“Killing the Blues”: A role for cellular suicide (apoptosis) in depression and the antidepressant response?
Introduction
The molecular and cellular basis of stress-related psychiatric disorders such as depression and anxiety remains elusive. It is becoming clear that alterations in cellular homeostasis occur in these disorders that are in part reversed by chronic treatment with antidepressant interventions (Krishnan and Nestler, 2008). A growing corpus of data suggests that molecular pathways underlying cellular death and survival mechanisms are particularly relevant to these disorders. Apoptosis is a cell death process that plays a key role in tissue development as well as pathological disorders (Jacobson et al., 1997, Benn and Woolf, 2004). Distinct biochemical pathways leading to cell death have been identified, with the most recognised being the death receptor and mitochondrial pathways, both culminating in activation of a group of enzymes known as caspases (Danial and Korsmeyer, 2004).
Acute stress causes physiological changes in the brain which allow organisms to adapt to environmental challenges. One hypothesis would be that cell death following acute stress may be advantageous and allow for the integration of newly generated neurons by neurogenesis, which have unique properties (reviewed in Lledo and Saghatelyan, 2005, Zhao et al., 2008). Newly generated neurons may functionally integrate into networks depending on the activity of the network (Ge et al., 2007); in fact newly generated neurons have been shown to display increased plasticity within a certain time frame (Schmidt-Hieber et al., 2004). However, excessive stress induces abnormal changes in the brain that impair its ability to appropriately regulate physiological and behavioural responses to subsequent stressors (de Kloet et al., 2005). Chronic stress, which can precipitate depression (Kendler et al., 1999), has been shown to increase the susceptibility of certain populations of neurons to cell death (Joels et al., 2004).
Stress-related disorders including depression and anxiety disorders are among the most common health problems worldwide. Depression is characterized by lowered mood, a loss in the ability to experience pleasure (anhedonia), suicidal thoughts and changes in sleep, appetite, sexual desire and often gastrointestinal motility (Belmaker and Agam, 2008). The World Health Organization predicts that unipolar depression will be the second most prevalent cause of illness-induced disability by 2020 (Murray and Lopez, 1997). Recent epidemiological studies have put the prevalence of major depression at somewhere between 5% and 6% of the general population. This was higher in women, people of middle age (45–54) and individuals who are obese (B.M.I. ≥ 30 kg/m2) (Kessler et al., 2003, Ohayon, 2007). Suicide which is often as a result of depression is now the third largest cause of death (9.7%) among young adults (15–24 years old) in Western countries (Licinio and Wong, 2005). Individuals suffering from these disorders are also at great risk for other health problems including heart disease (Cryan and Holmes, 2005).
Although still an emerging field, studies to date show that apoptosis occurs in certain brain regions following stress in rodents but very little is known about the mechanism by which it occurs. Further, it has yet to be identified which if any genes/proteins are essential. The major questions which this review will hope to address will be: What effect does stress have on apoptotic pathways? How do antidepressants modulate these pathways? What pathways are involved and which proteins are essential?
Section snippets
Apoptosis and survival
According to recent classifications there are three forms of cell death: necrosis, apoptosis and autophagic cell death (Kroemer et al., 2009). Apoptosis or programmed cell death is a tightly regulated, energy dependent process, in which the dying cell participates in its own death. It is characterised by cytoplasmic shrinkage, chromatin condensation, nuclear pyknosis, ordered DNA fragmentation, cell rounding and membrane blebbing (Kerr et al., 1972). The cell ultimately forms membrane bound
Chronic stress
Excessive stress induces abnormal changes in the brain that impair its ability to appropriately regulate physiological and behavioural responses to subsequent stressors (Cryan and Holmes, 2005). It is now widely accepted that chronic exposure to stress and stressful life events may lead to the development of major depression (Kendler et al., 1999, Pittenger and Duman, 2008, Nemeroff and Vale, 2005, Anisman and Matheson, 2005, van Praag, 2004, Charney and Manji, 2004, Tafet and Bernardini, 2003,
Classes of antidepressants
Although it has been 50 years since the first classes of antidepressants were discovered serendipitously to have beneficial effects relating to depression and mood disorders, the molecular basis as to how they elicit their therapeutic effects remains elusive (Wong and Licinio, 2004, Berton and Nestler, 2006, Slattery et al., 2004), with the exception that that they all acutely upregulate monoamine neurotransmission (Wong and Licinio, 2004). The majority of these drugs are thought to directly
Future directions and perspectives
While a number of the reports above have highlighted that chronic antidepressant treatment increases the expression of anti-apoptotic Bcl-2 family members, very few have mentioned the effect on BH3 only proteins. The BH3 only proteins act as sentinels of cellular stress and are transducers of death signals to the mitochondria. While there is some overlap in the detection specificity among family members, some of these proteins are specific in the stresses they detect, e.g., Puma and Noxa can
Conclusions
The main conclusion to be drawn from studies so far is that antidepressants are successful in preventing cell death to some degree. The main method by which this is accomplished is by the upregulation of pro-survival molecules, some of which are CRE-dependent genes. ERK/MAP kinase pathways also play a role, as do the anti-apoptotic Bcl-2 family members although there is some interaction between these groups. Further experiments are needed to determine the interactions of antidepressants with
Acknowledgements
JFC and TGD are supported in part by Science Foundation Ireland in the form of a Centre grant (Alimentary Pharmabiotic Centre). The centre is also funded by the Industrial Development Authority of Ireland in collaboration with GlaxoSmithKline. The authors would like to thank Drs Javier Bravo and Olivia O’Leary for helpful comments.
References (275)
Neurobiological bases for the relation between sleep and depression
Sleep Medicine Reviews
(2002)- et al.
Bcl-2 family regulation of neuronal development and neurodegeneration
Biochimica et Biophysica Acta
(2004) - et al.
Stress, depression, and anhedonia: caveats concerning animal models
Neuroscience and Biobehavioral Reviews
(2005) - et al.
Chronic unpredictable stress promotes neuronal apoptosis in the cerebral cortex
Neuroscience Letters
(2008) - et al.
Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat
Biological Psychiatry
(2007) The role of CREB in depression and antidepressant treatment
Biological Psychiatry
(2006)- et al.
The CREB family of transcription activators
Current Opinion in Genetics and Development
(1992) - et al.
Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor
Cell
(1999) - et al.
Corticosterone differentially regulates bax, bcl-2 and bcl-x mRNA levels in the rat hippocampus
Neuroscience Letters
(2002) - et al.
The many faces of CREB
Trends in Neurosciences
(2005)
Neurotrophic effects of antidepressant drugs
Current Opinion in Pharmacology
Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development
Cell
Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members
Cancer Cell
Desipramine-induced apoptosis in human PC3 prostate cancer cells: activation of JNK kinase and caspase-3 pathways and a protective role of [Ca2+]i elevation
Toxicology
Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function
Molecular CELL
Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity
The Journal of Biological Chemistry
Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell
Biochemical and Biophysical Research Communications
Pro-inflammatory programmed cell death
Trends in Microbiology
Finding the intracellular signaling pathways affected by mood disorder treatments
Neuron
Mitogen-activated protein kinase-independent pathways mediate the effects of nerve growth factor and cAMP on neuronal survival
The Journal of Biological Chemistry
Developing more efficacious antidepressant medications: improving and aligning preclinical and clinical assessment tools
Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP)
The Journal of Biological Chemistry
Cell death: critical control points
Cell
14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation
Molecular Cell
Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis
Developmental Cell
BAX is required for neuronal death after trophic factor deprivation and during development
Neuron
Stress: the shared common component in major mental illnesses
European Psychiatry
Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death
Biochimica et Biophysica Acta
A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment
Biological Psychiatry
Depression: a case of neuronal life and death?
Biological Psychiatry
Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder
Biological Psychiatry
Genetic control of programmed cell death in the nematode C. elegans
Cell
Larger amygdala volumes in first depressive episode as compared to recurrent major depression and healthy control subjects
Biological Psychiatry
A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain
Neuron
The Bcl-2 protein family: arbiters of cell survival
Science (New York, NY)
Mechanism of activation of protein kinase B by insulin and IGF-1
The EMBO Journal
Molecular mechanisms of glucocorticoid antiproliferative effects: antagonism of transcription factor activity by glucocorticoid receptor
Journal of Leukocyte Biology
Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate
FASEB Journal
Effects of long-term adrenalectomy on apoptosis and neuroprotection in the rat hippocampus
Endocrine
Desipramine induces apoptotic cell death through nonmitochondrial and mitochondrial pathways in different types of human colon carcinoma cells
Pharmacology
Death receptors: signaling and modulation
Science (New York, NY)
Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death
Nature
Recruitment of the sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis
The European Journal of Neuroscience
Major depressive disorder
New England Journal of Medicine
Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures
Proceedings of the National Academy of Sciences of the United States of America
Adult neuron survival strategies—slamming on the brakes
Nature Reviews
New approaches to antidepressant drug discovery: beyond monoamines
Nature Reviews Neuroscience
The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling
Molecular Psychiatry
Electroconvulsive therapy in melancholia: the role of hippocampal neurogenesis
Acta Psychiatrica Scandinavica
Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms
Science (New York, NY)
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