Antidepressants alter cerebrovascular permeability and metabolic rate in primates.

External detection of the annihilation radiation produced by water labeled with oxygen-15 was used to measure cerebrovascular permeability and cerebral blood flow in six rhesus monkeys. Use of oxygen-15 also permitted assessment of cerebral metabolic rate in two of the monkeys. Amitriptyline produced a dose-dependent, reversible increase in permeability at plasma drug concentrations which are therapeutic for depressed patients. At the same concentrations the drug also produced a 20 to 30 percent reduction in cerebral metabolic rate. At higher doses normal autoregulation of cerebral blood flow was suspended, but responsivity to arterial carbon dioxide was normal.

Medical therapies for mood disorders alter the blood-brain barrier.

The effects of amitriptyline, lithium, and electroconvulsive shock on cerebral permeability and blood flow were tested. These three treatments share in common (i) the ability to influence the functional activity of central adrenergic neurons by way of effects on the release, reuptake, or metabolism of norepinephrine and (ii) therapeutic efficacy in mood disturbances. Under control conditions, cerebral permeability increases linealy with increasing arterial partial pressure of carbon dioxide and hence cerebral blood flow. All three treatments altered this relationship in a manner consistent with their adrenergic effects. Amitriptyline potentiated this increase in cerebral permeability whereas lithium and electroconvulsive shock blunted this phenomenon. These results support the hypothesis that one function of central adrenergic neurons is regulation of the blood-brain barrier and raise the possibility that a related effect may underlie the clinical usefulness of such treatment.

Evidence of the dual mechanisms of action of venlafaxine.

BACKGROUND: Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake. METHODS: Healthy male volunteers aged 18 to 45 years received either 75 mg or 375 mg of venlafaxine hydrochloride per day, the 5-HT uptake inhibitor sertraline hydrochloride (50 mg/d), or the NE uptake inhibitor maprotiline hydrochloride (150 mg/d) (n = 8 for each of 4 treatment groups). Changes in platelet 5-HT uptake and the pressor response to intravenous tyramine were assessed following the initial dose and after 1 and 2 weeks of drug administration. RESULTS: Platelet 5-HT uptake was inhibited by venlafaxine across the dose range and by sertraline but not maprotiline. Inhibition was competitive, related to increases in affinity and not related to capacity. Steady-state drug levels were associated with a 5-HT uptake inhibition of 87% or more in subjects taking venlafaxine or sertraline. The pressor response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine. CONCLUSION: This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.

The effect of tricyclic antidepressants on cerebral fluid dynamics.

Tricyclic antidepressants are thought to act primarily via effects on adrenergic neurotransmitters. Recent research supports the concept that a major function of the central adrenergic system is the modulation of cerebral fluid dynamics. Based on this concept, studies in the rat were conducted to assess the effects of these drugs on cerebral capillary permeability and flow by quantitating changes in the extraction fraction of water (Ew). Amitriptyline and nortriptyline produced significant increased in Ew for the total forebrain (from control values of 0.67 to experimental values as high as 0.99) while protriptyline had no effect on Ew. The amitriptyline-induced increase in Ew occurred at doses which produced plasma levels (500 ng/ml) near the range defined as therapeutic in depression studies. The magnitude of the effect was similar for both amitriptyline and nortriptyline representing a 35--40% increase over control values. The effects were uniformly observed throughout the forebrain: rostral telencephalon, caudal telencephalon, and diencephalon.

Amitriptyline normalizes tetrabenazine-induced changes in cerebral microcirculation.

The cerebromicrocirculation in the tetrabenzaine (TBZ) model of depression has been found to be abnormal with respect to (1) responsiveness of cerebral blood flow to increases in arterial CO2 content and (2) the effective permeability of the blood-brain barrier to water. Development of these abnormalities temporally paralleled the behavioral disturbances and catecholamine depletion induced by TBZ. These TBZ-induced changes occurred globally throughout the brain, being apparent in the forebrain, cerebellum, and medulla-pons. Pretreatment with the antidepressant amitriptyline prevented both behavioral and physiological effects of TBZ, whereas amitriptyline administered after TBZ was less effective. The results suggest that an important action of tricyclic antidepressants may be cerebromicrocirculatory effects.

An intravenous technique for the measurement of cerebral vascular extraction fraction in the rat.

An intravenous injection method to measure cerebral vascular extraction fractions of highly diffusible substances in the rat is described. The brain extraction fractions of 3H-labeled water (Ew) and ethanol (Ee) were defined as the ratio of either of those tracers to the freely diffusible reference tracer, 14C-butanol, in the brain, divided by the ratio of the tracers available for the extraction during the time between simultaneous intravenous injection of the tracers and decapitation of the rat. Ew and Ee were measured in five regions of brain, including brainstem and cerebellum, under PaCO2 conditions ranging from 15 to 85 mm Hg. The extraction fractions for both test tracers were shown to vary with PaCO2-induced flow changes according to the equation, ln(1 - E) = -PS/F. When PS/F values calculated from regional measurements of Ew and Ee were plotted versus PaCO2, least squares regression equations of the plots could be used to compare permeabilities of both tracers at any given PaCO2 value. Ratios of the permeabilities of water and ethanol varied regionally but were relatively constant in a given region under different flow states. This intravenous injection method allows for accurate measurement of the extraction fractions of even highly diffusible tracers under varied flow conditions in all brain regions regardless of arterial blood supply.

Fluoxetine impairs clearance of alprazolam but not of clonazepam.

Volunteer male subjects received single 1.0 mg oral doses of alprazolam and of clonazepam on two occasions, during coadministration of 40 mg/day fluoxetine or of placebo. When the sequence of trials was placebo first and fluoxetine second, fluoxetine coadministration significantly prolonged alprazolam half-life (20 versus 17 hours) and reduced clearance (48 versus 61 ml/min). No effect of fluoxetine was seen when fluoxetine was given first and placebo second, because norfluoxetine persisted into the placebo phase even though fluoxetine had been discontinued 2 weeks earlier. Fluoxetine had no significant effects on clonazepam elimination half-life or clearance regardless of the sequence of fluoxetine and placebo administration. In the fluoxetine-placebo sequence, fluoxetine significantly increased the rate of clonazepam absorption. Thus fluoxetine appears to impair clearance of alprazolam by way of microsomal oxidation but does not alter clearance of clonazepam by way of nitroreduction. The very slow elimination of norfluoxetine should be considered in the design of clinical or pharmacokinetic studies that involve fluoxetine.

Tricyclic-antidepressant-induced delirium and plasma drug concentration.

Fourteen patients receiving routine doses of amitriptyline developed plasma drug concentrations above 300 ng/ml. Of the 7 patients with plasma levels above 450 ng/ml, 6 developed a drug-induced delirium as opposed to none of the 7 with levels below 450 ng/ml. Thus, this adverse effect could be avoided by monitoring levels and reducing dosage when appropriate.

Plasma levels of imipramine and adverse effects in children.

In 22 prepubertal depressed children, the total plasma concentration of imipramine and its major metabolite, desipramine, varied by more than sevenfold. The plasma drug concentrations correlated with slowing of intracardiac conduction, elevation of diastolic blood pressure, and increase in heart rate. These drug-induced changes were uniformly observed when the total tricyclic level exceeded 225 ng/ml. However, subjective reporting of nuisance side effects was not related to plasma drug concentration. These findings suggest that children can be safely treated when their plasma levels are below 225 ng/ml. If higher plasma levels are attained, closer monitoring is warranted.

A comparison of the cortisol suppression index and the dexamethasone suppression test in prepubertal children.

Results of the dexamethasone suppression test (DST) and the cortisol suppression index (CSI) were compared in 50 depressed prepubertal children and 36 control subjects. The 4:00 p.m. DST, the two-point DST, and the 8:00 a.m. revised criterion CSI yielded the best results and had similar clinical utility and diagnostic confidence values.

Dexamethasone suppression test and clinical outcome in prepubertal depressed children.

Hospitalized prepubertal depressed children with abnormal dexamethasone suppression test (DST) results were treated and given repeat DSTs at 6 weeks (N = 21) and 5 months (N = 14). DST results were significantly correlated with clinical status at 5 months but not at 6 weeks.

The dexamethasone suppression test in hospitalized prepubertal depressed children.

The dexamethasone suppression test was performed on 20 hospitalized prepubertal children who met DSM-III criteria for major depressive disorder. Fourteen children (70%) did not suppress cortisol secretion at either 8:00 a.m. or 4:00 p.m. The 4:00 p.m. value alone predicted 93% of the nonsuppressors.

Migraine prophylaxis. A comparison of propranolol and amitriptyline.

The comparative efficacy of propranolol and amitriptyline in the prophylaxis of migraine headache was studied in 30 patients in a double-blind, placebo-controlled, crossover design. Headache response to medication was measured monthly by compilation of headache scores derived from quantitative data recorded by patients in a daily diary; at each visit, Zung and Hamilton tests for depression and the Spielberger state test for anxiety were performed. In the absence of clinical toxicity at monthly visits, the decision to maintain the current dose or raise it was made by a computer, which compared current headache score with that of the previous month. Both drugs were superior to placebo. Neither drug was superior to the other. The effectiveness of neither drug correlated with a decrease in anxiety or depression demonstrated by psychological testing.

Bilateral altitudinal anopia caused by infarction of the calcarine cortex.

The patient reported here had a bilateral inferior altitudinal hemianopia from lesions of the calcarine (striate) cortex of the occipital lobes. The only significant pathologic findings were bilateral calcarine artery occlusive disease, with infarcts of the striate cortex on both sides. The ages of the infarcts appeared compatible with the clinical development of the respective visual field defects. The rest of the visual system was anatomically intact.

Recent pharmacologic advances in antidepressant therapy for the elderly.

Major depression is a common, serious, and potentially life-threatening illness in the elderly. Moreover, this population is perhaps the most difficult to treat effectively and safely for this disease. Changes in physiology associated with advancing age produce clinically significant differences in drug metabolism and pharmacokinetics in these patients versus younger individuals. The elderly are also more likely than young patients to receive treatment for multiple illnesses. This fact increases the potential for serious pharmacodynamic and pharmacokinetic drug-drug interactions. The practicing clinician now has five distinct classes of antidepressant medications that may be used for treating depression in the elderly: tricyclic antidepressants (TCAs; e.g., desipramine, nortriptyline), monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, tranylcypromine), selective serotonin reuptake inhibitors (SSRIs; i.e., fluoxetine, sertraline, and paroxetine), aminoketones (i.e., bupropion), and triazolopyridines (i.e., trazodone). Although all are effective antidepressants, the SSRI class may be the best choice for the treatment of elderly depressed patients, based on a number of considerations. SSRIs have a broad spectrum of antidepressant activity, being effective in different types of major depressive episodes (e.g., melancholic, atypical), have a wide therapeutic index, and are free of many potentially serious adverse effects associated with other antidepressants, such as central nervous system and cardiovascular toxicity (TCAs, bupropion), orthostatic hypotension (TCAs, MAOIs, and trazodone), and sedation (TCAs, trazodone). While SSRIs as a group share a common presumed mechanism of action, there are clinically important differences among the members of this class. First, the pharmacokinetics of sertraline are the same in both elderly and younger patients, whereas elderly, in comparison with younger, patients develop higher plasma levels of fluoxetine (and its active metabolite, norfluoxetine) or paroxetine, when given the same dose. Second, the SSRIs differ in their potential for pharmacokinetic interactions with other psychotropic and nonpsychotropic drugs. Fluoxetine, norfluoxetine (the major metabolite of fluoxetine), and paroxetine are potent inhibitors of the hepatic isoenzyme P450 IID6, whereas sertraline has much weaker inhibitory effects on its activity. Inhibition of P450 isoenzymes can cause potentially dangerous increases in the plasma levels of a large number of drugs, including TCAs, neuroleptics, and mood stabilizers, such as carbamazepine. Thus, sertraline has several characteristics that offer advantages over other members of this class of antidepressants for the treatment of the elderly patient with major depression.

Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism.

This paper presents an overview of the clinically relevant pharmacology of selective serotonin reuptake inhibitors (SSRIs) with an emphasis on their pharmacokinetics and effects on cytochrome P450 (CYP) enzymes. The SSRIs are potent inhibitors of the neuronal reuptake pump for serotonin (5-hydroxytryptamine; 5-HT) and have minimal effects on a number of other sites of actions (e.g. neuroreceptors and fast sodium channels). For this reason, drugs in this class have remarkable similarity as regards acute and maintenance antidepressant efficacy and tolerability profile. However, individual members of this class differ substantially in their pharmacokinetics and effects on CYP enzymes. Most SSRIs have a half-life (t1/2) of approximately 1 day. Fluoxetine, however, has a longer t1/2 of 2 to 4 days, and its active metabolite, norfluoxetine, has an extended t1/2 of 7 to 15 days. Fluoxetine, paroxetine and, to a lesser extent, fluvoxamine inhibit their own metabolism. That is not the case for citalopram or sertraline. There are nonlinear increases in paroxetine plasma concentrations with dosage increases, but proportional changes with citalopram and sertraline. Indirect data suggest that fluoxetine and fluvoxamine also have nonlinear pharmacokinetics over their usual dosage range. Age-related increases in plasma drug concentrations for citalopram (approximately 130%) and paroxetine (approximately 50 to 100%) have been observed in healthy elderly (65 to 75 years) persons versus those who are younger. There is an age-gender interaction for sertraline, with its plasma concentrations being 35 to 40% lower in young men than in elderly or young females or elderly males. While there is no apparent change in fluvoxamine plasma levels as a function of age, plasma drug concentrations are 40 to 50% lower in males than in females. Limited data from clinical trials suggest that age-related differences with fluoxetine may be comparable to those of citalopram and paroxetine. Marked differences exist between the SSRIs with regard to effects on specific CYP enzymes and, thus, the likelihood of clinically important pharmacokinetic drug-drug interactions. The most extensive in vitro and in vivo research has been done with fluoxetine, fluvoxamine and sertraline; there has been less with paroxetine and citalopram. The available in vivo data at each drug's usually effective antidepressant dose are summarised below. Citalopram produces mild inhibition of CYP2D6. Fluvoxamine produces inhibition (which would be expected to be clinically meaningful) of two CYP enzymes. CYP1A2 and CYP2C19, and probably a third, CYP3A3/4. Fluoxetine substantially inhibits CYP2D6 and probably CYP2C9/10, moderately inhibits CYP2C19 and mildly inhibits CYP3A3/4. Paroxetine substantially inhibits CYP2D6 but doses not appear to inhibit any other CYP enzyme. Sertraline produces mild inhibition of CYP2D6 but has little, if any, effect on CYP1A2, CYP2C9/10, CYP2C19 or CYP3A3/4. Understanding the similarities and differences in the pharmacology of SSRIs can aid the clinician in optimal use of this important class of antidepressants.

Therapeutic drug monitoring of antidepressants: cost implications and relevance to clinical practice.

Despite evidence to support its potential benefit in clinical practice, therapeutic drug monitoring (TDM) is under-utilised and underdeveloped in the field of psychiatry. In antidepressant pharmacotherapy drug dose is emphasised as the critical treatment variable. However, dose in, and of, itself can be a strikingly misleading predictor of drug concentration and, hence, treatment effect. For antidepressant drugs, plasma concentrations at a given dose have been shown to vary in excess of 40-fold. The clinical relevance of this variability is that at a standard antidepressant dosage only some patients will have tissue drug concentrations associated with an optimal response whereas others will have either low, ineffective drug concentrations or unnecessarily high concentrations which may be poorly tolerated. Among clinicians and healthcare agencies there is an under-appreciation of the degree of pharmacokinetic variability found in patients and how that might impact on the patients response to pharmacotherapy. Hence there is a perception that TDM is an unnecessary, complicated and costly procedure. This is actually unfounded. There are data to suggest that TDM can favourably affect the outcome of antidepressant treatment by providing a rational alternative to the inherently slower, trial and error practice of dosage titration based on clinical response. It is unlikely that TDM will become a standard of care for all antidepressant agents and all patients. Therefore the question becomes for which antidepressant agents, for which patients and under what circumstances, is TDM more cost-effective than traditional dose titration. The use of TDM to optimise the efficient use of selected antidepressant agents could potentially free up healthcare resources to fund other equally deserving treatments. This article provides a discussion of the major classes of antidepressant drugs with regard to their pharmacological features that predict the utility of TDM in clinical practice. Recommendations are made for the practical application of TDM and the directions for further research.

A study of the potential effect of sertraline on the pharmacokinetics and protein binding of tolbutamide.

The effect of the selective serotonin reuptake inhibitor (SSRI) sertraline 200 mg/day on the metabolism of intravenously administered tolbutamide was examined in a randomised nonblinded parallel-group study in 25 healthy male volunteers. There was a small but statistically significant decrease (16%) in the clearance of tolbutamide in patients receiving the maximum recommended dosage of sertraline. The terminal elimination rate constant was also significantly reduced, corresponding to the increase in the terminal elimination half-life (from 6.9 to 8.6 hours). The decrease in clearance was not associated with any significant changes in plasma protein binding or in the apparent volume of distribution of tolbutamide. This suggests that the change in tolbutamide clearance may be due to a slight inhibition of the cytochrome P450 (CYP) isoenzyme CYP2C9/10 when sertraline was administered in its maximum recommended dosage. However, the small changes in the volume of distribution and plasma binding of tolbutamide after sertraline treatment indicate that there is a minimal interaction between sertraline and tolbutamide.

Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers.

A double-blind randomised placebo-controlled study was conducted in healthy male volunteers to determine the effects of sertraline on the pharmacokinetics of diazepam and its primary metabolite, N-demethyldiazepam. The effect of sertraline on the plasma protein binding of diazepam was also studied. Sertraline 50 mg/day titrated over a 10-day period to 200 mg/day or placebo was administered for 32 days. A single intravenous dose of diazepam 10 mg was given before the start, and after 21 days of sertraline or placebo treatment. The pharmacokinetic analyses were based on data from 20 individuals. The systemic clearance of diazepam decreased by 32% (-0.100 ml/min/kg) in the sertraline group compared with a 19% decrease (-0.054 ml/min/kg) in the placebo group (p = 0.0266). However, this small difference (13%) between the 2 groups was not considered meaningful. Other than a prolonged time to maximum plasma concentration for N-demethyldiazepam, no other pharmacokinetic parameters were significantly altered by sertraline. The plasma protein binding of diazepam was unchanged by concomitant administration of sertraline. These results suggest that sertraline at the maximum recommended dosage under steady-state conditions, and demethylsertraline, the principal metabolite of sertraline, are unlikely to exert significant inhibitory effects on the CYP2C19 and CYP3A3/4 hepatic isoenzymes responsible for the metabolism of diazepam. Therefore, it would be expected that sertraline would, similarly, have a minimal effect on the pharmacokinetic profile of other drugs metabolised by these hepatic isoenzymes.

Tricyclic antidepressant plasma level monitoring: an improvement over the dose-response approach.

Monitoring plasma levels of tricyclic antidepressants (TCAs) can facilitate treatment response by providing objective guidelines for dosage adjustment. It provides a means of assessing the patient's compliance and ensuring the maintenance of an adequate medication trial while avoiding the complications of drug toxicity. The traditional dose-response method of medication adjustment depends on several assumptions that are not met in the case of TCAs, which makes plasma monitoring particularly useful for patients receiving most TCAs.