, Atypicals and Opiates?--Cam??, posted by MB on May 27, 2003, at 13:36:20
> How would all this stuff apply the the Atypical Depressives (in whom the HPA axis is often underactive)? I fall into the Atypical category. I overeat and crave carbs/chocolate when depressed. I sleep and sleep and sleep when depressed. Also, I have some mood reactivity (a nice event or a cup of coffee might lift my spirits momentarily, but the hopelessness soon comes rushing back followed by two bowls of cereal and a pint of chocolate icecream).
>
> I read an article that manipulating the HPA axis *might* be able to help Atypicals in conjunction with AD therapy:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10999245&dopt=Abstract
>
> Being an Atypical Depressive, I find it disheartening that SSRIs further increase my fatigue, increase the time I spend sleeping, and exacerbate my carbohydrate cravings. I know that MAOIs are the best (is that still unanimous?) for Atypicals, but I hear they're not that great, either, for attenuating the reverse vegatative symptoms that are the markers for Atypical Depression (i.e., "Wow, my mood's great, but I'm still sleeping 14 hrs/day, can't work, and am getting even fatter!"). Anyway, I'm reluctant to try them.
>
> Also, parenthetically, opiates energize me, attenuate the reverse vegetative symptoms of my depression (hyperphagia, hypersomnia, leaden fatigue, etc.), and *cure* my depression. Even after I've built a tolorance to the euphorogenic effects of a certain dose of opiate, the antidepressant effects continue. It almost feels like something metabolic is being corrected. I must admit, though, that the opiate dose necessary is pretty high. I was stabalized on 225 mg of morphine/day. That's quite a lot, but after a few months, I was no longer feeling "high," I just felt "corrected"...I felt like I did as a kid before depression hit me in the third grade.
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> This all seems counterintuitive, since Atypicals seem to have hypoactive HPA axes, and opiates suppress the HPA axis. Shouldn't they make me more depressed, not better? I don't get it, I don't get it, I don't get it, and, furthermore I'm F****** FRUSTRATED.
>
> MB
MB,you pose a lot of interesting questions. I myself am an atypical depressive. As for cortisol replacement therapy, I would agree with davpet in that this is really only a short-term solution. I once emailed Charles Nemeroff himself on this issue, and he responded that a low dose of prednisone might be beneficial. However, I really don't think that such a therapy is getting to the root of the problem and the side effects of this drug might be more trouble than it is worth. Levels of cortisol have been inconclusive when measured in atypicals (some find them normal, some too high, some too low). Also, cortisol acts as a negative feedback mechanism for CRF, so more cortisol isn't necessarily a good thing. Some experts believe that a potentiator of CRH might be beneficial for atypical depressives, while others disagree.
Perhaps with the advent of the CRF antagonists, more research will be dedicated to finding compounds that modulate or slightly enhance CRF to see what effect this will have in treating our condition. And this is most likely the next step in the CRF research.
But this just begins to tell only part of the story of atypical depression. The question remains, why are some depressed people not able to sleep, eat, etc., and why do some react oppositely? There are two hypothesis to answer this question: 1) Atypical depressives are those individuals whose stress system have crashed, meaning that high levels of HPA output have desensitized the receptors and made them less able to respond in normal day-to-day life situations; 2) Atypical depressives are really an offshoot of bipolar depression and the symptoms atypical depressives exhibit are manifestations of larger cortical dysregulation found to be typical of the bipolar illness as whole. Considering that there have been genetic differences seen between the two different unipolar conditions (melancholic vs atypical), then this theory might hold some water.
But which hypothesis makes more sense? Actually, I think both are probable factors in the disorder, one nature in causation, the other one nuture in theory. Hypothesis #1 (the stress overload theory) is really the environmental stressor, and #2 (the genetic predisposition to it). Bipolars are usually atypical in nature and their energy levels do not respond naturely to the normal biological clock of night and day that most people do. Also, the fact that atypicals tend to have sleep disruption (usually seen in HPA overactivity) despite being overly tired most of the day, points to further chinks in the armor of the theory that the cause of atypical depression is purely that of HPA underactivity.
http://www.psycheducation.org/depression/clock.htm
So what does this mean? Perhaps underactivity of the stress system isn't the only part of the issue (or maybe not the direct issue at all). Maybe it's also about realigning the biological clock as well. Subjectively, this makes a lot of sense to me. I remain sleepy throughout the day and have a lot more rebound energy at night. I've even found that if I push my sleep cycle further into the night and wake up later in the day, that I have a much a more normal circadian clock. And remember, circadian rhythm just doesn't effect feeling "tired" or "awake" but also plays a very major role in your mood state.
So what does this mean in terms of treatment? It means there's still a lot more work to do. But, we do know that mood stabilizers like depakote and lithium help to reset the circadian clock. In other areas, 5HT1A post-synaptic agonism also helps create an advance-sleep shift through release of ACTH (and by metabolization, cortisol). This is why a few of the 5HT1A partial agonists coming out in the next few years will probably be good for atypical depression. Gepirone, a 5HT1A partial agonist (probably going to be approved next year), has been shown to be effective against atypical depression. This is probably due not only due to its 5HT1A action but also because one of its metabolites is an alpha-2 adrenergic antagonist (which increases NE and dopamine). Other 5HT1A compounds in trials will hopefully further delineate the role of these drugs for atypical depression. Another serotonergic subreceptor, the 5HT7 receptor, also will likely play a role since it has a very specific function in regulating circadian rhythm.
And back to the CRF antagonists. There is really no real data to believe that this sort of treatment might not be beneficial to some atypical depressives as well. After all, the stress system of the atypical condition is still not clear, since as mentioned before, it is not certain whether a circadian clock dysfunction is at fault or whether it's a failure of CRH to respond properly (most likely both). In bipolar disorder, there is hypermetabolic activity in the subcortical regions responsible for CRH output. So perhaps, some form of CRF antagonist might play a more positive role than a negative one in treating atypical depression. CRF antagonist research has shown no signs of suppressed basal, stimulated ACTH, and/or cortisol secretion after administration. Thus, it means there is no endocrine side effects such as adrenal insufficiency from taking them. It was also found that the beneficial response to a CRHR1 antagonist is not limited to patients with elevations in plasma cortisol concentrations (e.g., melancholic types).
http://www.cmeondemand.net/CNS/novelperspectives/CNS701_Holsboer.html
All in all, CRF antagonism will be a giant leap for treating the "typical" unipolar population. As atypicals though, we will probably have to just hope that CRF antagonists are a more tolerable drug class -- with less exacerbation of sleepiness, anergia, apathy, and hyperphagia that you speak of MB. And most likely, they will be.As touched on before, compounds that effect the stress system via glutamate and the glucocorticoid receptor are also being developed. These will hopefully provide us with some other options in the arsenal as well.
And if you want to look even more ahead, there is already a lot of research that ties in
diabetes and Alzheimer's with depression treatment as well research as that is looking towards brain cell regeneration -- all of which seems applicable to the atypical cause. New areas for research are being discovered every month.But enough future soothsaying, unfortunately all this talk doesn't help you today. My only advice to you would be to talk to your doc about maybe lowering your SSRI if the effects are too sedating, or maybe switching onto a new one, or adjuncting with something else (e.g., Wellbutrin). Don't know what to tell you about the opioids. If you can get a doc to prescribe one, all the more power to you. Perhaps one way to do this is to email Dr. Alec Bodkin at McLean Hospital and have him consult with your doc (he would most likely be willing to do so). Recognize though that opioid tx is still very outre. I would definitely read up on it as much as possible so you have an idea of what it entails. On another note, have you experimented with supplements -- SAMe, Folate, Fish oil, DHEA, NADH. What about light therapy (it's actually helped my energy levels). And what about CBT? Given it any thought? There's lots of proof that atypical depression responds to it.
There's a bunch of things to try. Keep optimistic
JB
poster:jrbecker
thread:228381
URL: http://www.dr-bob.org/babble/20030525/msgs/229989.html