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...

Neuroanatomy Of The Acetylcholine System

Acetylcholine (ACh) is phylogenetically a very old molecule that is widely distributed in eukaryotic as well as prokaryotic cells. Furthermore, ACh is found in many non-neuronal tissues, in which it appears to modulate basic cellular actions. ACh is formed by the synthesis of acetyl coenzyme A and choline via the enzyme choline acetyltransferase. Acetyl coenzyme A is available from mitochondria, and choline is obtained through the diet. ACh is rapidly inactivated in the synaptic cleft by the...

Physiological Manipulations

Direct administration of naturally occurring neuropeptides, hormones, and cytokines has been used in animal models to identify physiological factors that induce behavioral symptoms of depression in humans. For example, chronic stress levels of cortisol systemically administered to squirrel monkeys impair prefrontal-dependent cognitive control of impulsive behavior (Lyons et al. 2000). Cortisol administered to healthy humans induces prefrontal-dependent cognitive impairments that resemble those...

Anticholinergic Effects

The tricyclics block muscarinic receptors and can cause a variety of anticholinergic side effects, such as dry mouth, constipation, blurred vision, and urinary hesitancy. These effects can precipitate an ocular crisis in patients with narrow-angle glaucoma. The tricyclic and tetracyclic compounds vary substantially in their muscarinic potency (see Table 12-1). Amitriptyline is the most potent, followed by clomipramine. Of the tricyclics, desipramine is the least anticholinergic. Amoxapine and...

Hypothalamicpituitaryadrenal Axis

The HPA axis transforms stressful stimuli into hormonal messages that enable the organism to adapt to environmental change and to maintain the body's homeostasis. Corticotropin-releasing hormone (CRH) is synthesized in the hypothalamus and is stimulated by stressors, which can be either physical (e.g., exercise, starvation) or psychological (e.g., perceived danger, stressful life events). The HPA axis is closely linked to the autonomic nervous system, and brain stem catecholamine systems can...

The BOLD Signal in Functional MRI

Pulsating Bold Response

Functional MRI exploits the fact that deoxyhemoglobin has paramagnetic properties and oxyhemoglobin does not. Deoxyhemoglobin disturbs the local magnetic environment, causing the surrounding protons to dephase even faster than they would otherwise (Figure 10-3). FIGURE 10-3. Schematic diagram of the effect of hemoglobin (Hb) on the local magnetic field of brain tissue. FIGURE 10-3. Schematic diagram of the effect of hemoglobin (Hb) on the local magnetic field of brain tissue. Only...

Indications And Efficacy Depression

Comparison With Other Agents Tricyclic and tetracyclic antidepressants The efficacy of paroxetine in major depression has been established in several randomized, placebo-controlled studies, as well as in studies comparing the effects of paroxetine with those of active comparators, including fluoxetine, TCAs, and other agents. The preponderance of early data with paroxetine in establishing efficacy in depression was in comparison trials with TCAs, particularly imipramine and amitriptyline, and...

Neurotransmitter And Neuropeptide Systems Serotonergic System

Noradrenergic

Largely on the basis of the observation that most current effective antidepressants and antipsychotics target these systems, the monoaminergic systems (e.g., serotonin, norepinephrine, dopamine) have been extensively studied. Serotonin (5-HT) was given that name because of its activity as an endogenous vasoconstrictor in blood serum (Rapport et al. 1947). It was later acknowledged as being the same molecule (secretin) found in the intestinal mucosa and that is secreted by chromaffin cells...

Chronic Stress

Chronic stress models in rodents prevent acclimatization by presenting a variety of stressors in an unpredictable sequence over several weeks. Rats exposed to immobilization, immersion in cold water, and other stressors fail to show the typical increase in open-field activity observed in rats not exposed to chronic stress (Katz et al. 1981). A variety of antidepressants restore normal open-field activity in rats exposed to chronic stress, whereas nonantidepressants do not reproduce this effect...

Model Types And Validity

Two principal types of animal models are prevalent in psychopharmacology. Assay models are used to screen drugs with unknown therapeutic potential and need not resemble anything seen in a psychiatric disorder. The validity of assay models is determined by their ability to predict that a drug reliably belongs to a therapeutic class. In rats, for example, passive avoidance deficits induced by olfactory bulbectomies are reversed by antidepressants but not by psychostimulants, neuroleptics, or...

Premenstrual Dysphoric Disorder

One of the most well-studied mood disorders, with respect to the influence of ovarian steroids on mood, is PMDD. In any studies of this disorder, it is necessary to define carefully the study population and limit both endocrine investigations and treatment to women with clear luteal phase depressive symptoms who are well during the follicular phase many more women report significant variations in mood premenstrually in retrospective reports than are found to have symptoms with prospective...

Conclusion Of Psychopharmacology

Paroxetine has been demonstrated to be an effective treatment for several psychiatric disorders, including major depression and virtually all of the anxiety disorders. It is well tolerated with convenient once-daily dosing and is available in both IR and CR formulations. Most patients can expect symptomatic relief within 4 weeks, and some patients as early as 2 weeks. Concern for pharmacokinetic interactions with other drugs is minimal, although concomitant MAOI use is contraindicated....

Tamya Kolachana

Abkevich V, Camp NJ, Hensel CH, et al Predisposition locus for major depression at chromosome 12q22-12q23.2. Am J Hum Genet 73 1271-1281, 2003 PubMed Altshuler D, Pollara VJ, Cowles CR, et al An SNP map of the human genome generated by reduced representation shotgun sequencing. Nature 407 513-516, 2000 PubMed Altshuler D, Daly MJ, Lander ES Genetic mapping in human disease. Science 322 881-888, 2008 PubMed American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders,...

Medical Safety

Paroxetine treatment in clinical trials has not been associated with any significant abnormalities in standard laboratory tests, including hematological indices and chemistry panels, electroencephalogram (EEG), or electrocardiogram (ECG). One possible concern regarding paroxetine had been the potential for decreased heart rate variability (HRV), because depressed patients have been shown to exhibit lower HRV than nondepressed persons and this decrease represents a significant risk factor for...

Pregnancy and Lactation

One of the most challenging questions faced by patients and health care practitioners in family planning is whether to initiate or continue antidepressant therapy during conception, pregnancy, and the postpartum period. In exploring the risk-benefit analysis, one needs to consider the potential teratogenic risk of exposure of the antidepressant to the infants against the risks to the unborn children of women with untreated depression during pregnancy. Newborns of women with depression have been...

Overdose

Because antidepressants are used for depressed patients who are at risk for overdose, the lethality of antidepressant drugs in overdose is of great concern. A tricyclic overdose of 10 times the total daily dose can be fatal (Gram 1990 Rudorfer and Robins 1982). Death most commonly occurs as a result of cardiac arrhythmia. However, seizures and central nervous system depression can occur. Although the use of tricyclics for the treatment of depression has declined, amitriptyline remains widely...