Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. III. Effect of antidepressants and lithium carbonate.

Serum cortisol levels were significantly increased following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, to patients with affective disorders. A three- to five-week period of treatment with lithium carbonate or monoamine oxidase (MAO) inhibitor augmented the mean 5-HTP-induced increase in serum cortisol concentration in manic or depressed patients, respectively: tricyclic antidepressant (TCA) and second-generation antidepressant treatment diminished the mean serum cortisol response in patients with major depression. These results are consistent with the hypothesis that lithium carbonate may enhance serotonin (5-HT) receptor sensitivity, whereas TCA and second-generation antidepressants diminish 5-HT receptor sensitivity. The enhancement of the cortisol response to 5-HTP by MAO inhibitors may be due to decreased metabolism of 5-HT. It is important to assess the effect of thymoleptic drug treatment on various responses to biogenic amine precursors or agonists in patients rather than laboratory animals.

Bupropion treatment of fluoxetine-resistant chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) includes many symptoms of major depression. For this reason, many antidepressants have been used to treat the symptoms of this disorder. Among the more recently released antidepressants are fluoxetine and bupropion. In this open study, nine CFS patients who either could not tolerate or did not respond to fluoxetine showed significant response when administered 300 mg/day of bupropion for an 8-week period in both rating of HDRS (t = 4.80, p < 0.01) and BDI (t = 2.48, p < 0.05). Furthermore, bupropion improvement in Hamilton Depression Rating Scale correlated significantly with change in plasma homovanillic acid (HVA) (r = 0.96, p < 0.01). Plasma total methylhydroxyphenolglycol (MHPG) also increased significantly during bupropion treatment (t = 2.37, p = 0.05). Measures of T1 microsomal antibodies also decreased over treatment time; increases in natural killer cell numbers correlated inversely with change in plasma levels of free MHPG (r = -0.88, p < 0.05). Bupropion responders were more likely to have trough blood levels above 30 ng/ml (chi 2 = 3.6, p = 0.05).

Amino acid concentrations in cerebrospinal fluid: effects of aging, depression, and probenecid.

Cerebrospinal fluid (CSF) amino acid concentrations were measured in six Bipolar I, eight Bipolar II, eight Unipolar, and four other and control patients. All but four were also studied after administration of probenecid. Fourteen amino acids showed significant correlations of concentrations with age of subjects. Significant diagnostic group differences were found for five amino acids; only that of tyrosine persisted after taking subject's age into account. Following probenecid administration, there were statistically significant changes in CSF concentration of several amino acids, but these changes were small and likely indicative of diurnal changes.

Bupropion slow-release response in depression: diagnosis and biochemistry.

BACKGROUND: Bupropion has been previously shown to be particularly beneficial in bipolar and atypical depression. Previous research has supported a possible association of response to plasma levels and to changes in plasma homovanillic acid (HVA). These findings were here extended to bupropion slow-release (SR), a formulation with slower release kinetics. METHODS: Forty-one patients with major depressive disorder (DSM-III-R) completed 8 weeks of a fixed dose of 300 mg/day in two doses/day. Clinical outcome measures were the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). Biological parameters included plasma HVA and 3-methoxy-4-hydroxyphenyl-glycol (MHPG), as well as a final measurement of plasma bupropion and its metabolites. RESULTS: Response to bupropion SR differed among the three groups: results for change in HDRS and in BDI were greater in the bipolar and atypical than in the "typical" depressed patients. Mean change in HDRS was, respectively, of 15.6, 17.1, and 7.6 (F = 5.57, p < .01); mean change in the BDI, 21.1, 16.9, and 7.3 (F = 3.32, p < .05). Threobupropion levels correlated with HDRS scores (r = .47, p = .02, n = 23); plasma HVA and MHPG increased significantly (t = 2.31, p = .03; t = 2.15, p = .04, n = 17). Bipolar depressed patients' improvement in HDRS was related to increases in MHPG (r = .87, p = .01) and in HVA (r = .70, p = .08). CONCLUSIONS: This fixed-dose study indicates that there may be specific benefits for bupropion SR in atypical and bipolar depression, and that these benefits may be related also to plasma levels and biochemical changes in catecholamines. Due to the small sample size, replication is of key importance.

Lithium elimination half-life and duration of therapy.

The elimination half-life (t1/2E) of lithium carbonate in red blood cells, plasma, and urine was measured in 30 patients hospitalized for primary affective disorder. Duration of Li treatment at time of sampling was found to have a direct effect on lengthening time course. Patients on their initial course of Li had the lowest t1/2s: 1.12 (urine), 1.28 (plasma), and 1.22 days (red blood cells); those less than 1 yr on Li had intermediate values: 1.85, and 1.65, and 1.75 days; and those more than 1 continuous year on Li had the longest mean t1/2s: 2.40, 2.43, and 2.24 days. These results for urine (p less than 0.01) and plasma (p less than 0.05) are further evidence that Li may stimulate the production of an endogenous regulator of Li efflux. This regulator may prove to be an important factor in planning of long-term Li prophylaxis.

Blood levels and acute response to bupropion.

Twenty-three patients with major depressive disorder were treated with bupropion in an open-design protocol. Fifteen (65.2%) of the 23 responded with a more than 50% decrease in scores on the Beck Depression Inventory. Patients with trough blood levels of 10-29 ng/ml had a significantly better response than those with trough levels of 30 ng/ml or more. This preliminary result warrants further, double-blind evaluation.

Plasma lithium level and interepisode functioning in bipolar disorder.

There were no differences in interepisode functioning or side effects between bipolar patients (N = 44) with plasma lithium levels above the median and those with levels below the median. Low levels were able to stabilize mood and individual symptoms for 40.5 months.

Predictors of interepisode symptoms and relapse in affective disorder patients treated with lithium carbonate.

For 98 affective disorder patients receiving lithium prophylaxis for a mean of 45 months, number of interepisode symptoms correlated with relapse rate. Response to prophylaxis appeared highly determined by prelithium frequency of episodes and duration of lithium treatment.

Relation of serum valproate concentration to response in mania.

OBJECTIVE: This study was designed to determine the relation of valproate serum levels to clinical improvement and development of adverse effects in hospitalized patients with acute mania. The initial fixed-dose escalation design, the monotherapy with divalproex, and the control of variables that is possible only with hospitalized patients reduced the confounding factors present in most outpatient studies of serum level-response relationships. METHOD: Sixty-five hospitalized patients who met the Research Diagnostic Criteria for bipolar disorder with mania were treated with divalproex, 750 mg/day for 2 days and then 1,000 mg/day on days 3-5; the dosage was subsequently adjusted as clinically indicated for the remainder of the 21-day study. Manic symptoms were assessed with the Mania Rating Scale, which is derived from the Schedule for Affective Disorders and Schizophrenia. RESULTS: At day 5, patients with serum valproate levels > or = 45 micrograms/ml were two to seven times as likely as patients with levels < 45 micrograms/ml to show 20% or greater improvement in scores on the manic syndrome subscale, the behavior and ideation subscale, elevated mood, increased activity, motor hyperactivity, and psychosis. Endpoint analyses yielded similar results. Adverse experiences characteristic of divalproex treatment were disproportionately associated with serum levels > or = 125 micrograms/ml. CONCLUSIONS: Acutely manic patients treated with divalproex who have valproate serum levels between 45 and 100-125 micrograms/ml are much more likely to have efficacious and well-tolerated responses than patients with lower or higher levels of valproate.

Pharmacokinetic optimisation of therapy with newer antidepressants.

Since the early 1950s, when imipramine was first introduced, a whole series of antidepressants with differences in structures, neurochemical effects and pharmacokinetics have been developed. Structurally or functionally, they have been classified as tricyclic antidepressants (TCAs), tetracyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). In addition, there is a series of antidepressants with unique structures. Many of the newer TCAs appear to have shorter half-lives than the standard TCAs (e.g. imipramine), allowing for the possibility of a more rapid response, but requiring the drugs to be given in multiple daily doses, which may reduce patient compliance. The short time to peak plasma concentration (tmax) can also lead to rapid onset of adverse effects. The tetracyclic antidepressants have longer elimination half-lives (t1/2) than the TCAs, but there is only very minimal evidence for a relationship between drug concentrations in the blood and clinical response. The triazolopyridines, like the newer TCAs, show pharmacokinetic evidence for rapid onset of adverse effects and the need for multiple daily doses due to short tmax and t1/2. The newer MAOIs are a significant addition to therapy, as the rapid binding action of these medications increases their safety margin with regard to tyramine interactions. Further information in this area is required. In addition, moclobemide has pharmacokinetic features that are clinically beneficial (e.g. aging and renal dysfunction have little effect on the elimination of the drug), but also features that are not beneficial (e.g. nonlinear pharmacokinetics). Among the SSRIs, there are a range of t1/2 values for the parent drugs, from relatively short t1/2 values of less than 24 hours (paroxetine, fluvoxamine) to among the longest found (e.g. 2 days for fluoxetine). Only 2 of the agents (sertraline and citalopram) have linear pharmacokinetics, and 1 drug has nonlinear pharmacokinetics within the usual therapeutic range (fluvoxamine). Once a therapeutic blood concentration is established, linearity is helpful in avoiding the small dose changes and repeated rechecking of concentrations of medications that would be required for those agents with nonlinear pharmacokinetics. Sertraline stands out as having the best effects on behaviour among all antidepressants. However, fluoxetine and fluvoxamine are least likely to penetrate into breast milk. All 3 of the structurally unique newer antidepressants [amfebutamone (bupropion), viloxazine venlafaxine] have relatively short tmax values (1 to 2 hours), which may relate to the early onset of adverse effects. Amfebutamone has the benefits of linear pharmacokinetics with potential for defined therapeutic blood concentrations, lack of effect of liver enzymes on metabolism of the drug, and lack of significant effects of either aging or hepatic dysfunction on elimination of the drug. Thus, the antidepressants best suited for pharmacokinetic optimisation of therapy are the following: desipramine, sertraline, fluvoxamine, citalopram and amfebutamone.

Chemotherapy of cognitive disorders in geriatric subjects.

Many of the neurochemical changes associated with aging brain, particularly lower choline acetyltransferase and higher monoamine oxidase, occur with greater severity in senile dementia, Alzheimer's type (SDAT). These alterations correlate with neuropathologic indices, e.g., the number of senile plaques and tangles. Although many different treatment techniques have been used, most have been unsuccessful. No strong data have supported the use of stimulants, Gerovital H3, or hyperbaric oxygen. Among the vasodilators, cyclandelate and hydergine may be of value in some but not most patients. Much recent work has focused on techniques to increase acetylcholine brain concentrations. To date, precursors, such as choline, seem to have very limited value. Postsynaptic treatments, e.g., physostigmine, hold more hope for future benefit, if longer acting oral preparations are developed. Other compounds, such as ACTH, vasopressin, and piracetam, may have some value but need better definition and treatment indications. Recent discoveries on the influences of lecithin on membrane fluidity and receptor binding, may affect the focus of future pharmacologic investigation.

Psychotropic treatment of chronic fatigue syndrome and related disorders.

BACKGROUND: Chronic fatigue syndrome (CFS) and fibromyalgia frequently are associated with symptoms of major depression. For this reason, antidepressants have been used in treatment of these disorders; however, little direction has been provided into this application in psychopharmacology. METHOD: First, nine studies were reviewed regarding the relationship of the symptoms of fatigue and depression. Next, 23 reports (12 double-blind studies, 7 open studies, and 4 case reports) were reviewed for the effectiveness of therapy as assessed by global response and improvement of both depression and pain. Studies were differentiated by type of controls, as well as by alleged mechanism of action of the pharmacologic agent. RESULTS: Disturbances in brain neurochemistry shared by CFS and major depression may serve as a basis for the effectiveness of some antidepressants in CFS. Response to some antidepressants in patients with CFS or fibromyalgia may occur at doses lower than those used in major depression, e.g., amitriptyline 25-75 mg/day. We further found that the more serotonergic treatments (e.g., clomipramine) were more successful in alleviating pain than depression, whereas catecholaminergic agents (e.g., maprotiline, bupropion) seemed particularly effective for symptoms of associated depression. CONCLUSION: To maximize response of the physiologic and psychological consequences of the disorder, more investigation is needed to replicate the apparent findings that relate the neurochemical impairment underlying CFS and fibromyalgia to the type of antidepressant mechanism.

Treatment of depression in patients with diabetes mellitus.

BACKGROUND: Depression occurs frequently in patients with diabetes mellitus. Little has been published on the epidemiology, biochemistry, and treatment of depression in diabetic patients. METHOD: We searched MEDLINE for literature from January 1966 to July 1993 and cross-referenced the terms diabetes, glucose, hyperglycemia, or hypoglycemia, with each of the following: antidepressants, monoamine oxidase inhibitors, tricyclic antidepressants, fluoxetine, paroxetine, sertraline, and bupropion. The results reviewed were 20 papers on epidemiology, 15 papers on neurochemicals and glucose control, and 28 papers on antidepressants and factors of importance to diabetics. Additional papers were selected from the reference lists of the retrieved articles. RESULTS: The prevalence of depression in diabetics varies from 8.5% to 27.3%. Severity of depression correlates strongly with many symptoms of diabetes mellitus. The hydrazine monoamine oxidase inhibitors (MAOIs), e.g., phenelzine, potentiate animal models of hypoglycemia due to direct influence on gluconeogenesis secondary to the hydrazine structure, not to MAOI considerations. Dopamine and norepinephrine influences in these models appear to be hyperglycemic. Serotonergic influences, in the presence of MAOIs, which decrease serotonin metabolism, are in contrast hypoglycemic. Clinically, MAOI use is limited by the possible severity of the induced hypoglycemia, induced weight gain, and required diets. The tricyclic antidepressants may lead to hyperglycemia, to an increase in carbohydrate craving (from 86% to 200%), and impaired memory. Serotonin selective reuptake inhibitors (SSRIs) may be hypoglycemic (causing as much as a 30% decrease in fasting plasma glucose) and anorectic (causing an approximately 2-lb decrease), while possibly improving alertness. CONCLUSION: Depression is frequent among diabetic patients and impairs diabetic management. To maximize response of both depression and diabetic disorder, one should consider the SSRIs in preference over the TCAs.

Mirtazapine in major depression with comorbid generalized anxiety disorder.

BACKGROUND: A high proportion of patients with generalized anxiety disorder (GAD) have comorbid depressive illness. The presence of anxiety in depression has significant prognostic implications. Because of mirtazapine's early anxiolytic effects, the present study was undertaken as a preliminary investigation in patients with a diagnosis of major depression with comorbid GAD. METHOD: Mirtazapine was administered to 10 patients with DSM-IV major depressive disorder and comorbid GAD in an 8-week open-label study. Mirtazapine was increased from an initial daily dose of 15 mg to a maximum daily dose of 45 mg. RESULTS: Patients were found to have significant reductions in Hamilton Rating Scale for Depression scores, Hamilton Rating Scale for Anxiety scores, and Beck Depression Inventory scores, with improvement noted after the first week of therapy and continuing improvement over the 8 weeks of study. CONCLUSION: These positive preliminary findings support the further investigation of mirtazapine's potential value as a treatment for generalized anxiety disorder in addition to its established efficacy as an antidepressant drug.

Pattern analysis of antidepressant response to fluoxetine.

Seventy patients with unipolar major depressive disorder were treated with fluoxetine or placebo in a 6-week double-blind trial and were evaluated by changes in scores on the Hamilton Rating Scale for Depression (HAM-D) and the global improvement measure of the Clinical Global Impressions (CGI) scale. High correlations were found between the changes in HAM-D scores from baseline to endpoint and the final CGI improvement ratings. In patients with moderate depression (baseline HAM-D score of 20 or more), the differences in endpoint analysis between active treatment and placebo groups were significant. A persistent pattern of improvement was noted in 27% of those receiving fluoxetine but in none of those receiving placebo. Physician and patient evaluations as determined by the improvement measure of the CGI were closely correlated.

Treatment of schizoaffective disorders.

Studies that compare the treatment response of patients diagnosed as primary affective disorder or schizoaffective disorder are reviewed. Although relatively few controlled or uncontrolled studies of the chemotherapy of schizoaffective disorders have been conducted, available evidence suggests that: (1) lithium carbonate is effective in the initial treatment of both schizoaffective mania and mania; (2) antidepressants alone, neuroleptics alone, or their combination can be effective in the initial treatment of both schizoaffective depression and primary depression; and (3) prophylactic administration of lithium carbonate may reduce the frequency and duration of relapse in both schizoaffective manic and schizoaffective depressed patients. Thus, treatment studies indicate that the schizoaffective disorders are very similar to the primary affective disorders with regard to response to pharmacologic treatment. Evidence from this laboratory that schizoaffective manic patients respond more slowly than manic patients to lithium or neuroleptic treatment is presented.

Adverse events after the abrupt discontinuation of paroxetine.

Paroxetine is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. In contrast to other SSRIs, it has a relatively short half-life and lacks active metabolites. In three patients the abrupt discontinuation of paroxetine seemed associated with sudden and impairing effects. All three reported marked sleep disturbances and dizziness. They were prescribed the drug for a minimum of 10 weeks, and the maximum dosage was 40 mg/day. All patients experienced rapid remission of symptoms after paroxetine was reintroduced. We failed to observe similar reactions from the abrupt discontinuation at lower dosages. Gradual tapering of the agent for patients receiving more than 20 mg/day is recommended.

Effect of lithium carbonate on serotonin uptake in blood platelets of patients with affective disorders.

Lithium carbonate treatment for 2-3 weeks produced a significant decrease in the maximum velocity (Vmax) of serotonin (5-HT) uptake, a measure of the number of 5-HT uptake sites in blood platelets from bipolar patients. The decrease was more pronounced in bipolar manic patients than bipolar depressed patients. There was no significant affect on the affinity for 5-HT (Km) of the uptake sites in the platelets of manic or depressed bipolar patients although Km did decrease (indicating increased affinity) in the majority of subjects from both groups of patients. However, lithium treatment of at least 1 year duration was associated with significant increases in Vmax without affecting Km. Lithium in vitro, at concentrations up to 1 mM, had no effect on the Km or Vmax of 5-HT uptake in blood platelets of normal controls. The possible mechanisms of the inhibitory and stimulatory effect of lithium carbonate treatment on platelet 5-HT uptake are discussed.

Selective serotonin reuptake inhibitors in affective disorders--I. Basic pharmacology.

The selective serotonin reuptake inhibitors (SSRIs), citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, are the result of rational research to find drugs that were as effective as the tricyclic antidepressants but with fewer safety and tolerability problems. The SSRIs selectively and powerfully inhibit serotonin reuptake and result in a potentiation of serotonergic neurotransmission. The property of potent serotonin reuptake appears to give a broad spectrum of therapeutic activity in depression, anxiety, obsessional and impulse control disorders. However, despite the sharing of the same principal mechanism of action, SSRIs are structurally diverse with clear variations in their pharmacodynamic and pharmacokinetic profiles. The potency for serotonin reuptake inhibition varies amongst this group, as does the selectivity for serotonin relative to noradrenaline and dopamine reuptake inhibition. The relative potency of sertraline for dopamine reuptake inhibition differentiates it pharmacologically from other SSRIs. Affinity for neuroreceptors, such as sigma1, muscarinic and 5-HT2c, also differs widely. Furthermore, the inhibition of nitric oxide synthetase by paroxetine, and possibly other SSRIs, may have significant pharmacodynamic effects. Citalopram and fluoxetine are racemic mixtures of different chiral forms that possess varying pharmacokinetic and pharmacological profiles. Fluoxetine has a long acting and pharmacologically active metabolite. There are important clinical differences among the SSRIs in their pharmacokinetic characteristics. These include differences in their half-lives, linear versus non-linear pharmacokinetics, effect of age on their clearance and their potential to inhibit drug metabolising cytochrome P450 (CYP) isoenzymes. These pharmacological and pharmacokinetic differences underly the increasingly apparent important clinical differences amongst the SSRIs.

Selective serotonin reuptake inhibitors in affective disorders--II. Efficacy and quality of life.

Since their introduction, the selective serotonin reuptake inhibitors (SSRIs) have become one of the most widely used classes of medication in psychiatry. Their popularity is based on apparent efficacy over a wide range of disorders and a favorable side-effect profile. However, as with any psychotropic medication, considerable data are required to define where a drug works and where it does not. There is now a wealth of evidence demonstrating that SSRIs may differ in their efficacy profiles in certain depressive symptoms, in different subtypes of depression, with respect to their ability to maintain efficacy over time, on broader outcomes such as quality of life, and in the consistency of the usually effective minimum therapeutic dose across the age spectrum and across indications. Although this review includes data on all SSRIs, it focuses on fluoxetine and sertraline, which in addition to being the most widely used SSRIs are also the most widely studied. The relative quantity and quality of data on these two SSRIs means that it is possible to make relatively firm inferences regarding their differential effects on affective symptoms and quality of life.