Mechanism Of Action

Despite almost four decades of intensive investigation directed at understanding the pathogenesis and pathophysiology of depression and related psychiatric disorders and the precise mechanism(s) of the therapeutic action of antidepressants, the answers to these questions remain elusive.

Early theorists suggested a causal association between an aberration in synaptic monoamine neurotransmitter concentrations and depression, based largely on the precipitation of depressive symptoms in a significant number of individuals treated with the antihypertensive agent reserpine, a monoamine-depleting drug (Goodwin and Bunney 1971). The once-celebrated "monoamine hypothesis of depression" provided the theoretical framework for the development and investigation of successive generations of antidepressants. This hypothesis, although seminal, has since been challenged as being too simplistic to explain either the pathophysiological underpinnings of depression or the mechanisms of action of antidepressants (Duman et al. 1997; Ressler and Nemeroff 2000). Antidepressants that effectively increase monoamine neurotransmitter concentrations in the synapse, such as MAOIs, TCAs, SRIs, and SNRIs, clearly implicate the serotonergic and noradrenergic neuronal systems as targets of action of these drugs; however, drug binding to a specific receptor or transporter and consequent manipulation of its affiliated neural circuitry do not necessarily equate to the ultimate mechanism of action of a pharmacological agent (Dubovsky 1994). Although our understanding of antidepressant pharmacology and the biology of depression has grown exponentially, the relationship between the evident pharmacodynamic actions of antidepressants and their well-documented therapeutic effects remains relatively obscure.

Paroxetine and all of the other SRIs cause immediate elevations in extracellular fluid 5-HT concentrations in serotonergic synapses, resulting from the decreased 5-HT clearance associated with 5-HTT inhibition (Wagstaff et al. 2002). Blier et al. (1990) demonstrated that administration of paroxetine initially causes a paradoxical decrease in 5-HT neurotransmission, likely caused by activation of a negative feedback system mediated by increased 5-HT binding to the 5-HT1A autoreceptor and subsequent diminution in serotonergic neural activity. After 2 weeks of paroxetine treatment, a desensitization of the 5-HT1A autoreceptors occurs and is associated with an increase in serotonergic neurotransmission (Chaput et al. 1991). The delayed changes in 5-HT1A receptor sensitivity and 5-HT neurotransmission seen after long-term paroxetine administration are temporally associated with clinical improvement, hinting at a possible mechanistic link.

These and related findings led to the study of pindolol, a nonselective ^-adrenergic receptor antagonist/5-HT1A antagonist, as a novel approach to accelerate the therapeutic response to SRIs, as well as to convert SRI nonresponders to responders. Preclinical studies revealed greater and more persistent increases in extracellular 5-HT concentrations after treatment with pindolol and an SRI than after treatment with an SRI alone (Dreshfield et al. 1996; Hjorth 1993; Sharp et al. 1997). This observation, coupled with the hypothesis that blockade of the presynaptic 5-HT1A autoreceptor might serve to avert the initial reduction in serotonergic transmission induced by SRI treatment, suggested that the combination of pindolol and paroxetine might produce a more rapid and more robust clinical response (Perez et al. 1999).

Results from open studies supported both hypotheses (Artigas et al. 1994; Blier and Bergeron 1995). Double-blind, placebo-controlled trials also indicated that the addition of pindolol (2.5-5 mg three times a day) to paroxetine in the early phase of treatment for major depression might decrease latency to clinical improvement. However, the augmentation of clinical efficacy with pindolol was not compelling, especially in individuals refractory to monotherapy with paroxetine (Bordet et al. 1998; Perez et al. 1999; Tome et al. 1997; Zanardi et al. 1997). Currently, the available data do not support the use of pindolol to accelerate or augment the efficacy of paroxetine or other SRIs. To be fair, at the doses of pindolol used, PET imaging revealed that only a relatively low percentage of 5-HT1A binding sites were occupied; therefore, the studies should be repeated with adequate doses of pindolol or another 5-HT1A autoreceptor antagonist (Martinez et al. 2000).

Consistent with the potency of paroxetine in blocking NE reuptake are reports that it increases NE concentrations in extracellular fluid, as demonstrated by microdialysis techniques (Hajos-Korcsok et al. 2000). Although not studied extensively, chronic treatment with paroxetine, unlike TCAs such as desipramine, does not produce downregulation of postsynaptic (^-adrenergic receptor binding sites in cerebral cortex and hippocampus (Duman et al. 1997).

While 5-HT and ^-adrenergic receptor adaptation remains an attractive area of research, attention has increasingly been focused on postreceptor intracellular signal transduction changes observed after long-term antidepressant treatment. Chronic administration of antidepressants has been shown to activate second-messenger systems, such as cyclic adenosine monophosphate (cAMP) and tyrosine kinase B, associated with hippocampal neurons (Duman 1998). Data derived from postmortem human brain tissue studies suggest increased levels of brain-derived neurotrophic factor (BDNF) within the hippocampus of subjects with depression who had been treated with antidepressants, compared with control subjects with depression who had been nonmedicated (Chen et al. 2001). It has been suggested that neuronal injury mediated by stress-related illnesses, such as depression and anxiety, may be reversed by antidepressant-induced increases in BDNF expression in the CNS posited to contribute to clinical response (Duman 1998). Antidepressants from diverse classes, including SRIs, have all been shown to increase the rate of neurogenesis in the hippocampus of adult animals (Duman et al. 2001).

A recent boon to the study of antidepressant effect has been the development and fine-tuning of techniques in the field of functional brain imaging. One study compared the modulation of cortical-limbic systems in depressed patients who were treated with either paroxetine or cognitive-behavioral therapy (CBT) (Mayberg et al. 2004). PET was used to obtain images serially during the course of treatment and revealed interesting distinctions in brain activity in response to the two treatment modalities. Paroxetine responders experienced significant increases in prefrontal cortical activity in the setting of decreases in hippocampal and subgenual cingulate processing. This is in marked contrast to treatment-emergent changes seen in the CBT group in which patients developed increases in hippocampal and dorsal cingulate metabolism subsequent to subtle decreases in dorsal, ventral, and medial frontal cortical processing. The implication is that antidepressant therapy seems to entail a "bottom up" approach distinguishable from the "top down" effect seen with CBT. These results may help explain why combination treatment with antidepressants and various psychotherapies consistently outperforms monotherapy, particularly in moderate to severe depression.

Another major advance in the study of antidepressant action has been the link between paroxetine and the corticotropin-releasing factor (CRF)/hypothalamic-pituitary-adrenal (HPA) axis. It is well established that a sizeable percentage of patients with depression exhibit HPA axis hyperactivity and hypersecretion of CRF from hypothalamic and extrahypothalamic circuits (Heim and Nemeroff 1999). Early life stress, as exemplified by maternal separation, is associated with profound hyperactivity of the HPA axis and increased CRF messenger RNA (mRNA) expression (Nemeroff 1996; Newport et al. 2002). In adult animals, these effects are reversed by chronic, but not acute, paroxetine treatment. Thus, paroxetine exerts multiple effects on neurotransmitter systems implicated in the pathophysiology of mood and anxiety disorders, including 5-HT, NE, and CRF.

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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