Pedro L. Delgado

The Arizona Sexual Experience Scale (ASEX): Reliability and Validity

Although sexual dysfunction is common in psychiatric patients, quantification of sexual dysfunction is limited by the paucity of validated, user-friendly scales. In order to address this problem, the authors have developed the Arizona Sexual Experiences Scale (ASEX), a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Possible total scores range from 5 to 30, with the higher scores indicating more sexual dysfunction. This study assesses the internal consistency, test-retest reliability, and convergent and discriminant validity of the ASEX.Although sexual dysfunction is common in psychiatric patients, quantification of sexual dysfunction is limited by the paucity of validated,user-friendly scales. Inorder to address this problem,the authors have developed the Arizona Sexual Experiences Scale (ASEX), a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Possible total scores range from 5 to 30, with the higher scores indicating more sexual dysfunction. This study assesses the internal consistency, test-retest reliability, and convergent and discriminant validity of the ASEX.

Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action.

BACKGROUND Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). We have previously reported that rapid TRP depletion more frequently reversed the antidepressant response to monoamine oxidase inhibitors and 5-HT reuptake inhibitors than to desipramine (DMI). This study further investigates the relationship of relapse during TRP depletion to antidepressant type in nonrefractory, depressed patients randomly assigned to treatment with either DMI or fluoxetine (FLU). METHODS Fifty-five drug-free depressed (DSM-III-R) patients were randomly assigned to antidepressant treatment with either DMI or FLU. All patients were either treatment naive (n = 34) or had previously received successful antidepressant treatment (n = 21). During the treatment phase, 35 patients had therapeutic responses by predetermined criteria (DMI 18/25; FLU 17/23) and 30 of these (15 DMI responders and 15 FLU responders) went on to TRP depletion testing. Patients received two 2-day test sessions involving administration of similar amino acid drinks. One session led to rapid TRP depletion and the other did not. Behavioral ratings [Hamilton Depression Scale (HDRS)] and plasma for TRP levels were obtained prior to, during, and after testing. Relapse was defined as a 50% increase in HDRS with total < or = 17. RESULTS Total and free TRP decreased 70% to 80% 5 hours after the TRP-free drink. While 8/15 FLU responders relapsed, only 1/15 of the DMI responders relapsed. No patient experienced significant depressive symptoms during control testing. CONCLUSIONS Rapid depletion of plasma TRP transiently reverses the antidepressant response in many patients on FLU but not DMI. Depressive relapse during TRP depletion appears to be more related to antidepressant type than to patient variables since patients were randomly assigned to the two treatments. Antidepressant response to FLU appears to be more dependent on 5-HT availability than that of DMI, suggesting that antidepressants mediate their therapeutic effects through different mechanisms.

Lithium and serotonin function: implications for the serotonin hypothesis of depression

Lithium enjoys wide clinical use in the treatment of affective disorders, but the mechanism of its action in these conditions is still controversial. Recent studies have shown that lithium can interact with other antidepressant drugs to enhance their efficacy, perhaps by specific effects on serotonin (5-HT) function. A large body of independent evidence suggests that 5-HT function is abnormal in depression. This review documents preclinical evidence of lithiums effects on 5-HT function at the levels of precursor uptake, synthesis, storage, catabolism, release, receptors, and receptor-effector interactions. The weight of this evidence suggests that lithiums primary actions on 5-HT may be presynaptic, with many secondary postsynaptic effects. Studies in humans, using very different methodological approaches, generally suggest that lithium has a net enhancing effect on 5-HT function. These actions of lithium may serve to correct as-yet unspeccified abnormalities of 5-HT function involved in the pathogenesis of depression.

Neuroendocrine and behavioral effects of dietary tryptophan restriction in healthy subjects

The neuroendocrine and behavioral effects of gradual dietary tryptophan (TRP) depletion, utilizing two magnitudes of a 10-day TRP-restriction diet (700 mg/day and 200 mg/day), were studied in 22 healthy subjects. The prolactin response to a 7 gm L-TRP infusion was measured prior to and on day 10 of the diet. Both diets significantly reduced fasting total plasma TRP by 15 to 20%, but only the 200 mg/day TRP diet led to an enhancement of the prolactin response to intravenous L-TRP. Female subjects demonstrated a more robust increase in plasma prolactin following L-TRP infusion pre-diet and exhibited a larger decrease in plasma TRP following dietary TRP restriction compared to males. There were no significant behavioral effects of either diet. Gradual dietary TRP depletion leads to an enhancement of the prolactin response to L-TRP infusion, suggestive of postsynaptic serotonin receptor supersensitivity.

Tryptophan depletion and depressive vulnerability

BACKGROUND Rapid and transient depletion of tryptophan (TRP) causes a brief depressive relapse in most patients successfully treated with and taking selective serotonin reuptake inhibitors, but little change in drug-free, symptomatic depressed patients. This study investigates the effects of TRP depletion in drug-free subjects in clinical remission from a prior major depressive episode (MDE). METHODS Twelve subjects with a prior MDE, currently in clinical remission and drug-free for at least 3 months (patients), and 12 healthy subjects without personal or family history of Axis I disorder (controls), received TRP depletion. The study was conducted in a double-blind, controlled [full (102-g) and quarter-strength (25 g) 15-amino acid drinks], crossover fashion. Behavioral ratings and plasma TRP levels were obtained prior to, during, and after testing. RESULTS All subjects experienced significant depletion of plasma TRP on both test-drinks, showing a significant dose-response relation. Healthy control subjects had minimal mood changes, but patients had a depressive response of greater magnitude. CONCLUSIONS In the context of prior TRP depletion studies with antidepressant-treated, and drug-free symptomatic depressed patients, these results suggest that depression may be caused not by an abnormality of 5-HT function, but by dysfunction of other systems or brain regions modulated by 5-HT.

Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion.

This study investigated the relationship between depressive symptom response during tryptophan (TRP) depletion and a functional polymorphism of the promoter region of the serotonin (5-HT) transporter gene (SLC6A4).1 Forty-three subjects in remission from a major depressive episode who underwent TRP depletion were genotyped. DNA was extracted from blood lymphocytes or from cheek cells.2 The two common alleles are designated long (l) and short (s). Depressive symptoms were measured with the 25-item Hamilton Depression Rating Scale (HDRS).3 There was a significant association between the l homozygous genotype and the depressive response to TRP depletion, with a significant main effect of time (F = 8.763, df = 3, 38, P = <0.001), and time × l homozygous allele interaction (F = 3.676, df = 3, 38, P = 0.02). Individuals whose genotype predicted increased 5-HT transporter activity may be more susceptible to depressive changes in response to transient 5-HT perturbations. The use of endophenotypic markers for affective disorders such as the mood response to TRP depletion may facilitate studies of complex genetic traits such as depression by decreasing its heterogeneity.

Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial

BACKGROUND Enhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide. METHODS This study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events. RESULTS Ten baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinsons, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present. CONCLUSIONS This is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.

Tryptophan depletion and risk of depression relapse: A prospective study of tryptophan depletion as a potential predictor of depressive episodes

BACKGROUND This study investigated the relationship between depressive symptom response during tryptophan depletion and future depressive episodes. METHODS Twelve subjects with prior major depressive episodes in remission and medication-free for > or =3 months (patients), and 12 matched healthy (control) subjects received two tryptophan depletion tests 1 week apart. During follow-up the Hamilton Depression Rating Scale was administered weekly for 1 month, monthly for 3 months, and once at 6 and 12 months. RESULTS With results from both tests, tryptophan depletion has a sensitivity of 78%, specificity of 80%, positive predictive value of 70%, and negative predictive value of 86% to identify future depressive episodes. Survival analysis shows that mood response to tryptophan depletion reliably predicts major depressive episodes during the follow-up year (r =.2725, p =.014). CONCLUSIONS Tryptophan depletion may be clinically useful in identifying individuals at risk for future major depressive episodes.

Plasma d-dimer predicts poor outcome after acute intracerebral hemorrhage

Objective: To investigate if systemic d-dimer activation occurs after acute intracerebral hemorrhage (ICH) and to study its influence on clinical outcome. Methods: The authors determined plasma baseline d-dimer in 98 consecutive acute (<24 hours) ICH patients. Glasgow Coma Scale and NIH Stroke Scale scores were recorded to assess neurologic status on baseline and follow-up visits (24 hours, 48 hours, 7th day, and 3rd month). They also determined the d-dimer temporal profile at follow-up visits in a subgroup of 21 patients. ICH volume was measured on baseline and follow-up CT scans. Early neurologic deterioration (END) and mortality during the 1st week were recorded. Results: ICH patients showed higher plasma d-dimer level than reference laboratory values at baseline (1,780 vs 360 ng/mL; p = 0.013) and 3 months after ICH onset (1,530 vs 470 ng/mL; p = 0.013). The d-dimer level was related to baseline ICH volume (r = 0.23, p = 0.049) and to the presence of intraventricular (2,370 vs 1,360 ng/mL; p = 0.019) or subarachnoid (4,180 vs 1,520 ng/mL; p = 0.001) extension. Nearly one-fourth of patients presented END, and 20% died as a result of ICH. As predictors of END, the authors identified d-dimer level >1,900 ng/mL (odds ratio [OR] 4.5, 95% CI 1.03 to 20.26, p = 0.045) and systolic blood pressure >182 mm Hg (OR 6.8, 95% CI 1.25 to 36.9, p = 0.026). Moreover, ICH volume >30 mL (OR 19.13, 95% CI 2.06 to 177, p = 0.009) and d-dimer levels >1,900 ng/mL (OR 8.75, 95% CI 1.41 to 54.16, p = 0.020) emerged as independent predictors of mortality. Conclusion: Increased plasma d-dimer level following acute intracerebral hemorrhage is associated with early neurologic deterioration and poor outcome.

Efficacy of fluvoxamine in treatment-refractory depression

The efficacy of the potent and selective unicyclic serotonin reuptake inhibitor, fluvoxamine, was evaluated in 38 consecutively admitted depressed patients judged refractory to standard antidepressants using operationalized criteria. Twenty-eight patients completed a single-blind protocol involving greater than or equal to 2 weeks of placebo and 4-6 weeks of active fluvoxamine. Eight (29%) were judged responders to fluvoxamine alone, eight (29%) responded to lithium augmentation of fluvoxamine and two (7%) responded to fluvoxamine, lithium and perphenazine. These data suggest that selective and potent serotonin reuptake inhibitors may be effective in patients refractory to generally available antidepressant medications.