In the Sunday New York Times Magazine, an article by Siddhartha Mukherjee entitled “Post-Prozac Nation” appeared. I eagerly read this article, wondering what position the author might take with regard to the anti-depressants. Mukherjee acknowledges that the initial belief depression is caused by a deficiency is serotonin is far too simplistic. (Refreshing.) But next, Mukherjee cites a bundle of neuroscience research which at first glance might imply that it’s really serotonin after-all. Since the reader who does not devote time reading the exploding volume of neuroscience research might walk away thinking “maybe it is serotonin”, I’ll detail the facts that contradict the serotonin deficiency theory.
Mukherjee cites the studies finding that limiting intake of tryptophan (the amino acid precursor used by the body to produce serotonin) results in a deflated mood for those who are prone to depression or who have recovered from depression on an SSRI. These findings do not necessarily imply the conclusion that lack of serotonin is the culprit here. When tryptophan intake is limited, CRF, a pro-anxiety molecule, increases in the spinal fluid (Tyrka, Carpenter, McDougle, Kirwin, Owens, Nemeroff, Strong, Price, 2004). It is probably case that given a dietary deficiency, the body is going to adjust in some way. Who knows which proteins get shuffled around and which neurotransmitters levels are altered. It’s not necessarily serotonin.
In fact, the brain is very complicated. Neuroscientist Chris Lowry has shown that there are six independent circuits using serotonin in the brain. Lowry acknowledges discoveries made by his colleagues Maier and Watkins, who are also at the University of Colorado. Maier and Watkins showed that the proximal mediator for learned helplessness behavior is a serotonin circuit. Thus, the neurotransmitter for making the animal give up in despair is serotonin. One of the serotonergic circuits discovered by Lowry places a brake on the learned helpless circuit. So the serotonin story is complicated indeed. The body is using the same neurotransmitter to accomplish opposite outcomes. Of course, the body is not confused. The inputs and outputs to the circuits are distinct. But, it does mean that if an external mechanism for increasing serotonin is engaged, namely the green and white Prozac pill, it will be difficult to predict or explain the behavioral impact.
Mukherjee also cited Rene Hen’s work on neurogenesis (birth of new neurons) and Brain Derived Neurotrophic Factor, which increases the survival of new neurons. Initially, everyone was excited because antidepressants increase BDNF in the hippocampus and stress will decrease BDNF in the hippocampus. Thus, there was an explanation for the cause of depression and a potential curative mechanism. But, then others showed that blocking BDNF or neurogenesis in the hippocampus through other mechanisms did not necessarily induce depression (Airan et al., 2007; Santarelli et al., 2003). Further, Eric Nestler’s group found that BDNF in the Nucleus Accumbens was increased by stress. Interestingly, with regard to serotonin, serotonin in the hippocampus will decrease levels of BDNF (Vaidya, Marek, Aghajanian, & Duman, 1997). Thus, identification of a “smoking gun” proved elusive here as well and the role of serotonin may be the opposite of the role hypothesized by the “it’s serotonin” enthusiasts.
My own favorite theory is that inflammation best explains depression. Inflammation ties many disparate findings together. Stress will increase brain inflammation. Activating white blood cells along an inflammatory path will decrease brain levels of BDNF in the hippocampus. Creating inflammation will activate Helen Mayberg’s brain area which is activated in those who are depressed (whose work was also referenced by Mukherjee).
Mukherjee acknowledged Irving Kirsch’s FDA data analysis indicating that antidepressants have limited efficacy for the mild and moderately depressed. He also emphasized that antidepressants are effective in the severely depressed. Antidepressants do decrease inflammation. If the brain’s white blood cells are cultured outside the brain with Prozac, inflammatory factors decline. Thus, Prozac may achieve efficacy not because of a direct impact on a neuron or a neurotransmitter, but rather because of the impact on the immune system. Thus, there is a mechanism through which Prozac might achieve efficacy in those with severe depression. The problem with the antidepressants is that after two years many inflammatory markers increase (see past blogs). Thus, for the long haul, depression is exacerbated by the antidepressants.
Fortunately, alternatives to drugs for decreasing inflammation are available. Exercise will decrease inflammation, increase brain levels of BDNF, and is a proven antidepressant. Omega-3 fatty acids (available in fish and walnuts) and curcumin (in turmeric) are anti-inflammatory and have demonstrated anti-depressant properties. Increasing vagal tone with yoga or time with trusted friends places a break on inflammation. Avoid high-fructose corn syrup and saturated fats (any fat that is solid at room temperature) as they are inflammatory. Pay attention to Sandra Steingard’s recommendations on food. She has it right.
Mukherjee also referenced Helen Mayberg. Mayberg, an Emory psychiatrist, has garnered considerable attention for electrically turning off neuronal firing in the subcallosal cingulate to ameliorate depression. (I don’t think there is a clear connection between serotonin and the subcallosal cingulate, but Helen Mayberg’s research is interesting, so I’ll talk about it.) Mayberg reports that when the subcallosal cingulate is turned off, patients report that the curtain lifts. Self-focus is replaced by awareness of the outside world. My favorite Mayberg story is that when Mayberg asked her patient what he would be doing if he were home, the patient reported that he would clean the garage. Perhaps this patient’s statement is heuristic. The antidote to depression is finding something you want to do and then doing it. Increasing activity is where psychotherapists need to focus. (In fact, Peter Lewinson developed a therapy for increasing activity in persons with depression.) Vigorous activity will decrease inflammation and raise BDNF levels in the hippocampus. It’s a win all round.
Mukherjee concluded that we owe a debt to Prozac because it enabled our increased understanding. I think we owe a debt to neuroscientists who are unconcerned with the commercial implications of their research. Rather than advancing knowledge, Prozac stimulated the hypothesis that serotonin deficits cause depression. The world has wasted a lot of time on that one.
Related Mad In America links:
SSRIs: More Harm Than Good
Airan, R. D., Meltzer, L. A., Roy, M., Gong, Y., Chen, H., & Deisseroth, K. (2007). High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science, 317(5839), 819-823.
Hale, M. W., & Lowry, C. A. (2011). Functional topography of midbrain and pontine serotonergic systems: implications for synaptic regulation of serotonergic circuits. Psychopharmacology, 213(2-3), 243-264.
Ito, W., Chehab, M., Thakur, S., Li, J., & Morozov, A. (2011). BDNF restricted knockout mice as an animal model for aggression. Genes, Brain and Behav. doi: 10.1111/j.1601-183X.2011.00676.x
Krishnan, V., & Nestler, E. J. (2008). The molecular neurobiology of depression. Nature, 455(7215), 894-902.
Kubera, M., Obuchowicz, E., Goehler, L., Brzeszcz, J., & Maes, M. (2011). In animal models, psychosocial stress-induced (neuro) inflammation, apoptosis, and reduced neurogenesis are associated to the onset of depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 35, 744-759.
Lowry, C. A., Hale, M. W., Evans, A. K., Heerkens, J., Staub, D. R., Gasser, P. J., & Shekhar, A. (2008). Serotonergic systems, anxiety, and affective disorder: focus on the dorsomedial part of the dorsal raphe nucleus. Annals of the New York Academy of Sciences, 1148, 86-94.
Lowry, C. A., Hollis, J. H., de Vries, A., Pan, B., Brunet, L. R., Hunt, J. R., et al. (2007). Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior. Neuroscience, 146(2), 756-772.
Maes, M. (2011). Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Progress is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Progress in Neuropsychopharmacology, 35 (3), 664-675.
Maier, S. F., Amat, J., Baratta, M. V., Paul, E., & Watkins, L. R. (2006). Behavioral control, the medial prefrontal cortex, and resilience. Dialogues in Clinical Neuroscience, 8(4), 397-406.
Maier, S. F., & Watkins, L. R. (1995). Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock. Brain Research, 695(2), 279-282.
Maier, S. F., & Watkins, L. R. (1998). Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychological Review, 105(1), 83-107.
Tyrka, A. R., Carpenter, L. L., McDougle, C. J., Kirwin, P.D., Owens, M. J., Nemeroff, C. B., Strong, D. R., & Price, L. H. (2004). Increased cerebrospinal fluid corticotropin-releasing factor concentrations during tryptophan depletion in healthy adults. Biological Psychiatry, 56 (7), 531-534.
Vaidya, V. A., Marek, G. J., Aghajanian, G. K., & Duman, R. S. (1997). 5-HT2a receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. Journal of Neuroscience, 17 (8), 2765-2795.
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