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Serotonin has been implicated in the pathophysiology of depression and bipolar disorder (for reviews, see Mann, 1999; Oquendo and Mann, 2000; Shiah and Yatham, 2000; Mann et al., 2001; Nemeroff et al., 1997; Meltzer and Lowy, 1987; Coppen, 1969; Mace and Taylor, 2000; Kandel, 2000; Charney et al., 1981) (Table 11.1 and Figure 11.1). This hypothesis proposed that the vulnerability to either depression or mania was related to low serotonergic activity, attrib-utable to either less serotonin release or fewer serotonin receptors or impaired serotonin receptor-mediated signal transduction. Prange et al., (1974) formulated a permissive hypothesis of serotonin function in bipolar disorder. They suggested that a deficit in central seroton-ergic neurotransmission permits the expression of bipolar disorder, and that both the manic and depressive phases of bipolar disorder are characterized by low central serotonergic neurotransmission. Over the last 30 years, a variety of studies of the serotonergic sys-tem have reinforced its role in major depression and identified ad-ditional associations with suicidal behavior, impulsivity, aggression, eating disorders, obsessive–compulsive disorder, anxiety disorders, personality disorders, seasonal changes in mood and behavior, and alcohol abuse and dependence. The serotonergic system also plays a role in the regulation of a variety of basic biological functions in-cluding sleep, appetite, circadian rhythm and cognitive function.
Medications that target the serotonin transporter site and se-lectively inhibit reuptake of serotonin (e.g., fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram) have all been shown to be effective antidepressants (Nemeroff et al., 1997; Sampson, 2001;
Mace and Taylor, 2000). Some antidepressant drugs specifically act at one of the many serotonin receptor subtypes. For example, suggested antidepressive/anxiolytic medications buspirone and gepirone are 5-HT1A receptor agonists, and fewer 5-HT1A receptors are implicated in the pathophysiological mechanism of depression and anxiety (Yocca, 1990; Apter and Allen, 1999).
Considered together, studies of serotonin function in major depression suggest both hypofunction and likely compensatory changes that would increase serotonergic activity (Brown et al., 1994; Leonard, 1994; Dubovsky and Buzan, 1999). Findings such as 1) lower serotonin and 5-HIAA levels in postmortem brain stem and lower CSF 5-HIAA; 2) relapse of depression with diet acute depletion of tryptophan; 3) fewer serotonin transporter sites in prefrontal cortex; 4) fewer postsynaptic 5-HT1A receptors; and 5) the antidepressant properties of medications that enhance serotonergic transmission suggest that underactivity of the serotonin system is part of the pathogenesis of depression. Conversely, more 5-HT2A receptor binding in the frontal cortex of depressed individuals who committed suicide, fewer brainstem 5-HT1A autoreceptors and fewer serotonin transporters in the raphe nuclei would tend to increase serotonergic transmission in major depression. There is evidence for the contribution of serotonin in mania and in the mechanism of action of mood stabilizers (Shiah and Yatham, 2000); however, the data on the role of the serotonergic system in mania are fewer and not consistent. Alterations in functioning of other neurotransmitters in mania such as norepinephrine, dopamine, acetylcholine and GABA, and their interaction with serotonin may also contribute. Future studies of serotonergic activity in mood disorders will need further to differentiate primary pathogenesis from compensatory changes.
There are multiple lines of evidence that the noradreneric system is disordered in depression (Berman et al., 1996; Charney, 1998; He-ninger et al., 1996; Leonard, 1997; Owens, 1997; Kandel, 2000; Pot-ter et al., 1993; Schatzberg and Schildkraut, 1995; Nemeroff et al., 1997; Ressler and Nemeroff, 1999) (Table 11.2 and Figure 11.2).
A large body of metabolite data are consistent with the hy-pothesis that there are abnormalities in the noradrenergic system in depression. The conflicting findings, however, are not consist-ent with simple increased or decreased noradrenergic activity.
Some studies have found that CSF levels of the dopamine metabolite homovanillic acid (HVA) are lower in patients with major depression than in controls and that lower CSF HVA levels are found in more severely depressed patients (see Kapur and Mann, 1992; Brown et al., 1994, for a summary) (Table 11.3). However, other studies failed to replicate these findings or found higher CSF HVA in patients with depression (Jimerson, 1987; Vestergaard et al., 1978).
Gamma-aminobutyric acid (GABA) is the major inhibitory neu-rotransmitter in almost all areas of the CNS and regulates many CNS functions (Nemeroff et al., 1997). A decrease in GABAergic activity may play a role in depression by regulating receptor re-sponses to catecholamines (Enna et al., 1986; Nemeroff et al., 1997). Pathophysiological contributions of GABA and thera-peutic effects of GABAergic medications in mood disorders may be mediated via effects on other neurotransmitter systems (Dubovsky and Buzan, 1999; Nemeroff et al., 1997).
Cholinergic neurons containing acetylcholine project diffusely throughout the cortex (Thase, 2000). The involvement of cholinergic system in the pathogenesis of depression is supported by the following findings: cholinergic input reduces REM latency (decreased REM la-tency is seen in depression); some antidepressants have anticholiner-gic properties; lecithin, an acetylcholine precursor, reduces mania in some cases and can induce depression; and cholinergic rebound fol-lowing abrupt withdrawal of anticholinergic medications can cause a relapse of depression (Dubovsky and Buzan, 1999; Dilsaver and Coffman, 1989; Janowsky and Risch, 1984; Keshavan, 1985).
There are emerging data that drugs that antagonize NMDA receptors have antidepressant effects (Przegalinski et al., 1997; Papp and Moryl, 1994; Trullas and Skolnick, 1990).
It is important to note that all neurotransmitters and receptors interact with and influence each other (Brown et al., 1994; Leonard, 1994; Dubovsky and Buzan, 1999). Most cerebral functions are the result of the converging action of many different neurotransmitters. It is not likely that the pathophysiology of mood disorders is due to a single neurotransmitter (Brown et al., 1994). More probably, mood disorders are disorders of the overall interaction of multiple transmitter systems. Alternatively, different components of depres-sion may be related to different neurotransmitter dysfunction.
The binding of a neurotransmitter to a postsynaptic receptor triggers a cascade of chemical processes that include the second messenger systems (Thase, 2000; Dubovsky and Buzan, 1999; Thase and Howland, 1995). The bidirectional actions of second messengers allow unitary changes in second messenger function to produce diverse changes in transmitter synthesis and release, and in receptor activity, leading to complex neurotransmitter and receptor effects. There is evidence that mood-stabilizing drugs (e.g., lithium) act upon G proteins or other second messengers (Jesberger and Richardson, 1985; Kofman and Belmaker, 1993; Wang et al., 2001; Chen et al., 2001).
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