Related Papers Menu


Permission graciously given by the author to reproduce this paper:   


John Salmon


Severe depression afflicts 5-10% of the adults in the United States each year. 3-5% more adults experience a milder form of depression each year (Comer, 2004). Moreover, 5% of children and 10-20% of teens experience significant depression. That amounts to 800,000 teens each year experiencing depression. Of those 800,000 teens, 500,000 will require medical attention as a result of a suicide attempt (Mash & Wolfe, 2005).  Clearly, depression represents a significant problem in our society.

Depression does appear to have a genetic contribution.  In fact, if one member of a monozygotic twin has depression, the other member has a 69% change of experiencing depression as well. This percentage drops to 13% in dizygotic twins, suggesting a genetic component. At the same time, the incidence of depression has increased and the age of onset has decreased since 1915 (Mash & Wolfe, 2005). In fact, Seligman (1995) notes that people who were born in the 1930’s reported their first episode of depression as occurring between the ages of 30 and 35. Today, adults report their first episode occurring between 15 and 19 years of age and prospective studies show the first episode occurring between 13 and 15 years of age (Mash & Wolfe, 2005). Seligman (1995) also reports that between 1968 and 1971, 4.5% of older teens experienced depression while 7.2% of younger teens experienced depression between 1972and 1974. In other words, in the short period of time between 1968 and 1974, the age of onset for depression appears to move to younger adolescence. It is unlikely that genetics alone can explain this change in the age of onset for depression and number of people diagnosed with depression.  In fact, several explanations have been offered. For instance, rapid social change, the break up of the family, and increased drug use may contribute to this phenomenon. Overall, the current society seems to have lost many of the protective factors that may have buffered depression in the past. In addition, the increase in the diagnosis of depression has led to a significant increase in the prescription of antidepressant medications for people of all ages.  We have yet to discover the long term effects of these medications on children. Clearly, depressive disorders represent a major medical concern for our society today.


Depressive symptoms can be ranked among several dimensions. In Table 1 (attached), Yapko (1988) describes many of these dimensions and related symptoms. This section will also review many of the most common symptoms noted.

People who suffer with depression describe many affective symptoms. For instance, they describe themselves as “miserable” or “empty” (Mash & Wolfe, 2005). They find little pleasure, even in activities and things that used to bring them great pleasure. People who suffer with depression are often irritable and lose their sense of humor. They generally lose motivation and feel a sense of inadequacy. Unfortunately, this overlaps with their social interactions as they may feel apathetic about relationships, lacking motivation to contact others or engage in the activities necessary to build or maintain relationships. In addition, people with depression often focus on the very feelings that maintain the depression.

People with depression also become less active physically, staying in bed all day and even speaking more slowly. On the other hand, some children will become more active. Either way, the person experiences a disturbance in their typical activity level. In addition, people with depression may engage in substance abuse to “escape” the negative feelings or engage in “acting-out” behaviors.  They often become more impulsive as a result of cognitive symptoms also related to depression. Unfortunately, this impulsiveness may result in destructive acts such as suicidal attempts.

Cognitively, people with depression tend to exhibit extremely negative views about themselves. They express a sense of worthlessness and hopelessness, blaming themselves for negative events. Overall, they exhibit a pessimistic style of thinking (Comer, 2004). More specifically, they exhibit an internal, global, and stable attribution style (Seligman et al, 1995 & Reivich et al, 2002). In addition, they tend to ruminate on these negative thoughts and attributions. Moreover, people with depression complain of poor intellectual ability (Comer, 2004) such as diminished concentration, increased confusion, and difficulty making decisions. In fact, memory impairment represents the most reliably documented cognitive abnormality for those with depression (Campbell et al, 2004).

Each of the dimensions described above impact on the person’s relationships as well. In fact, people with depression tend to become over responsible, hypercritical of others and themselves, highly reactive to others, and operate out of a “victim” stance (Yapko, 1988). People with depression also tend to become excessively approval seeking. These relational symptoms can lead to a vicious cycle in with the person seeks approval but is hypercritical of their own and other’s behavior.  They feel victimized and blamed by any comment about them and withdraw into isolation as a result. In their isolation, they seek approval, but have distanced themselves from any supports who might offer that approval. As a result, they may become hypercritical of those who “ignore” them and, once again, feel like the victim. Each cycle serves to reinforce the negative cognitive and affective symptoms already described.

People with depression may also experience nightmares as well as sleep disturbances. Specifically, they experience shallow, fragmented sleep with a higher proportion of REM sleep during the first half of the night, increased eye movement during REM sleep, and quicker onset of REM sleep (Carlson, 2001).  In fact, 90% of people who suffer with depression complain of difficulties falling asleep, frequent nocturnal awakenings, and early morning awakenings (Berger et al, 2003). In addition, people with severe insomnia have four times the chance of having depression (Berger et al, 2003).  People with depression may also have a history of significant loss or aversive, uncontrollable events in their lives (Yapko, 1988).

In summary, depression impacts people along multiple dimensions that interact with the other to create the individual manifestations of the illness.

Serotonergic System

Several brain areas have been implicated in depression, each one contributing to the symptoms noted above. For instance, the serotonergic system in the brain has been implicated in depression. Serotonin cell bodies are found in the raphe nuclei. Axons project from the raphe nuclei to the cerebral cortex, basal ganglia, and dentate gyrus, all of which have been implicated on some level with depression. These serotonergic axons release serotonin with slow, regular pacemaker-type activity, influencing a large population of target neurons in the forebrain (Celeda et al, 2004). Within this system, serotonin release is also controlled by glutamatergic inputs from the prefrontal cortex and GABA-ergic input from local neurons (Celeda et al, 2004). In addition, 5-HT (serotonin) is self-inhibiting through 5-HT (1A) autoreceptors in raphe nuclei. In addition, 5-HT(2A) receptors are localized in the neocortex on GABA-interneurons and, specifically, on the catecholaminergic axons in the medial prefrontal cortex. Interestingly, stimulating 5-HT(2A) receptors evokes excitation in pyramidal neurons in the prefrontal cortex by enhancing AMPA mediated inputs (AMPA receptors control sodium channels) and inhibitory influences by increasing synaptic GABA inputs. The excitatory effect seems to predominate (Celeda et al, 2004).

More on the Prefrontal Cortex

As noted, the prefrontal cortex plays a role in the serotonergic system and has itself been implicated in depression. The left prefrontal cortex appears hypoactive in people with depression (Celeda et al, 2004; Schutter & van Honk, 2005). In fact, a stroke in the left prefrontal cortex is associated with a high incidence of depression (Celeda et al, 2004). On the other hand, some suggest that the right prefrontal cortex represents the problem, suggesting distorted left/right prefrontal cortex homeostasis (Schutter & van Honk, 2005). Overall, the prefrontal cortex is involved in higher brain functioning, exerting a top-down influence on brain functioning (Celeda et al, 2004). It exerts this influence by processing and integrating information from other areas of the brain. The prefrontal cortex also innervates, through glutamatergic (generally excitatory) axons, several subcortical areas that potentially relate to various depressive symptoms. For instance, the prefrontal cortex has connections with the nucleus accumbens, which plays a role in reinforcement and may be involved in anhedonia of depression; the amygdala, which plays a role in emotional regulation and may play a role in the fear and anxiety related to depression; the limbic structures, which may play a role in the depressed mood of depression; and other PFC areas, which may play a role in the cognitive disturbances related to depression (Celeda et al, 2004).  The prefrontal cortex also has a connection to the hypothalamus, which is part of the hypothalamus-pituitary-adrenal (HPA) axis (Celeda et al, 2004). Interestingly, the prefrontal cortex has a reciprocal connectivity with these brain areas (Celeda et al, 2004).  The prefrontal cortex also appears to have two pathways to the raphe nuclei, one direct excitatory pathway and one indirect inhibitory pathway (Celeda et al, 2004).  The prefrontal cortex can also send excitatory input to the noradrenergic neurons of the locus coeruleus. As a result, input from the prefrontal cortex will help regulate the release of catecholamine in the prefrontal cortex (Celeda et al, 2004). In summary, the raphe nuclei, along with the tegmental ventral area and the substantia nigra, give rise to the dopamine, serotonin, and norepinephrine of the forebrain, including the prefrontal cortex.  The prefrontal cortex integrates incoming excitatory signals from other cortical areas, the thalamus, and other subcortical areas, and projects the related information to the areas noted above. As a result, changes in the activity of the prefrontal cortex (i.e., hypoactivity) will impact several brain areas and may then contribute to various symptoms of depression (Celeda et al, 2004).

Parietal Cortex and Cerebellum

Two other areas connect with the prefrontal cortex and have recently been studied in regards to depression. First, the right parietal cortex appears hypoactive in people with depression (Schutter & van Honk, 2005). The right parietal cortex is involved in arousal and, when hyperactive, may result in a comorbid diagnosis of anxiety with depression (Schutter & van Honk, 2005). The left prefrontal cortex appears to have connectivity with the right parietal cortex. A hyperactive HPA system (associated with depression and discussed in next session) reduces the functional connectivity between the left prefrontal cortex and the right parietal cortex (Schutter & van Honk, 2005).  Second, researchers have recently implicated the cerebellum in the regulation of emotion and associated depression with reduced cerebellum volume (Schutter & van Honk, 2005). In fact, the cerebellum and prefrontal cortex appear to be linked in a bidirectional manner (Schutter & van Honk, 2005).  The cerebellum sends efferent axons to the thalamus which then project to the prefrontal cortex. The prefrontal cortex projects through the pontine nucleus of the brain stem to the cerebellum (Schutter & van Honk, 2005). Stimulation of the medial cerebellum has resulted in electrical activity in the prefrontal cortex and subjects experiencing medial cerebellum stimulation reported mood elevation and increased alertness (Schutter & van Honk, 2005). Finally, the fact that the cerebellum has efferent pathways to the substantia nigra may implicate it in dopamine levels which can contribute to depression as well. In fact, growing evidence exists for an association between low dopaminergic activity and depression (Schutter & van Honk, 2005). Specifically, stimulating the cerebellum may increase dopamine release (Schutter & van Honk, 2005).

HPA Axis and Depression

The hypothalamic-pituitary-adrenal (HPA) axis plays a role in circadian rhythms and the secretion of hormones/neurotransmitters that help modulate periods of activity and inactivity. It appears hyperactive in people with depression (Barden, 2004; Schutter & van Honk, 2005). In fact, some have suggested that the hyperactive HPA system contributes to prefrontal hypoactivity (Amen, 1998). In the HPA axis, the paraventricular nucleus of the hypothalamus releases CRH which stimulates the anterior pituitary gland to release ACTH. ACTH stimulates the adrenal cortex to release glucocorticoids (Carlson, 2001). Glucocorticoids help a stressed organism to survive the stress. They also terminate stress through a negative feedback loop at the pituitary, hypothalamus, and several limbic areas, hippocampus, amygdala, and septum (Barden, 2004). Specifically, the brain has glucocorticoid receptors (GR) that, when activated, inhibit the stress response. As a result, glucocorticoid plays a dual role of preparing for acute stress while inhibiting a long-term stress response. In people with depression, the CRH receptors become desensitized. As a result, a hypersensitivity to ACTH develops, resulting in an increased release of glucocorticoids (Barden, 2004). Unfortunately, a long-term increase in glucocorticoids results in the loss of GR containing cells in the hippocampus. The GR containing cells mediate the suppression of CRH neurons in the paraventricular nucleus (Barden, 2004). As a result, the process continues, ultimately releasing more glucocorticoids and causing more damage. The long term exposure to glucocorticoid also seems to destroy hippocampal cells in the CA1 area, which interferes with learning (Carlson, 2001).  Research suggests that MAO agonists such as SSRI’s may act by stimulating corticosteroid receptor gene expression, producing more GR’s, increasing HPA sensitivity to the inhibition function of glucocorticoids, and ultimately allowing a decrease in HPA system activity (Barden, 2004).  In fact, serotonin appears to play an essential regulatory component of the pituitary-adrenocortical stress response (Barden, 2004).  


The hippocampal complex also appears vulnerable to atrophy in depression (Campbell & MacQueen, 2004).  As noted above, the hippocampus plays an inhibitory role in regulating stress by mediating the suppression of CRH. However, a long-term exposure to glucocorticoids interferes with hippocampus function. Specifically, elevated glucocorticoids may cause excitotoxic damage to hippocampal cells and interfere with neurogenesis (Campbell & MacQueen, 2004). The hippocampus is one of the few brain areas that experiences adult neurogenesis (Ernst et al, 2006). This loss of cells and interference with neurogenesis may account for the atrophy of the hippocampus noted in people with depression. In fact, meta-analytic review of MRI studies of the hippocampus exhibit decreased right and left hippocampus volume in people with depression (Ernst, 2006). Interestingly, antidepressants appear to stimulate neurogenesis and this effect may result from “downstream effects” of serotonergic activation (Ernst, 2006). New neurons take about 4-5 weeks to become functional (Ernst, 2006), about the same time frame for the delay effect of antidepressants. The hippocampus is involved in learning and the consolidation of declarative (explicit) memories (Carlson, 2001; Campbell & MacQueen, 2004). Those who suffer with depression exhibit memory impairment. More specifically, depression has a large impact on declarative memories but little impact on non-declarative memories (Campbell & MacQueen, 2004).

In general, genetic vulnerability, early abuse, and chronic stress may predispose people to depression and predict small hippocampus. An interesting study comparing monozygotic twins in which one member was exposed to combat suggested that genetic factors led to small hippocampus volume which leads to vulnerability to stress and depression (Campbell & MacQueen, 2004). In addition, prepubertal abuse is associate with long-term dysregulation of the HPA axis (Campbell & MacQueen, 2004), which may contribute to vulnerability to hippocampal damage and depression.

Substance P—Amygdala, Nucleus Accumbens, and Hippocampus

Throughout the description of brain mechanisms involved in depression, the catecholamine serotonin was noted. The catecholamine, dopamine, was also mentioned as potentially involved in depression. However, one other substance may play a role in depression. The amygdala has a high concentration of Substance P and NK1 receptors, which are the receptors through which Substance P acts. In addition, the amygdala is a critical for the regulation of affective behavior, playing a key role in emotionally and socially relevant information in response to aversive stimuli (Carletti et al, 2005). In people with depression, the amygdala exhibits an increased blood flow and glucose metabolism as well as increased volume. However, Carletti et al (2005) demonstrated a down-regulation of PPT-A mRNA (the precursor for Substance P) in the basolateral amygdala. This finding helps to implicate substance P and NK1 receptors in mood disorders. In addition, SP levels in the cerebral spinal fluid of depressed people tend to be elevated. Carletti et al (2005) hypothesizes that a decrease in PPT-A mRNA represents a negative feedback mechanism to compensate for increased Substance P release in people with mood disorders. This is further confirmed as the density of NK1 receptors in the amygdala nuclei remains unchanged (Carletti et al, 2005).  In summary, Substance P appears to play a role in mood disorders. As Substance P increases, PPT-A mRNA decreases to compensate for the increase. 

Substance P also has an impact in the nucleus accumbens. The nucleus accumbens represents an interface where emotional events originating in the limbic area become converted into motor outputs (Kombian et al, 2003).  90% of the neurons leaving the nucleus accumbens are inhibitory GABA-ergic projections (Kombian et al, 2003).   These neurons also branch extensively within the nucleus accumbens to exert internal inhibition. Of the remaining neurons, some are inhibitory GABA-ergic and some are cholinergic neurons, providing excitatory input within the nucleus accumbens. Overall, the major projections of the nucleus accumbens have negative resting potentials due to the inhibitory inputs (Kombian et al, 2003). As a result, the nucleus depends on excitatory input to produce output. Overall, inhibition plays a critical role in the functioning of the nucleus accumbens (Kombian et al, 2003).

Substance P co-localizes with GABA-ergic projecting neurons in the nucleus accumbens. As such, Substance P may provide local feedback for regulating the strength of the inhibitory stimuli leaving the region (Kombian et al, 2003). In other words, substance P may modulate GABA-mediated inhibitory transmission in the nucleus accumbens. Kambian et al (2003) demonstrated that Substance P in the nucleus accumbens depresses GABA receptor mediated inhibitory synaptic transmission in the nucleus indirectly by increasing extracellular levels of dopamine and adenosine. Substance P binds to the NK1 receptors on dopaminergic terminals and causes them to increase their release of dopamine. Dopamine then acts on receptors to generate adenosine. Adenosine acts on GABA-ergic terminals to inhibit GABA release in the presynaptic side, decreasing the inhibitory postsynaptic potential (IPSP) (Kombian et al, 2003; Caberlotto et al, 2003). Overall, Substance P may act as a gate keeper for the nucleus accumbens output and as “housekeeper” to set the resting tone of projecting neurons in the nucleus so that they respond appropriately to afferent excitation (Kombian et al, 2003).

Finally, the dentate gyrus appears to have a high density of NK1 receptors. Substance P is also found in this region (Caberlotto et al, 2003).  In fact, substance P appears to play a role in the facilitation of learning (Caberlotto et al, 2003).  As noted earlier, the hippocampus experiences a reduction in volume during depression due to decreased neurogenesis.  Substance P also plays a role in facilitating learning and may then be involved in this phenomenon as well.

Summary of Brain Mechanisms

In summary, several interconnected brain regions and neurotransmitters/modulators appear to be involved in depression. Specifically, the raphe nuclei, prefrontal cortex, right parietal lobe, cerebellum, nucleus accumbens, and mesolimbic/nigrostriatal system, hippocampus, amygdala, and the HPA axis all have been implicated in depression. The prefrontal cortex appears to play a central role to each of these brain regions through its processing and integrative functions. In addition, serotonin, dopamine, norepinephrine, substance P, and adenosine appear to play a potential role in depression.

Potential Interventions Based on Physiology

Understanding the physiology of behavior leads to several potential theories of intervention.  With an increased understanding of the potential physiological mechanisms behind the behavior, a person can explore potential interventions. With that in mind, this section will explore several interventions to date and raise potential areas for further research in each area.

Serotonin Agonists

The serotonergic system has been implicated in depression. The two most important clusters of serotonin cell bodies are found in the dorsal and medial raphe nuclei, projecting to the cerebral cortex and basal ganglia. Of particular interest in this discussion are the projections from the dorsal raphe to the prefrontal cortex. The receptors in the dorsal raphe consist mostly of 5-HT(1) and 5-HT(1A) receptors (Celeda et al, 2004).  The 5-HT(1A) receptors are autoreceptors that inhibit the presynaptic release of 5-HT (Celeda et al, 2004). 5-HT(1A) autoreceptors play an important role in the delayed effect of SSRIs. Specifically, SSRIs increase the extracellular concentration of serotonin in the extracellular fluid by blocking reuptake of serotonin. However, the increased serotonin diffuses to the 5-HT(1A) autoreceptors and inhibits presynaptic release, offsetting the extracellular concentration. With long-term use, the 5-HT(1A) receptors become desensitized and serotonin release rate return to normal. At that time, the extracellular concentration of serotonin increases and antidepressant effects begin to show. Overall, this process creates a delay rate of about 6 weeks. With this in mind, some have suggested that 5-HT(1A) antagonists may serve to augment the effectiveness of serotonin agonists like SSRIs, enhancing a quicker response.  Interestingly, several other changes take place in the brain during that same time period. For instance, neurogenesis in the hippocampus takes 4-5 weeks (Ernst, 2006). This has led to additional theories about which serotonin actions produce the antidepressant results.

The prefrontal cortex has mostly 5-HT(2) receptors. In general, the medial prefrontal cortex and the dorsal raphe have a strong reciprocal communication (Celeda et al, 2004). The medial prefrontal cortex in particular innervates the dorsal raphe. Stimulating the medial prefrontal cortex results in the direct activation of 5-HT neurons in the dorsal raphe and produces inhibitory effects. In addition, excitatory axons from the prefrontal cortex can inhibit 5-HT neurons in the dorsal raphe through GABA-ergic interneurons (Celeda et al, 2004).  As a result, the medial prefrontal cortex can “finely tune” 5-HT neurons through direct excitatory or indirect inhibitory inputs; although the primary input appears to be excitatory (Celeda et al, 2004).  Celeda et al (2004) suggests the possibility that 5-HT(2A) receptor activation increases glutamate release from thalamic afferents, increasing EPSC. In fact, applying a 5-HT(1A) agonist to inhibit or a 5-HT(2A) agonist to excite in the medial prefrontal cortex will result in a parallel model of firing in the dorsal raphe and a reciprocal change in the medial prefrontal cortex (Celeda et al, 2004).  With this in mind, Celeda et al (2004) proposes that SSRIs may work to alter the balance of activation between the 5-HT(1) receptors and the 5-HT(2) receptors. Further research is needed to determine how serotonin-related medications can best mediate the balance of activation in the prefrontal cortex.

Other Possible Ways to Influence Serotonin Levels

Tryptophan is the precursor for serotonin (Carlson, 2001). Many foods we eat contain tryptophan.  With this in mind, Amen (1998) suggests that eating tryptophan may help build serotonin. He also suggests that a diet high in carbohydrates helps to build serotonin. Foods high in tryptophan include foods such as turkey, chicken, salmon, peanut butter, eggs, green peas, potatoes, and milk. Perhaps adding such items to one’s diet may help maintain an appropriate balance of serotonin. At the same time, proteins and fats remain important. In fact, proteins provide building blocks for many neurotransmitters (Amen, 1998). And, Amen (1998) sites a study in which those with the lowest level of cholesterol had the highest suicide rates. These findings suggest the benefit of a balanced diet to maintain strong brain functioning and possible reduce the risk of manifesting depression due to predisposed vulnerabilities.  

Saarinen et al (2005) completed an interesting case study regarding serotonin transporter densities and psychodynamic therapy. The authors used SPECT scans to monitor the density of serotonin transporters in the brain of a depressed patient to whom they provided psychodynamic therapy. Initially, they found that a person with depression has a decreased density of serotonin transporter cells. In the person with whom they were working, they found a density 2 standard deviations below the norm. After 12 months of psychodynamic therapy, the person had a typical density of serotonin transporters in the raphe nuclei.  Within 18 months, the person was symptom free.  Overall, the authors suggest that the type of therapy used (psychodynamic therapy utilizing the dream screen) helped to integrate deeper brain areas through use of the dream screen (Saarinen et al, 2005).  Of course, this represents a case study and further controlled studies should follow.  It would be of interest to explore the impact of various therapy styles on long-term potentiation, neurogenesis, and serotonergic systems in the brain. We know that learning increases neurogenesis (Ernst et al, 2006). Would cognitive therapy then encourage neurogenesis? It would be interesting to see if cognitive therapy stimulates the prefrontal cortex in a depressed person who exhibits hypoactivity in the prefrontal area.  Or, it might prove interesting to explore if and how affective therapies activate the limbic system. Is it possible to utilize stories to elicit emotion related to abuse and then use the story to help develop a context for traumatic memories that might be impacting depression, thus promoting neurogenesis in the hippocampus?  In addition, how might visual imaging impact brain activity and healing? These are areas of further research.


It has been hypothesized that decreased neurogenesis in the hippocampus is linked to depressive disorders (Ernst et al, 2006). In the human brain, neurogenesis occurs in the hippocampus. Exercise represents one environmental influence that stimulates neurogenesis (Ernst et al, 2006). In fact, animals that engage in exercise show sustained increases in hippocampal neurogenesis within three days and reliably observable neurogenesis within one week (Ernst et al, 2006). Ernst et al (2006) reports that a review of 14 studies completed by 1999 concluded that exercise has antidepressant effects of the same magnitude as cognitive therapy. Unfortunately, these studies had methodological flaws. Since that time, studies of higher quality have supported the results. For instance, those who exercise exhibit fewer depressive symptoms and are less likely to develop a major depressive disorder (Ernst et al, 2006). In addition, adults with a major depressive disorder who engaged in moderate aerobic exercise exhibited significantly more improvement than those who engaged in flexibility exercises and low-intensity aerobic exercises (Ernst et al, 2006). The antidepressant effects of exercise appear to extend beyond the exercise program for as long as 21 months (Ernst et al, 2006). In fact, a single 30 minute aerobic endurance exercise period significantly improved reaction time (a measure of executive functioning) in patients with depression (Ernst et al, 2006). Overall, the effects of exercise on depression are fairly impressive.

These effects may occur as exercise increases the release of beta-endorphins, vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase which is involved in the synthesis of serotonin (Ernst et al, 2006). Beta-endorphins belong to a class of opiate peptides that function as neurotransmitters. When they bind to receptors, cyclic adenosine monophosphate (cAMP) is reduced in the neurons and the conductance of voltage-gated calcium channels decreases (Ernst et al, 2002). In addition, beta-endorphins stimulate neurogenesis (Ernst et al, 2006).  VEGF also increases neurogenesis in the dentate gyrus, possible through its release from vascular niches located there (Ernst et al, 2006). BDNF most likely increases cell proliferation in the hippocampus by enhancing the survival of new cells (Ernst et al, 2006). Finally, exercise increases the level of tryptophan hydroxylase, an enzyme involved in the biosyntheses of serotonin (Carlson, 2001), in the raphe nuclei which sends projections to the hippocampus (Ernst et al, 2006). This may then lead to an increase in serotonin in the hippocampus and serotonin is linked to adult neurogenesis (Ernst et al, 2006).

In summary, it appears as though exercise increases beta-endorphins, VEGF, BDNF, and tryptophan hydroxylase in the brain. Beta-endorphins stimulate the birth of new neurons in the dentate gyrus while VEGF and BDNF enhance the survival of these new neurons. Exercise also stimulates increased serotonin levels in the brain and serotonin contributes to neurogenesis.

Sleep and Depression

90% of depressed patients complain about difficulties falling asleep, frequent night-time wakening, and early morning awakenings (Berger et al, 2003). Sleep difficulties and depression appear to be intimately tied. Some have suggested that insomnia may be a predictor of depression or may actually trigger depression (Berger et al, 2003). People with depression exhibit several pattern changes in sleep. Specifically, they exhibit a reduction in slow wave sleep, a shorter interval between sleep onset and first REM sleep, prolonged first REM sleep, increased REM sleep (especially during the first half of the night), and heightened eye movement during REM sleep (Berger et al, 2003). The reciprocal interaction model suggests that aminergic neurons and cholinergic neurons balance REM sleep.  Specifically, aminergic neurons, made up of noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe, inhibit REM sleep while cholinergic neurons throughout the central nervous system stimulate REM sleep (Berger et al, 2003). Under this model, studies suggest that cholinergic supersensitivity may be a trait or vulnerability marker of affective illness (Berger et al, 2003).

Total sleep deprivation results in a temporary improvement in 50-60% of people with depression (Berger et al, 2003). Unfortunately, 80% of that group will experience a relapse after the first episode of recovery sleep (Berger et al, 2003). Interestingly, morning naps appear more detrimental than afternoon naps in this respect. In addition, those people who exhibit a fluctuating mood, improving toward afternoon and evening as well as those who exhibit a shortened REM latency, tend to have a better response to total sleep deprivation. Adenosine inhibits the cholinergic neurons which inhibit slow wave sleep and stimulate REM sleep (Berger et al, 2003). Adenosine increases during extended waking periods, especially in the cholinergic region of the basal forebrain (Berger et al, 2003).  The level of adenosine normalizes with recovery sleep.  As such, adenosine may be the “sleep factor” responsible for alteration in sleep/wake cycle.  Sleep deprivation increases adenosine concentration and, paradoxically, upregulates adenosine A(1) receptors, reinforcing adenosine’s sleep promoting effect.  Recall that adenosine also increases in the nucleus accumbens in response to substance P through dopaminergic terminals (Kombian et al, 2003) and has an ultimately excitatory effect.

Selective sleep deprivation involves depriving a person of REM sleep in particular.  Berger et al (2003) found that selectively reducing REM sleep by 50% over a three week period produces results similar to those of imipramine. They also found that reducing REM sleep in the second half of the night produced this effect while reducing REM sleep in the first half of the night did not. Berger et al (2003) also developed a phase advance protocol to enhance the effect of selective sleep deprivation. Specifically, after a period of selective sleep deprivation, the person was allowed to sleep from 5 p.m. until midnight. Over the next week, the person’s sleep phase was shifted to normal times. This protocol maintained the positive effect of selective sleep deprivation in 60-75% of the subjects (Berger et al, 2003).

Once again, one finds several overlapping mechanisms and transmitters (norepinephrine, serotonin, adenosine, and raphe nuclei) involved in sleep processes and depressive symptoms. This, in combination with the antidepressant effects of sleep deprivation, supports connectivity between sleep mechanisms and depression. At this time, more research is required in regards to sleep deprivation’s effect on depression and what role, if any, sleep may play in mood regulations.

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation involves the application of a brief magnetic pulse or series of pulses to the scalp using a coil of wire. When the magnetic field creates a magnetic pulse that alternates rapidly enough, a secondary electric current is induced that alters local electric fields near the point of conduction. In fact, this secondary electric current can be made strong enough to create neural depolarization and a resulting action potential (Schutter & van Honk, 2004). Slow pulses tend to reduce neural excitability while fast pulses enhance neural excitability (Schutter & van Honk, 2004). Unfortunately, the strength of the secondary electric current decays rapidly and over a short distance. Therefore, it can only impact superficial brain tissue directly and the tissue of those neural networks functionally connected to directly stimulated tissue (Schutter & van Honk, 2004). At this point, transcranial magnetic stimulation has been applied to the prefrontal cortex wit some success.  Slow pulse transcranial magnetic stimulation has produced antidepressant effects when applied to the right prefrontal cortex while fast pulse transcranial magnetic stimulation as produced antidepressant effects when applied to the left prefrontal cortex (Schutter & van Honk, 2004). Unfortunately, the effects have not remained consistent. The authors suggest that increasing the intensity of the current may increase effectiveness (Schutter & van Honk, 2004). In addition, the authors suggest utilizing transcranial magnetic stimulation on other brain areas may produce positive results (Schutter & van Honk, 2004). Specifically, Schutter and van Honk (2004) suggest stimulating the right parietal lobe or the cerebellum.  The right parietal lobe is hypoactive in people with depression and appears to have a functional connectivity to the left prefrontal cortex. In fact, initial studies suggest that transcranial magnetic stimulation of the right parietal lobe may decrease depressive symptoms (Schutter & van Honk, 2004).  Schutter and van Honk (2004) also note that people with depression exhibit decreased volume in the cerebellum. In addition, electrical stimulation of the cerebellum produced positive effects in mood and personality in psychiatric patients (Schutter & van Honk, 2004). Furthermore, transcranial magnetic stimulation of the medial cerebellum moderated electrical activity in the prefrontal cortex. In addition, subjects noted elevated mood (Schutter & van Honk, 2004).  Schutter and van Honk suggest that transcranial magnetic stimulation of the cerebellum may impact dopamine release, producing the elevated mood noted above (Schutter & van Honk, 2004). Perhaps, stimulating dual areas will have more effective results. Further research is required in regards to transcranial magnetic stimulation.

Interestingly, this sounds somewhat like entrainment. Strong (1998) indicates that auditory rhythms can entrain internal brain wave frequencies.  He has shown that listening to a variable rhythm for 10 minutes can improve spatial abilities by 15% in normal children and acts to increase neuronal activity, exciting the whole brain (Strong, 1998).  Playing a rhythm at eight beats per second targeted alpha frequencies while rhythms in 21/16 calm most individuals with autism and rhythms in 47/16 helps to reduce self-stimulatory behaviors (Strong, 1998).  Perhaps, applying this principle, the prefrontal cortex could be excited or the HPA axis inhibited with the appropriate rhythm entrainment or with the correct frequency of transcranial magnetic stimulation. Of course, this is purely theoretical and would require empirical investigation.


Overall, depression appears to be a complex disorder that implicates many brain regions and neurotransmitters/modulators including the raphe nuclei, prefrontal cortex, right parietal lobe, cerebellum, nucleus accumbens, and mesolimbic/nigrostriatal system, hippocampus, amygdala, and the HPA axis all have been implicated in depression. The prefrontal cortex appears to play a central role to each of these brain regions through its processing and integrative functions. In addition, serotonin, dopamine, norepinephrine, substance P, and adenosine appear to play a potential role in depression. As researchers learn more about depression and the neural mechanisms behind the disorder, clinicians may learn to target various expressions of depression differently. In fact, depression that exhibits a fluctuating mood responds better to sleep deprivation. This may represent slightly different neural mechanisms at work and thus respond better to different treatments. Another example might include the right parietal lobe. A hypoactive right parietal lobe is associated with depression whereas a hyperactive right parietal lobe is associated with a comorbid diagnosis of anxiety.

At the same time, it remains interesting that interventions as variant as psychodynamic therapy, serotonin agonists,  exercise, and sleep deprivation can produce similar results. Perhaps research into other areas will continue to discover effective interventions. Those of interest might include the neural impact of rhythm entrainment, cognitive and affective therapies, and meditation.


Amen, D. (1998). Change Your Brain, Change Your Life: The Breakthrough Program for Conquering Anxiety, Depression, Obsessiveness, Anger, and Impulsiveness. New York, NY: Three Rivers Press

 <>APA (American Psychological Association). (1994). Diagnostic and Statistical Manual of Mental Disorders (4th Edition). Washington, DC: Author.  

Barden, N. (2003). Implication of the Hypothalamic-Pituitary-Adrenal Axis in the Physiopathology of Depression. Journal of Psychiatry and Neuroscience, 29 (3), 185-193.

Berger, M., van Calker, D., & Riemann, D. (2003).
Sleep and Manipulations of the Sleep-Wake Rhythm in Depression. ACTA Pscyhiatrica Scandinavica, 108 (418), 83-91.  

Beutler, L. E., Cano, M. C., Beula-Casal, E. M., & Beula, G. (2003).
The Role of Activation in the Effect of Total Sleep Deprivation on Depressed Mood. Journal of Clinical Psychology, 59 (3), 369-384. 

<>Buysse, D. J. Psychiatric Disorders Associated with Disturbed Sleep and Circadian Rhythms. Presentation for Worldwide Project. Retrieved from the Web August 1, 2006. 

Caberlotto, L., Hurd, Y. L., Murdock, P., Wahlin, J. P., Melotto, S., Corsi, M., & Carletti, R. (2003). Neurokinin 1 Receptor and Relative Abundance of the Short and Long Isoforms in the Human Brain. European Journal of Neuroscience, 17, 1736-1746.

Campbell, S., MacQueen, G. (2004). The Role of the Hippocampus in the Pathophysiology of Major Depression. Journal of Psychiatry and Neuroscience, 29 (6), 417-426.

Carletti, R. Corsi, M. Melotto, S. & Caberlotto, L. (2005). Down-Regulation of Amygdala Preprotachykinin A mRNA But Not 3H-SP Receptor Binding Sites in Subjects Affected by Mood Disorders and Schizophrenia. European Journal of Neuroscience, 21, 1712-1718.

Carlson, Neil R. (2001). Physiology of Behavior.
Needham Heights, Massachusetts: Allyn and Bacon. 

Celeda, P., Puig, M. V., Amargos-Bosch, M. Adell, A. & Artigas, F. (2004).
The Therapeutic Role of 5-HT (1ª) and 5-HT(2ª) Receptors in Depression. Journal of Psychiatry and Neuroscience, 29 (4), 252-265.  

Comer, R
onald J. (2004). Abnormal Psychology (5th Edition). New York, NY: Worth Publishers.  

Ernst, C., Olson, A. K., Pinel, J.P.J., Lam, R. W., & Christie, B. R. (2006). Antidepressant Effects of Exercise: Evidence for an Adult-Neurogenesis Hypothesis?. Journal of Psychiatry and Neuroscience, 31 (2), 84-92.

Even, C., Thuile, J., Santos, J., & Bourgin, P. (2005). Modafinil as an Adjunctive Treatment to Sleep Deprivation in Depression. Journal of Psychiatry and Neuroscience, 30 (6), 432-433.

Gottman, J. (1997). Raising an Emotionally Intelligent Child: The Heart of Parenting: Fireside Publishers.

Greenshaw, A. J. (2003). Neurotransmitter Interactions in Psychotropic Drug Action: Beyond Dopamine and Serotonin. Journal of Psychiatry and Neuroscience, 28 (4), 247-250.

Holden, C. (2004). Prozac Treatment of Newborn Mice Raises Anxiety. Science, 306 (5697), 3-4.

Holden, C. (2004). Mutant Gene Tied to Poor Serotonin Production and Depression. Science, 306 (5704), 2023.

Kombian, S. B., Ananthalakshmi, K. V. V., Parvathy, S. S. & Matowe, W. C. (2003). Dopamine and Adenosine Mediate Substance P-induced Depression of Evoked IPSCs in the Rate Nucleus Accumbens In Vitro. European Journal of Neuroscience, 18, 303-311.

Mash, E. J., & Wolfe, D. A. (2005). Abnormal Child Psychology (3rd Edition). Belmont, CA: Wadsworth.

Reivich, K. & Shatte, A. (2002). The Resiliency Factor: 7 Keys to Finding Your Inner Strength and Overcoming Life’s Hurdles: Broadway Books.

Schutter, D. J. L. G., van Honk, J. (2005). A Framework for Targeting Alternative Brain Regions With Repetitive Transcranial Magnetic Stimulation in the Treatment of Depression. Journal of Psychiatry and Neuroscience, 30 (2), 91-97.

Seligman, Martin E.P., Reivich, K., Jaycox, L., & Gillham, J. (1995). The Optimistic Child: A Proven Program to Safeguard Children Against Depression and Build Lifelong Resilience: Houghton Mifflin Company.

Saarinen, P. I., Lehtonen, J., Joensuu, M., Tolmunen, T., Ahola, P., Vanininen, R., Kuikka, J., &Tithonen, J. (2005). An Outcome of Psychodynamic Psychotherapy: A Case Study of the Change in Serotonin Transporter Binding and the Activation of the Dream Screen. American Journal of Psychotherapy, 59 (1), 61-73.

Strong, J. (1998). Rhythmic Entrainment Intervention: A Theoretical Perspective. Open Ear Journal. Retrieved from the Web June 5, 2006.

Xiaodong, Z., Jean-Martin, B., Tatyana, S., Raul, G., & Mar, C. (2004). Tryptophan Hydroxylase-2Controls Brain Serotonin Synthesis. Science, 305 (5681), 217.  

Yapko, Michael D. (1988). When Living Hurts: Directives for Treating Depression. ????: Brunner/Mazel, Incorporated.