Matthew V. Rudorfer

Antidepressants. A comparative review of the clinical pharmacology and therapeutic use of the 'newer' versus the 'older' drugs.

Supplementing but not supplanting the original series of tricyclic and monoamine oxidase (MAO) inhibitor compounds, a new generation of antidepressant medications has been developed and marketed throughout the past decade. Constituting a more diverse group of drugs than the standard agents, the newer drugs in general have more selective acute biochemical actions (reuptake blockade of a single neurotransmitter, inhibition of 1 subtype of MAO), enabling more precise targeting of symptoms and avoiding common antidepressant-associated side effects, especially anticholinergic and cardiovascular effects. Moreover, a number of recent additions to this group, such as bupropion and ademetionine (S-adenosyl-methionine), incorporate novel mechanisms of action, challenging previous concepts of how antidepressants work, and offering opportunities for research into the pathophysiology of mood disorders. Caution in prescribing the newer antidepressants must be applied, however, as recent experience, e.g. with nomifensine, suggests that unforeseen toxicities may not appear until a medication has been in use for several years.

Metabolism of Tricyclic Antidepressants

Abstract1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression.2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline).3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny.4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds.5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients.6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.

The effects of antidepressants on the cerebrospinal fluid homovanillic acid/5-hydroxyindoleacetic acid ratio.

Dopamine and serotonin systems are morphologically interconnected in the midbrain. Several studies have also demonstrated a functional relationship between these two monoamine systems. Concentrations of their metabolites, 5‐hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA), consistently correlate with one another in human cerebrospinal fluid. Previous studies of the effects of antidepressants on the dopamine and serotonin systems have focused on the two systems in isolation without considering the interactions between the two. One way of taking this interaction into account may be to form a ratio of dopamine and serotonin measures. The present study measured HVA and 5HIAA in cerebrospinal fluid of 31 patients with depression and 12 patients with Alzheimers disease before and after treatment with a variety of antidepressant drugs. The ratio of HVA/5HIAA was able to discriminate much more powerfully between effects of different drugs than HVA or 5HIAA examined separately.

Clinical studies on norepinephrine metabolism: how to interpret the numbers.

Metabolism, synthesis rates, and pharmacokinetics of major metabolites of endogenous norepinephrine were investigated in 38 drug-free depressed patients receiving a low monoamine diet on a closed ward. In a group of 21 patients, plasma and cerebrospinal fluid (CSF) concentrations of 3-methoxy-4-hydroxyphenyl-glycol (MHPG) correlated positively, but not significantly. In two groups of eight patients each, effects of desipramine and zimelidine on the central production rate of MHPG were examined using CSF and urine data. Both desipramine and zimelidine significantly reduced the central production rate of MHPG.

Cognitive effects of lithium treatment in normal volunteers

Patients taking lithium often report difficulties in concentration, memory, learning, and attention and many of these complaints are verified on psychometric testing. Laboratory tests of cognitive functions in healthy volunteers on chronic lithium demonstrate that disruptions in memory-learning processes are apparent at the time of memory retrieval. Subjects, following chronic lithium treatment, produce more errors of commission in remembering previously occurring events while errors of omission appear to be unaffected. These effects are different from those produced by other psychoactive drugs that can also selectively alter and disrupt cognitive processes.

Hypothalamic--pituitary--adrenal axis and monoamine transmitter activity in depression: a pilot study of central and peripheral effects of electroconvulsive therapy.

Central and peripheral measures of hypothalamic--pituitary--adrenal (HPA) axis and monoamine neurotransmitter activity were assessed in 8 depressed patients during a medication-free period and again after completion of a course of electroconvulsive therapy (ECT). Seven patients responded fully to ECT. At baseline there was corresponding activation of the HPA and noradrenergic systems, with apparent elevation in cerebrospinal fluid (CSF) concentrations of corticotropin-releasing hormone (CRH) in some patients. Neither CRH nor adrenocorticotropin (ACTH) in CSF changed significantly after ECT, with a mean 10% decline in CSF CRH. Urinary free cortisol (UFC) excretion was high both before and after treatment. Although peripheral noradrenergic hyperreactivity at baseline appeared to normalize with ECT, CSF concentrations of the principal norepinephrine metabolite, 3-methoxy-4-hydroxyphenyl-glycol (MHPG) were unaffected and remained correlated with CSF CRH. In contrast, there were increases in the CSF levels of the main metabolite of serotonin in half the patients.

Cardiovascular Changes and Plasma Drug Levels after Amitriptyline Overdose

Electrocardiographic and blood pressure parameters in 17 patients after amitriptyline overdose were reviewed in a retrospective study. Seven patients for whom baseline electrocardiograms (EKGs) were available showed significant increases in heart rate and QRS duration after overdose. Ventricular arrhythmias were observed in only one case, the sole fatality, who demonstrated the highest amitriptyline plus nortriptyline plasma level. Most patients experienced sinus tachycardia (88%) and hypotension (53%). Widened PR and QRS after overdose also were common. For the total group, postoverdose TCAD levels correlated with PR (r = .66, p less than .01) and QRS (r = .55, p less than .05) values, and with lowest observed systolic (r = -.60, p = .01) and diastolic blood pressure (r = .50, p less than .05) but not QTc or heart rate. The difference between the mean TCAD levels of subjects with lowest systolic blood pressure less than 100 mmHg and those with higher readings was significant at the 0.05 level.

The effect of clorgyline on noradrenergic function

A low dosage of the specific MAO-A inhibitor clorgyline (5–10 mg/day) was administered chronically to 10 depressed patients. Peripheral noradrenergic activity, as assessed by measurements of the plasma norepinephrine (NE) concentration, heart rate, and blood pressure, was determined before and after drug treatment. The administration of a low dosage of clorgyline was associated with a decrement in peripheral presynaptic noradrenergic activity. Comparison with the results of similar studies of the effects of desmethylimipramine (DMI) suggests that antidepressant drugs with unrelated primary actions affect peripheral noradrenergic functions differently.

Lymphocyte beta adrenergic receptor function versus catecholamines in depression

In human clinical psychobiology, the major focus of studies on nompinephrine (NE) has been on presynaptic biochemical measures; however, it is important to know their postsynaptic correlates. These latter measures derive from studies on blood elements that may provide models for events in other tissues (Motulsky and Insel 1982). For instance, changes in circulating beta-adrenergic receptors relate positively to receptor changes in solid tissue, such as lung and heart (Brodde et al. 1986; Hedberg et al. 1986; Davies et al. 1987). We studied beta-admnergic receptors on lymphocytes that have been shown to be modifiable by changes in noradrenergic function resulting from drug administration (Hedberg et al. 1986) and physiological manipulations, such as exercise (Butler et al. 1983). Furthermore, pathophysiological states, such as steroid exposure (Davies and Lefkowitz 1980), asthma (San0 et al. 1983), hypertension (Feldman et al. 1984a), and aging (Feldman et al. 1984b) show modification of lymphocyte beta-adrenergic function.

Effects of S-adenosyl-methionine on plasma norepinephrine, blood pressure, and heart rate in healthy volunteers

S-adenosyl-methionine (SAMe) is currently undergoing trials as a possible antidepressant. Because SAMes mechanism of action is obscure and norepinephrine (NE) is often implicated in affective disorders, we studied the effects of SAMe on this neurotransmitter in volunteers. Plasma NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the supine and standing position were studied before and after acute placebo or a single 400 mg dose of SAMe and following seven daily administrations; concomitant measures were heart rate (HR) and blood pressure. Subjects were unable to distinguish acute drug from placebo, and although chronic SAMe administration was open, they reported no behavioral effects. Standing HR and plasma NE were reduced following chronic SAMe. Qualitatively similar changes are obtained following chronic treatment with monoamine oxidase inhibitors (MAOIs). However, unlike MAOIs, chronic SAMe treatment was not associated with changes in plasma MHPG. Exaggerated standing NE is found in depressed patients; SAMe may reduce this abnormal response, providing a clue for its mechanism of action in depression.