Share on Facebook
Share on Twitter
Share on LinkedIn
Share by Email
Print
Depression is a profound problem in America and worldwide. The National Institutes of Mental Health (NIMH) estimate that 6.6% of Americans suffer from depression.1 Worldwide, as many as 350 million people are affected.2
At the May 2016 annual meeting of the American Psychiatric Association, outgoing president, Dr Renee Binder, emphasized the importance of decreasing the stigma of depression and mental illness.3 Depression is more than “having a bad day” or “feeling blue.” It is a long-lasting experience of low mood, loss of enjoyment in life, loss of interest, low energy, changes in sleep and/or appetite, and a decrease in one’s ability to think clearly (cognition). Often, family and friends cannot appreciate the depth of pain and suffering that depression can cause. “Pull yourself up by your bootstraps” or “Get over it,” are familiar phrases. Sentiments like this stigmatize depression and imply that it is a choice, rather than a biological disease.
Neuroscience and neuroimaging have revealed much to provide evidence that depression is a biological disease. Indeed, depression is not just one thing, despite the efforts of mainstream psychiatry to classify it into a single illness category. Nassir Ghaemi, MD, noted expert on psychopharmacology recently wrote:4
“Psychiatry…practice(s) non-scientifically; we use hundreds of made-up labels for professional purposes, without really getting at the reality of what is wrong with the patient…We have a huge amount of neurobiology research now to conclude that the 20th century neurotransmitter theories of psychopharmacology basically are false. The dopamine and monoamine (serotonin) hypotheses of schizophrenia and depression are wrong…we now know that drugs have major second messenger effects which (cause) neuroplastic changes in the brain, including connections between neurons. The brain is literally re-sculpted.”
Neuroimaging studies have shown several neurophysiological substrates for depression. Functional brain scans, such as SPECT (single photon emission computed tomography) or PET (positron emission tomography) have shown that while patients may present with the same symptoms of depression, they can have very different processes occurring in their brains.
Neuroanatomic correlates of depression
The anatomic circuits of depression and mood regulation have been revealed by converging evidence from SPECT, PET and fMRI (functional magnetic resonance imaging) studies of depression and analysis of both lesions resulting in depressive symptoms and surgical lesions used to treat severe cases of depression.5,6 These convergent findings have revealed a network of brain regions, including the dorsal prefrontal cortex, ventral prefrontal cortex, anterior cingulate gyrus, amygdala, hippocampus, striatum, and thalamus in the pathophysiology of depression.7-9 Drevets and others have emphasized that depression is the result of multiple pathophysiological processes and the dysfunction of multiple pathways.5,10
Distinct subtypes of depression now can be detected. Depression is often associated with decreased activity (and therefore metabolism and perfusion) of the frontal lobes, the insular cortex, and the anterior cingulate gyrus.5-10 Some patients with depression, however, have increased perfusion in the precuneus, which correlates with rumination and self-criticism.11 Some patients with depression also have decreased temporal lobe function. Many patients with depression show increased thalamic activity (metabolism or perfusion).12 Portions of the thalamus have direct connections to the amygdala, the seat of fear and anxiety.13
SPECT neuroimaging can also predict who will respond to certain antidepressants. For example, those who are likely to respond to SSRI antidepressants show increased perfusion in the ventral frontal cortex and anterior cingulate.14,15 The response to SSRI antidepressants is often decreased perfusion in these areas, as well as in the thalamus. In contrast, some patients with depression have markedly decreased dorsal frontal cortex and medial frontal cortex perfusion. These patients are less likely to respond to SSRI medications, but may respond better to noradrenergic antidepressants (personal observation).16,17 Treatment-resistant depression may show markedly increased perfusion in the subgenual cingulate.10
Diagnostic utility of neuroimaging in depression
Neuroimaging also helps to diagnose neurological disorders which may masquerade as psychiatric conditions. For example, over 40% of patients who experience a concussion (also known as mild TBI) will develop depression over the subsequent year.18,19 There is no reason to expect patients with TBI to respond the same way as those who have endogenous depression. Similarly, toxic brain injury,20,21 Parkinsonian syndromes,22 and dementia in the elderly23 can all present as depression.
Immune system activation in depression
Exciting neuroimaging work is going on at NIMH, exploring different markers. One of these is the radiolabeled translocator protein (TSPO). This protein was formerly known as the peripheral benzodiazepine receptor (indicating it might be important in psychiatric conditions) and it is involved in the transportation of cholesterol into the mitochondria (the cell’s energy production organelle). TSPO is highly expressed by macrophages, microglia and other inflammatory cells, which indicates that it has something to do with inflammation.24-26
TSPO is increased in Alzheimer disease, but only in areas of the brain which are known to have active pathology, such as the entorhinal cortex and parietal cortex.24,27,28 The cerebellum, for example, has very low binding of TSPO.24,29
In the situation of depression, TSPO binding tells a very interesting story. In depressed patients who are unmedicated, TSPO binding is elevated by 30-45%.24,30 Moreover, TSPO binding is increased all over the brain and also in the cerebellum. When patients took an antidepressant, TSPO binding levels were normal.24
What does this mean? It indicates that inflammation is an important mechanism in at least some forms of depression. Just remember the last time you had the flu – all you wanted to do was crawl into bed and hole up for a few days. Inflammation and increased cytokines are associated with sad mood.31 Patients with major depressive disorder (MDD) often have elevated levels of blood markers for inflammation, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α).32
Identification of alternative therapeutic candidates
The discovery that ketamine, an anesthetic, could rapidly and dramatically reverse depression heralded a rethink of the fundamental mechanisms of depression.33 Ketamine activates immediate, as well as prolonged, effects in the body. In particular, it upregulates brain-derived neurotrophic factor (BDNF).33 Part of this process involves a feedback via second messenger signals. Cyclic adenosine monophosphate (cAMP) is an important second messenger throughout the body and the brain. Certain enzymes, such as phosphodiesterases break down cAMP and stop its second messenger activity.33
Antidepressant effects of Rolipram
Neuroimaging work has given us some further clues about depression. Recently, Innis’s lab at NIMH has been investigating radiolabeled Rolipram, an inhibitor of phosphodiesterases. Its binding is correlated with the level of activity of the cAMP cascade.24 They have found Rolipram binding is 18% lower in unmedicated patients with MDD. And lower Rolipram binding means lower cAMP activity. Now it gets interesting….
When patients were treated with a selective serotonin reuptake inhibitor (SSRI) for 8 weeks, Rolipram binding increased by 13%.24 So, SSRI’s, even as ineffective as they are, could induce upregulation of the cAMP cascade and target the actual pathways of depression. Curiously, binding changes did not correlate closely with the magnitude of symptom changes.24 Moreover, the location of binding changes says much about the brain in depression.
Rolipram binding was decreased in ALL areas of the brain, including the cerebellum. In other words, the depressive episode was, in part, the result of a global decrease in cAMP activity in the brain. This drop in cAMP activity is probably insufficient to cause MDD, but it may be a necessary prerequisite. No one has yet looked at the effect of ketamine infusion therapy upon Rolipram binding. The results of that study could be quite illuminating.
So bringing this all together, Dr Ghaemi4 spoke of “neuroplastic changes” as a mechanism of relieving depression. This is, of course, a reference to the powerful effects of BDNF in the hippocampus, frontal cortex, and elsewhere. BDNF acts as a brain repair factor and reverses the degenerative effects of depression.33 Current oral antidepressants only weakly activate BDNF – indeed this phenomenon has only been demonstrated for a handful of antidepressants.
Future directions
Future directions in Psychiatry might include anti-inflammatory agents,30 more extensive use of ketamine infusion therapy,33 ketamine analogs, and neuroimaging-based selection of medications,14,17 which some have shown improves outcomes.16 Recognition that depressive episodes can be precipitated by neural injury, such as TBI or toxic injury may lead to radically different, even non-pharmacological treatments for depression following brain injury. A barrier to these advances is the fundamental resistance on the part of psychiatrists to look at the organ they are treating and to open their eyes to possible alternative explanations for the depression the patient describes to them.
Theodore Henderson, MD, PhD, is a psychiatrist in Denver, Colo., who specializes in the diagnosis and treatment of complex adult, child, and adolescent psychiatric cases. His website is www.childpsychiatristdenver.com.
References
1. http://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adults.shtml. Accessed 6/18/16.
2. http://www.who.int/mediacentre/factsheets/fs369/en/. Accessed 6/18/16.
3. http://www.psychnews.org/update/2016_apa_daily_2a.html. Accessed 6/17/16.
4. Nassir Ghaemi, MD, Psychiatry, Medscape Connect http://boards.medscape.com/[email protected]@.2a37df02!comment=1&cat=All. Accessed 2/12/13.
5. Price JL, Drevets WC. Neural circuits underlying the pathophysiology of mood disorders. Trends Cogn Sci. 2012;16(1):61-71.
6. Masdeu JC. Neuroimaging in psychiatric disorders. Neurotherapeutics. 2011;8(1):93-102.
7. Nagafusa Y, Okamoto N, Sakamoto K, et al. Assessment of cerebral blood flow findings using 99mTc-ECD single-photon emission computed tomography in patients diagnosed with major depressive disorder. J Affect Disord. 2012;140(3):296-9.
8. Willeumier K, Taylor DV, Amen DG. Decreased cerebral blood flow in the limbic and prefrontal cortex using SPECT imaging in a cohort of completed suicides. Transl Psychiatry. 2011;1:e28.
9. Kito S, Hasegawa T, Koga Y. Cerebral blood flow ratio of the dorsolateral prefrontal cortex to the ventromedial prefrontal cortex as a potential predictor of treatment response to transcranial magnetic stimulation in depression. Brain Stimul. 2012;5(4):547-53.
10. Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008;13(8):663-81.
11. Dumas R, Richieri R, Guedj E, et al. Improvement of health-related quality of life in depression after transcranial magnetic stimulation in a naturalistic trial is associated with decreased perfusion in precuneus. Health Qual Life Outcomes. 2012;10:87.
12. Conway CR, Sheline YI, Chibnall JT, et al. Brain blood-flow change with acute vagus nerve stimulation in treatment-refractory major depressive disorder. Brain Stimul. 2012;5(2):163-71.
13. Dougherty DD, Weiss AP, Cosgrove GR, et al. Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for treatment of major depression. J Neurosurg. 2003;99(6):1010-7.
14. Brockmann H, Zobel A, Joe A, et al. The value of HMPAO SPECT in predicting treatment response to citalopram in patients with major depression. Psychiatry Res. 2009;173(2):107-12.
15. Brody AL, Saxena S, Silverman DH, et al. Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res. 1999;91(3):127-39.
16. Thornton JF, Schneider H, McLean MK, et al. Improved outcomes using brain SPECT-guided treatment versus treatment-as-usual in community psychiatric outpatients: a retrospective case-control study. J Neuropsychiatry Clin Neurosci. 2014;26(1):51-6.
17. Kito S, Hasegawa T, Koga Y. Cerebral blood flow ratio of the dorsolateral prefrontal cortex to the ventromedial prefrontal cortex as a potential predictor of treatment response to transcranial magnetic stimulation in depression. Brain Stimul. 2012;5(4):547-53.
18. Jorge, RE, Robinson, RG, Moser, D, et al. (2004). Major depression following traumatic brain injury. Arch Gen Psychiatry. 2004;61(1):42-50.
19. Fann, JR, Burington, B, Leonetti, A., et al. Psychiatric illness following traumatic brain injury in an adult health maintenance organization population. Arch Gen Psychiatry. 2004;61(1):53-61.
20. Condray R, Morrow LA, Steinhauer SR, et al. Mood and behavioral symptoms in individuals with chronic solvent exposure. Psychiatry Res. 2000;97(2-3):191-206.
21. Bowler RM, Mergler D, Rauch SS, Bowler RP. Stability of psychological impairment: two year follow-up of former microelectronics workers’ affective and personality disturbance. Women Health. 1992;18(3):27-48.
22. Postuma RB, Aarsland D, Barone P, et al. Identifying prodromal Parkinson’s disease: pre-motor disorders in Parkinson’s disease. Mov Disord. 2012;27(5):617-26.
23. Stella F, Radanovic M, Balthazar ML, et al. Neuropsychiatric symptoms in the prodromal stages of dementia. Curr Opin Psychiatry. 2014;27(3):230-5.
24. Innis RB. Kuhl-Laasen lecture Society of Nuclear Medicine and Molecular Imaging Annual Meeting, 2016, San Diego.
25. Kreisl WC, Fujita M, Fujimura Y, et al. Comparison of [(11)C]-(R)-PK 11195 and [(11)C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: Implications for positron emission tomographic imaging of this inflammation biomarker. Neuroimage. 2010;49(4):2924-32
26. Liu GJ, Middleton RJ, Hatty CR, et al. The 18 kDa translocator protein, microglia and neuroinflammation. Brain Pathol. 2014;24(6):631-53.
27. Kreisl WC, Lyoo CH, McGwier M, et al. Biomarkers Consortium PET Radioligand Project Team. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain. 2013;136(Pt 7):2228-38.
28. Varrone A, Oikonen V, Forsberg A, et al. Positron emission tomography imaging of the 18-kDa translocator protein (TSPO) with [18F]FEMPA in Alzheimer’s disease patients and control subjects. Eur J Nucl Med Mol Imaging. 2015;42(3):438-46.
29. Lyoo CH, Ikawa M, Liow JS, et al. Cerebellum Can Serve As a Pseudo-Reference Region in Alzheimer Disease to Detect Neuroinflammation Measured with PET Radioligand Binding to Translocator Protein. J Nucl Med. 2015;56(5):701-6.
30. Setiawan E, Wilson AA, Mizrahi R, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72(3):268-75.
31. Reichenberg A, Yirmiya R, Schuld A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58(5):445–452.
32. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27(1):24–31.
33. Henderson TA. Practical application of the neuroregenerative properties of ketamine: real world treatment experience. Neural Regen Res. 2016;11(2):195-200.
