REVIEWThe 5-HT1A receptor in Major Depressive Disorder
Introduction
Major Depressive Disorder (MDD) is a highly prevalent and recurrent disorder that is predicted to be the leading cause of disease burden in the United States by the year 2030; as measured via Disability Adjusted Life Years (DALYs) (Mathers and Loncar, 2006). MDD is a type of mood disorder that involves a distinct change of mood that affects one׳s ability to function day-to-day and is characterized by sadness or irritability along with other psychophysiological items including changes in: sleep, appetite, and sexual desire. There may also be other symptoms present such as: anhedonia, which is the loss of ability to experience pleasure in previously enjoyed activities, suicidal thoughts or slowing of speech and movement. Moreover, cognitive functions including learning, memory and attention are also disrupted in MDD (Ogren et al., 2008). Within the elderly population, symptoms of dementia/neurodegenerative change may actually be attributable to MDD (pseudo-dementia) and cognitive function can return to baseline when the depression is effectively treated (Raskin et al., 2007). These changes must last a minimum of two weeks and cause significant functional impairment in work and family relations (Belmaker and Agam, 2008). Results from the National Comorbidity Survey Replication (NCS-R) indicate that lifetime incidence of MDD in the United States is 16.2% (32.6-35.1 million US adults) with 12% in men and 20% in women (Kessler et al., 2003).
Recently, however, a rationale for the differing prevalence rates of MDD between sexes has been the more closely examined. For several decades, epidemiological studies have reported that women are approximately twice as likely as men to develop MDD (Jovanovic et al., 2008, Parker and Brotchie, 2010). However, these prevalence rates depend on the reliability of current diagnostic classifications and structured diagnostic interviews (Karlsson et al., 2010). Since men and women can experience depression differently in terms of symptomatology, the criteria currently used to diagnose clinical depression may have led to an underdiagnosis of MDD in males. It has been shown that sex discordance exists within depression symptomatology such that men exhibit significantly more anger, irritability and symptomatic substance intake while women often suffer more from hypersomnia, withdrawal from friends and heaviness of the limbs (Winkler et al., 2005). Consistent with this view, a 2013 study reported that when changes in case criteria of MDD were implemented in a way that account for higher rates of anger, aggression and substance abuse in men, MDD prevalence estimates between sexes are eliminated (Martin et al., 2013). It is therefore possible that the significant difference in epidemiological reporting of MDD prevalence between sexes lies in the current diagnostic interview instruments currently used clinically (Angst and Dobler-Mikola, 1984). Although studies have presented a positive correlation between anger and depression, it is important to note, however, the difficulty in assessing the symptom of anger. This is due to the multidimensional nature of the symptom itself, in which hostility (the predisposition to become angry), anger (the emotion itself) and the ability both experience anger while not necessarily expressing anger (anger suppression) leads to difficulty in assessing and reporting of the symptom accurately (Riley et al., 1989, Winkler et al., 2005). Whether these differences in symptomatology are related to differences in psychopathology is still under investigation. However, whether due to genetic, environmental, or physiological differences, characterization of the etiology of sex differences in a psychopathology as prevalent as MDD is of utmost import for the field of psychiatry (Kaufman et al., 2015).
There are currently several theories that seek to explain the underlying pathophysiology of MDD. One such theory, known as the monoamine deficiency hypothesis of depression, proposes that a deficiency in monoanmine neurotransmission (serotonin, norepinephrine and dopamine) in the central nervous system (CNS) underlies the development of MDD (Belmaker and Agam, 2008, Schildkraut, 1965). A study finding that helped to initially link serotonergic abnormalities to MDD reported that patients who had remitted from a depressive episode could be induced into another depressive episode after having their tryptophan stores depleted via fasting. L-tryptophan is an amino acid necessary for serotonin synthesis (Lovenberg et al., 1967, Stockmeier, 2003). Several other studies have looked into how the end metabolite of serotonin, 5-HIAA, supports a role for serotonin in depressive illness (Åsberg et al., 1984, Dencker et al., 1966; Mann, 1999; Mendels et al., 1972; Murphy et al., 1978). However, a study in 1981 by Träskman et al. examined a cohort of subjects who had attempted suicide and compared monoamine metabolite levels to controls. The main finding of this study was that subjects who had attempted suicide had significantly lower levels of CSF 5-HIAA than controls, with a more pronounced reduction in the metabolite if the suicide attempt was violent. It was also found that subjects who had comorbid depression had significantly lower CSF 5-HIAA and homovanillic acid (HVA), another monoamine metabolite, levels when compared to controls (Traskman et al., 1981). As such, suicidality may represent a confounding factor in these analyses. It is important to note that although this review focuses on 5-HT, other monoamines i.e. norepinephrine and dopamine have been postulated to be abnormally regulated in patients with MDD. Decreased norepinephrine metabolism, increased tyrosine hydroxylase activity and reduced dopamine transporter activity have also been implicated within the monoamine deficiency hypothesis (Hasler, 2010, Schildkraut, 1965). Further credence for the monoamine deficiency hypothesis is provided by the fact that the three classes of antidepressants currently used to treat MDD i.e. monoamine oxidase inhibitors, tricyclic antidepressants and selective serotonin reuptake inhibitors (MAO-I, TCA and SSRI, respectively) all act by increasing the amount of serotonin present in the synaptic cleft by either inhibiting its synaptic reuptake or by inhibiting its metabolism (Gray et al., 2013). Moreover, a large body of previous research has theorized that serotonergic dysfunction, specifically of the serotonin 1A (5-HT1A) receptor, plays a vital role in the pathophysiology of MDD (Albert and Lemonde, 2004, Arango et al., 2001, Boldrini et al., 2008, Hesselgrave and Parsey, 2013, Miller et al., 2009, Miller et al., 2013, Parsey et al., 2006, Savitz et al., 2009, Stockmeier et al., 1998). As such, this review will describe the evolution of our current understanding of the serotonin 1A (5-HT1A) receptor and its role in the pathophysiology of the most common affective disorder: MDD, as established by the work cited above and other studies implicating serotonergic dysfunction in MDD (Agren, 1980, Asberg et al., 1976; Mann et al., 1992; Miller et al., 2009; Parsey et al., 2010; Parsey et al., 2006; Placidi et al., 2001; Stockmeier et al., 1998)
Section snippets
The serotonin molecule
5-Hydroxytryptamine (5-HT), more commonly known as serotonin (Figure 1), is a monoamine neurotransmitter that is found throughout the human body (Jonnakuty and Gragnoli, 2008). 5-HT is synthesized in a small population of neurons from the raphe nuclei, in the midbrain, that express the enzyme tryptophan hydroxylase (Banerjee et al., 2007). However, serotonin synthesis is not restricted to the CNS as the enzyme tryptophan hydroxylase is also found in enterochromaffin cells within the
5-HT1A receptor function and distribution
5-HT neurons originate in the raphe nuclei, of the pons and upper medulla, from which they have both ascending and descending projections. The ascending projections originate in both the median and dorsal raphe nuceli, and project to: forebrain, hippocampus, limbic system, basal ganglia and hypothalamus (Kundu et al., 2012). The descending projections originate in the caudal raphe nuclei, raphe magnus nucleus and nuclei raphe pallidus, and project to the caudal brain stem/spinal cord, dorsal
Animal studies
Animal models have allowed for the understanding and visualization of 5-HT1A modulations in MDD: most notably the murine and primate paradigms. In the murine model, the tail suspension test (TST) has been used to assess behavioral withdrawal in mice. This test is based on the idea that mice subjected to the stress of being suspended by their tail will actively try to escape up until a point when they develop an immobile posture. This immobile posture is used as a corollary for a depressive-like
Sex differences
The female ovarian sex hormones, estrogen and progesterone, have also been shown to be connected to modulation of mood (Pecins-Thompson and Bethea, 1999). The decline in these sex steroids that occur during childbirth and menopause have been correlated with the development of depression (Gitlin and Pasnau, 1989). Similarly hormone replacement therapy, such as transdermal estrogen, has been shown to alleviate the depression in some of these subjects (Gregoire et al., 1996). It has been
Post-mortem studies
Initial whole brain post-mortem studies of MDD examining 5-HT1A found modulation of 5-HT1A receptor levels was restricted to subcortical regions. In a cohort of depressed suicide victims, a lower density of 5-HT1A receptors in the hippocampus and amygdala were observed (Cheetham et al., 1990). Similarly, several other post-mortem studies using depressed, non-suicide cohorts have shown reduced receptor density in cortical regions such as the ventral prefrontal cortex (Bowen et al., 1989), a
Positron emission tomography (PET)
With positron emission tomography (PET), physiological functions including metabolism, neurotransmitter systems and drug occupancy, can be assessed, in vivo, with minimum disturbance to a subject׳s physiological homeostasis (Berger, 2003). PET involves several fundamental physical principles. Using a type of particle accelerator known as a cyclotron, charged particles are accelerating at extremely high speeds. These accelerated particles are then used to bombard stable atoms in order to produce
C(-1019)G promoter polymorphism in depression
In humans, the gene coding for the 5-HT1A receptor is located on chromosome 5q11.2-13 (HTR1A) (Albert and Lemonde, 2004). Because MDD has been associated with altered 5-HT1A levels, specifically higher levels of 5-HT1A autoreceptors, it was thought that abnormal regulation of 5-HT1A mRNA transcription may underlie the development of psychopathologies such as MDD. An initial polymerase chain reaction (PCR) study, used in this case for DNA sequencing, was performed on the repressor region of the
5-HT1A binding potential as a biomarker for MDD diagnosis
Currently, there are no objective diagnostic tests one can perform to determine if an individual is depressed. The clinician must make this determination based on the patient׳s self-report and the clinician׳s judgment. This subjective system is prone to error and is also unrelated to the biological causes of depression. Another challenge in diagnosing MDD is that due to ambiguity in the diagnostic criteria, there are 945 ways to meet diagnostic criteria for a major depressive episode. Thus, two
The role of sex in 5-HT1A
To date, few studies have looked at the role of sex in the modulation of 5-HT1A specifically in MDD using PET in humans. However, a 2010 study showed that serotonergic differences exist in both healthy individuals and those with MDD across sexes. This study examined alpha-[(11)C]MTrp brain trapping, which is an index of serotonin synthesis (Frey et al., 2010). Sex differences in serotonin synthesis were seen in multiple regions of the prefrontal cortex and limbic system, which are involved in
Conclusion
Our knowledge regarding the role of the 5-HT1A receptor in the development of MDD has greatly evolved, established atop a foundation of preclinical animal and post-mortem literature. The 5-HT1A system is highly complex and improved neuroimaging technologies and methodologies along with innovations in genetic studies have all aided in a more complete comprehension of how modulations in the 5-HT1A receptor, whether inherited or drug/hormone induced, lead to expression of the MDD phenotype.
Role of funding source
The work was supported by the following grants: R01MH074813 (PI: Parsey), R01MH090276 (PI: Parsey), and K01MH091354 (PI: DeLorenzo) awarded by the National Institutes of Health, a Clinical and Translational Science Award (CTSA) from Columbia University, and grants from the American Foundation for the Prevention of Suicide (AFSP) and the National Alliance for Research on Schizophrenia and Depression (NARSAD).
Contributors
N/A.
Conflict of interest
The authors report no conflicts of interest.
Acknowledgments
We acknowledge the biostatistical support from the Biostatistical Consulting Core at School of Medicine, Stony Brook University.
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