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Antidepressant Treatment and the Biology of Depression
Jerrold F. Rosenbaum MD Disclosures
Introduction
A state-of-the-art review of the biology of depression needs to include an understanding of antidepressant mechanisms of action and offer new data as well as current concepts on the biology of depression, imaging studies of the depressed brain before and after treatment, receptor effects of the new generation antidepressants, and stress and neurogenesis. One such review was presented during this year's Annual Meeting of the American Psychiatric Association.Brain Imaging and Depression
Over the years, depression has been viewed in many ways. Helen S. Mayberg, MD, of the University of Toronto,[1] stated that it is important to consider the historical shifts from thinking of depression existentially, to understanding the phenomenon as a syndrome with a categorical classification (ie, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]), to taking a more brain-based view. When viewed in terms of dysregulated brain function, symptoms cluster into categories of mood, somatic, motor, and cognitive regulation. This view allows for identification of different regions which make up the disorder.
Dr. Mayberg described the importance of the study of brain function and described functional imaging strategies including lesion mapping, pharmacologic challenge, and behavioral provocation. All of these strategies provide a window on the brain's resting state, blood flow and metabolism, disease markers, and clinical feature correlates.In the 1930s, it was realized that stimulating the surgically exposed brain in specific areas could evoke mood and emotional sensations. At the same time, surgical destruction of these same brain regions could alter negative mood. The results focused attention on the orbitofrontal cortex and the frontal, temporal, and basal ganglia as likely components of a depression circuit.
Dr. Mayberg looked at individual positron emission tomography (PET) scans of brain-glucose metabolism in depressed and nondepressed patients with Parkinson's disease, Huntington's disease, and primary unipolar depression.[2] The data show that depressed patients have striking bilateral and frontal hypometabolism in the inferior frontal lobe when compared with matched nondepressed patients. Imaging studies of the anterior insula, a deep limbic structure, also had shown hypometabolism in unipolar depressed patients but hypermetabolism in bipolar patients.
A study that imaged baseline glucose metabolism in depressed male inpatients then compared them with images taken after blind randomization to either fluoxetine or placebo treatment at 1 and 6 weeks.[3] At 6 weeks, dramatic increases in the previously hypometabolic frontal lobe relative to baseline were evident. There was also an increase in metabolism in the dorsal brainstem at both 1 and 6 weeks, whereas in the posterior cingulate, there was suppression of metabolic activity at week 1 that switched to become hyperactive at week 6. Additionally, fluoxetine increased metabolism in the hippocampus in the short term, but suppressed it in the long term by week 6. Hypometabolism seen in the frontal, parietal, and cingulate lobes and insula differentiated patients from controls.
When looking at brain images of treatment responders vs nonresponders, the data fit this idea of impact on both neocortical and limbic regions, according to Dr. Mayberg. Improved frontal hypometabolism is seen in responders. Increased posterior cingulate metabolism was not, however, seen in nonresponders. She also suggested that the critical changes for clinical improvement are not only normalization of the frontal activities but also suppression of the limbic areas, especially area 25.
Major depression can be understood as a dysfunctional distributed network or circuit within the brain, not based in 1 specific region, and treatment may require a resetting or balancing of the circuit. The latter could in theory be accomplished by interventions at different sites within the circuit.
Understanding What Antidepressants Do
Pierre Blier, MD, PhD, of the University of Florida at Gainesville discussed the biological effects of antidepressant molecules on neurotransmitters and receptors. He began by looking closely at selective serotonin reuptake inhibitors (SSRIs) and how these drugs impact the serotonin system.[4]
Dr. Blier reviewed the regulation of the brain's serotonin system. The cell bodies of the serotonin neurons are located in the brainstem, mostly in the median and dorsal raphe nuclei. Projections from these two nuclei reach multiple brain structures. He illustrated the activities of the serotonin (5-HT)-1A autoreceptor and the 5-HT uptake transporter. He explained that when the 5-HT-1A receptor is stimulated by an increase in the amount of serotonin, it will decrease the firing activity of the serotonin neurons.When an SSRI is introduced, initially there is an increase in serotonin levels at the cell body due to blockade of the 5-HT uptake transporter. The 5-HT-1A autoreceptors are stimulated and decrease the firing frequency of the neuron. Yet, at the level of the synaptic bouton, there is no marked increase in serotonin availability, even though the transporters are inactive, because the firing activity reaching the terminals is decreased. However, after a few weeks of treatment with the SSRI, the autoreceptors are desensitized and allow a recovery of firing activity. At the synaptic bouton, reuptake is still blocked, firing activity is restored, and there is more serotonin because the terminal autoreceptors are desensitized. This allows 5-HT neurons to release their transmitters without negative feedback action in the presence of reuptake inhibition. The time necessary to obtain these adaptive changes is consistent with the delayed onset of action of SSRIs in major depression.
What is the influence of serotonin neurons on norepinephrine (NE) neuron firing activity? It is possible to answer this question by lesioning the serotonin neurons and then observing the norepinephrine neuron firing activity. Results show that serotonin has an inhibitory action in the locus coeruleus, as the experiment results in a 75% increase in NE neuron firing. If one then attempts to potentiate 5-HT activity by giving an SSRI, NE activity decreases. Dr. Blier suggested that the observation of sustained SSRI treatment leading to a gradual decrease of the spontaneous firing rate of NE neurons may in part explain the beneficial action of SSRIs in panic disorder, a condition associated with a hyperadrenergic state.
Dr. Blier also investigated dopamine, norepinephrine, and serotonin neuron activities during sustained administration of bupropion. According to his hypothesis, if bupropion blocks NE, dopamine, and 5-HT reuptake transporters, firing activity should decrease due to an excess activation of the cell body autoreceptors. He found that subacute bupropion treatment inhibits NE neuron firing by enhancing the synaptic availability of NE, which in turn enhances 5-HT firing by activating excitatory alpha-1-adrenoreceptors on 5-HT neurons. Further study has led Dr. Blier to believe that bupropion acts as an NE releaser (as opposed to an NE reuptake blocker) because the NE reuptake blockers, desipramine and reboxetine, do not alter the firing of 5-HT neurons.[5]
Mirtazapine is selective for the NE alpha-2-autoreceptor but causes marked changes in serotonin action. Mirtazapine is an alpha-2-adrenergic antagonist. Systemic administration of mirtazapine blocks alpha-2-receptors at the cell body of the NE neuron and at the axon terminals, which will release more NE into the synapse. NE neurons project to the raphe nucleus and 5-HT availability in the raphe increases as a result. Long-term administration of mirtazapine results in increased NE firing activity in the locus coeruleus and increased firing of 5-HT neurons in the raphe.[6]
Depression and the Brain at the Neuronal Level
According to Eric Nestler, MD, PhD, of the University of Texas Southwestern Medical Center, Dallas,[7] it is important to review intraneuronal signal transduction. Over the past 7 to 8 years, understanding of synaptic transmission has advanced significantly. In particular, neuroscientists have discovered that multiple types of protein phosphorylation cascades inside nerve cells ultimately influence gene transcription. Neuronal signals are communicated through not only neurotransmitters but also other types of signaling molecules called neurotrophic factors (also called nerve growth factors), of which there are many types. Dr. Nestler focused on the effect of antidepressants on the second messenger cyclic adenosine monophosphate (cAMP) and the pathway by which it leads to changes in gene expression. One product expressed after antidepressant treatment is brain-derived neurotrophic factor (BDNF).
Neurotrophic factors are peptides that support the growth, differentiation, and survival of neurons. In contrast to peptide neurotransmitters, neurotrophic factors produce their effects by activation of tyrosine kinases. Research in this area suggests that the sustained perturbation of monoamine systems leads to cAMP pathway adaptations that, through the regulation of target genes that regulate neural plasticity, underlie antidepressant therapeutic action.Dr. Nestler proposed gene regulation as one mechanism that might explain the delayed effects of antidepressant drugs. According to this view, repeated exposure to a drug such as an antidepressant would repeatedly perturb the intracellular messenger cascades and regulate the expression of other genes. For example, these cascades regulate transcription factors and proteins that bind to the regulatory region of genes and control the rate and time at which target genes are expressed.
As a drug enters the brain, it immediately binds to and inhibits the transporters for serotonin and/or norepinephrine, thereby increasing the availability of these neurotransmitters at certain synapses. According to this model, repeated antidepressant administration leads to increased production of the second messenger, cAMP, increased activation of protein kinase A, and activation of the transcription factor cAMP response element binding protein (CREB); this activation in turn triggers changes in the expression of CREB-activated target genes such as BDNF.
Dr. Nestler and his colleagues investigated whether these hypothesized changes in cAMP, protein kinase A, and CREB levels were actually occurring. With the use of in situ hybridization to measure levels of CREB mRNA in the rodent hippocampus, they found dramatic induction of CREB mRNA after courses of chronic electroconvulsive seizures, fluoxetine, and tranylcypromine as compared with controls.[8] These data support the idea that repeated exposure to antidepressants leads to an upregulation in the cAMP cascade in certain nerve cell areas of the hippocampus.
The investigators then hypothesized that independent activation of the cAMP pathway (without affecting 5-HT or NE levels) should also be antidepressant. They tested this idea in animals by administering two phosphodiesterase inhibitors (enzymes that block the breakdown of cAMP)[9] and found that prolonged administration of each phosphodiesterase inhibitor alone increased CREB levels. These findings support the theory that enhancement of the cAMP pathway in the hippocampus is correlated with an antidepressant response. To draw direct causal relationships between CREB activity and the cAMP pathway to a real depression-like phenotype, Dr. Nestler and his colleagues used the method of viral gene transfer. In this method, a virus coupled to CREB is injected into a rodent hippocampus and then the animal is observed while it performs a forced swim test. (In a forced swim test, clinically effective antidepressants increase the period that a rodent will struggle before giving up.) When levels of CREB were increased, the results of the behavioral test mimicked antidepressant action.
Through what target genes could CREB be acting to cause these effects? Clinical evidence suggests a role for neurotrophic factors in depression. Some depressed patients are hypocortisolemic. Neuroimaging data showed small decreases in the total volume of the hippocampus in depression and posttraumatic stress disorder.
When an animal is acutely or chronically stressed, the hippocampal level of the growth factor BDNF dramatically decreases; antidepressants (but not other psychotropic medications) have the opposite effect. Stress by itself decreased BDNF but prior exposure to antidepressant completely blocked the ability of stress to produce that effect.
In sum, Dr. Nestler and his colleagues proposed a model that considered both genetic and nongenetic vulnerabilities, where stress reduces levels of BDNF in the hippocampus and can lead to increased vulnerability to a depressive episode. A chronic course of antidepressant treatment, however, through effects on the 5-HT and NE stems, leads to the regulation of target genes that may change the numbers of neurotransmitter receptors and the levels of CREB and BDNF. Thus, enhanced trophic support of the hippocampus may help restore the nerve cells to a healthier state.
Biology of Depression: A New Look
Over the next decade, psychiatric researchers expect to discover new vulnerability genes that influence the development of depression and other neuropsychiatric disorders and then use this information to develop novel treatments. Dennis S. Charney, MD, of the National Institute of Mental Health, Bethesda, Maryland, believes that new science ultimately will allow practitioners to look at the interaction between genes that confer vulnerability and resilience to depression and the environmental risk and protection factors that combine to generate the observed phenotype.[10] The current diagnostic criteria are not informative for this task area; they have not been useful in understanding the role of genes or interactions between genes and the environment, and there are no biological markers that map onto the diagnoses of the DSM-IV.
He emphasized the important contribution that both early life and recent stresses make to the risk factors for a major depressive episode. Data indicate that early stress can exert major and long-lasting effects on the neuropeptide system, including corticotropin-releasing hormone (CRH). In 1study, when mice were separated from their mothers for a few hours daily during their first 14 days of life, researchers observed a persistent elevation in CRH not seen in control animals.[11] In another study, monkeys that had been stressed as infants with the unpredictable availability of food to their mothers also showed elevated CRH levels.[12] Neuroimaging studies found that stress-related disorders are associated with reduced hippocampal volume, which may be related to elevation in plasma cortisol levels and the duration or severity of the stress or depressive episode. Reduced hippocampal volume in patients suffering from major depression are replicated findings.[13] Dr. Charney mentioned that the replication is especially important, given the heterogeneity of major depressive disorder. These data have generated interest in the pharmaceutical industry and it is speculated that the next years will bring increased study of CRH antagonists for the treatment of depression and other stress-related disorders.Other depression studies suggest that there may be loss of neurons and glial cells in patients who suffer from major depression.[14] Three patterns of cellular changes have been noted in major depression: cell loss in the subgenual prefrontal cortex, cell atrophy and loss in the dorsolateral prefrontal and orbitofrontal cortexes, and increased cell numbers in the hypothalamus and dorsal raphe nucleus. Dr. Charney noted that these postmortem data are consistent with concepts that Dr. Mayberg[1] had spoken of earlier in the symposium -- ie, there are important reciprocal connections between subcortical structures such as the hippocampus and amygdala and the prefrontal cortex. Through a combination of imaging, structural, and postmortem studies, it might be possible to define a more robust functional neuroanatomy of depression.
Dr. Charney revisited the study findings of hippocampal neurogenesis that Dr. Nestler had spoken of and tied those to Dr. Blier's explanation that antidepressant drugs enhance the function of the 5-HT system and the particularly important 5-HT-1A receptor. Serotonin itself stimulates the production of hippocampal granular cells, and its mechanism occurs with the 5-HT-1A receptor, thereby bringing together the concepts of Drs. Blier and Nestler to form a more unifying hypothesis involving both monoamines and neurotrophic effects. Enhancement of 5-HT-1A function may have profound treatment effects.
Dr. Charney admitted that the mechanisms of these structural abnormalities are not understood. Some future targets of research that reach beyond monoamines are the CRH system and the mechanisms of mood stabilizers, phosphokinase C, phosphodiesterase inhibitors, and the n-methyl-D-aspartic acid receptor. He predicted that several new classes of antidepressants will emerge over the next decade.
References
Mayberg HS. The depressed brain image. Program and abstracts of the 154th Annual Meeting of the American Psychiatric Association; May 5-10, 2001; New Orleans, Louisiana. Industry Symposium 5A.
Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675-682.
Mayberg HS, Brannan SK, Tekell JL, et al. Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830-843.
Blier P. What do antidepressants do? Understanding antidepressant molecules, neurotransmitters, and receptors. Program and abstracts of the 154th Annual Meeting of the American Psychiatric Association; May 5-10, 2001; New Orleans, Louisiana, Industry Symposium 5C.
Frazer A. Norepinephrine involvement in antidepressant action. J Clin Psychiatry. 2000;61(suppl 10):S25-S30.
Haddjeri N, Blier P, de Montigny C. Effects of long-term treatment with the alpha 2-adrenoceptor antagonist mirtazapine on 5-HT neurotransmission. Naunyn Schmiedebergs Arch Pharmacol. 1997;355:20-29.
Nestler EJ, Duman RS. Healing the depressed brain: signal transduction and neural plasticity. Program and abstracts of the 154th Annual Meeting of the American Psychiatric Association; May 5-10, 2001; New Orleans, Louisiana, Industry Symposium 5D.
Chen AC, Eisch AJ, Sakai N, et al. Regulation of GFRalpha-1 and GFRalpha-2 mRNAs in rat brain by electroconvulsive seizure. Synapse. 2001;39:42-50.
Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci. 1996;16:2365-2372.
Charney DS. The neurobiology of mood disorders. Program and abstracts of the 154th Annual Meeting of the American Psychiatric Association; May 5-10, 2001; New Orleans, Louisiana, Industry Symposium 5B.
Anisman H, Zaharia MD, Meaney MJ, Merali Z. Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci. 1998;16:149-164.
Lyons DM, Yang C, Mobley BW, Nickerson JT, Schatzberg AF. Early environmental regulation of glucocorticoid feedback sensitivity in young adult monkeys. J Neuroendocrinol. 2000;12:723-728.
Sheline YI, Gado MH, Price JL. Amygdala core nuclei volumes are decreased in recurrent major depression. Neuroreport. 1998;9:2023-2028.
Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry. 2000;48:766-777.
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