Depression is a profound problem in America and worldwide. The National Institute of Mental Health (NIMH) estimates 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, Renee Binder, MD, 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 traumatic brain injury [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’s 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 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 some of which have shown improved 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, CO, who specializes in the diagnosis and treatment of complex adult, child, and adolescent psychiatric cases. His website is www.childpsychiatristdenver.com.
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This article originally appeared on Psychiatry Advisor