Elsevier

Progress in Neurobiology

Volume 88, Issue 4, August 2009, Pages 246-263
Progress in Neurobiology

“Killing the Blues”: A role for cellular suicide (apoptosis) in depression and the antidepressant response?

https://doi.org/10.1016/j.pneurobio.2009.04.006Get rights and content

Abstract

Apoptosis or programmed cell death is a critical regulator of tissue homeostasis and emerging evidence is focused on the role of apoptosis mechanisms in the central nervous system. Generally, apoptosis is necessary to prevent cancerous growths. However, excessive apoptosis in post-mitotic cells such as neurons leads to neurodegeneration. Chronic stress, which can precipitate depression, has been shown to increase the susceptibility of certain populations of neurons to cell death while antidepressant treatment, in general, shows the ability to oppose these effects and promote neuroprotection. Here, we discuss the major players in cell death pathways, the physiological implications of chronic stress and depression, chronic stress models in animals which result in cell death and the different classes of antidepressants and mood stabilizers that have been shown to prevent cell death. We discuss the cellular effects of antidepressants and possible modes of action in preventing apoptosis. Investigations on the role of apoptosis in mediating the molecular, physiological and behavioural effects of antidepressants may help gain a better mechanistic insight into drug action and allow refinement of current therapeutics in order to target these pathways in a specific manner.

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.

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