Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects

Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% ( < 0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed ( > 0.05). Fluvoxamine concentrations were 48 +/- 26 ng/mL on week 1 and 83 +/- 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications.     

Short-term treatment of post-traumatic stress disorder with naltrexone: an open-label preliminary study

Eight patients (6 men and 2 women) with chronic post-traumatic stress disorder (PTSD) were treated with naltrexone 100-200 mg/day. Seven patients completed 2 weeks of treatment. A subtle and clinically insignificant improvement was noted in intrusive and hyperarousal symptoms (p < 0.05 for both), but not in avoidance symptoms. All patients demonstrated side effects which limited the targeted dose. It is suggested that the subtle positive effect of naltrexone and the hypersensitivity of these patients to its side effects do not encourage the use of naltrexone in the treatment of PTSD patients.     

Multiple shifts in the representation of a motor sequence during the acquisition of skilled performance

When do learning-related changes in performance occur? Here we show that the knowledge of a sequence of movements evolves through several distinctive phases that depend on two critical factors: the amount of practice as well as the passage of time. Our results show the following. (i) Within a given session, large performance gains constituted a signature for motor novelty. Such gains occurred only for newly introduced conditions irrespective of the absolute level of performance. (ii) A single training session resulted in both immediate but also time-dependent, latent learning hours after the termination of practice. Time in sleep determined the time of expression of these delayed gains. Moreover, the delayed gains were sequence-specific, indicating a qualitative change in the representation of the task within 24 h posttraining. (iii) Prolonged training resulted in additional between-session gains that, unlike the effects of a single training session, were confined to the trained hand. Thus, the effects of multisession training were qualitatively different than the immediate and time-dependent effects of a single session. Altogether, our results indicate multiple time-dependent shifts in the representation of motor experience during the acquisition of skilled performance.     

Dextromethorphan reduces immediate and late postoperative analgesic requirements and improves patients' subjective scorings after epidural lidocaine and general anesthesia

Central N-methyl-D-aspartate receptors modulate postoperative pain. We compared the effects of preincision oral dextromethorphan (DM), an N-methyl-D-aspartate receptor antagonist, on postoperative IV patient-controlled analgesia morphine demand and on subjective variables in 80 patients undergoing lower-body procedures who were randomly assigned to epidural lidocaine (LA; 16 mL, 1.6%) or general anesthesia (GA). The patients were premedicated 90 min before surgery with placebo or DM 90 mg (20 patients per group) in a double-blinded manner. Postoperative IV patient-controlled analgesia morphine administration started when subjective pain intensity was > or =4 of 10 (visual analog scale) and lasted 2 h. Observation continued up to 3 days, during which patients could use diclofenac. LA-DM and GA-DM patients required 45%-50% less morphine and diclofenac compared with their placebo counterparts (P < 0.001). However, GA-DM patients made twice as many attempts to self-administer morphine as LA-DM patients (P = 0.005). Eight LA-DM versus two GA-DM patients (P < 0.01) used no morphine or diclofenac. All DM patients experienced significantly (P < 0.001) less pain, were less sedated, and felt better than their placebo counterparts; however, compared with placebo, DM improved subjective scorings in the GA patients more significantly (P < 0.05) than in the LA patients. We conclude that oral DM 90 mg in patients undergoing surgery under LA or GA reduces morphine and diclofenac use by approximately 50% in the immediate and late postoperative period compared with placebo. Subjectively scored levels of pain, sedation, and well-being were better as well.     

Dextromethorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: a randomized,placebo-controlled,double-blind study

BACKGROUND: Postoperative pain is mediated centrally by N-methyl-D-aspartate (NMDA) receptors. The beneficial effects of preincision oral dextromethorphan (DM), which is an NMDA antagonist, on postoperative pain and intravenous patient-controlled analgesia (IV-PCA) morphine (MO) consumption have been examined in patients undergoing surgery. The authors investigated 75 patients who underwent surgery for bone and soft tissue malignancies, in whom postoperative pain is more severe compared with patients who undergo general surgery. METHODS: Patients received placebo, DM 60 mg, or DM 90 mg (25 patients per group) before surgery and on each of the two following days in a randomized, double-blind, placebo-controlled manner. Postoperative IV-PCA MO was started when subjective pain intensity was >/= 4/10 (visual score) and lasted for 72 hours. Rescue drugs on demand were oral paracetamol or dipyrone. RESULTS: The patients in the DM60 and DM90 groups similarly experienced 50-80% less pain (P < 0.01) compared with patients in the placebo group, both immediately and up to 3 days postoperatively, as well as a 50% reduction in the estimated overall maximal pain intensity (P < 0.01). Both DM groups consumed 50-70% less MO than the nonmedicated individuals in the placebo group (P < 0.01), and their demand for rescue drugs on the first postoperative day also was significantly lower (P < 0.01). Patients in the DM groups also were sedated less ( approximately 70%; P < 0.01). There were no differences among the groups in terms of when the patients left their beds, when they were discharged home, or the number of overall side effects. CONCLUSIONS: DM is associated with reduced pain intensity, sedation, and analgesic requirements, even in patients undergoing surgery for bone and soft tissue malignancies. A 3-day DM administration neither increased the incidence of side effects nor accelerated ambulation and discharge home.     

Cardiogenic shock complicating acute carbon monoxide poisoning despite neurologic and metabolic recovery

We report the cases of 2 previously healthy young patients with acute carbon monoxide intoxication who deteriorated to cardiogenic shock in the face of apparent metabolic and neurologic recovery. Prolonged exposure to sublethal levels of carbon monoxide (>24 hours, carboxyhemoglobin level of 20.4% and 22.6%) and massive binding of the toxin to myocardial myoglobin and mitochondrial cytochrome chain enzymes might explain their protracted cardiac failure. The good response to inotropic agents and the findings of repeated echocardiographic studies support the probable diagnosis of myocardial stunning. Complete cardiac recovery was observed in both patients.     

Combined endovascular and surgical treatment of head and neck paragangliomas--a team approach

BACKGROUND: Paragangliomas are highly vascular tumors of neural crest origin that involve the walls of blood vessels or specific nerves within the head and neck. They may be multicentric, and they are rarely malignant. Surgery is the preferred treatment, and these tumors frequently extend to the skull base. There has been controversy concerning the role of preoperative angiography and embolization of these tumors and the benefits that these procedures offer in the evaluation and management of paragangliomas. METHODS: Forty-seven patients with 53 paragangliomas were treated from the period of 1990-2000. Initial evaluation usually included CT and/or MRI. All patients underwent bilateral carotid angiography, embolization of the tumor nidus, and cerebral angiography to define the patency of the circle of Willis. Carotid occlusion studies were performed with the patient under neuroleptic anesthesia when indicated. The tumors were excised within 48 hours of embolization. RESULTS: Carotid body tumors represented the most common paraganglioma, accounting for 28 tumors (53%). All patients underwent angiography and embolization with six patients (13%), demonstrating complications (three of these patients had embolized tumor involving the affected nerves). Cerebral angiography was performed in 28 patients, and 5 of these patients underwent and tolerated carotid occlusion studies. The range of mean blood loss according to tumor type was 450 to 517 mL. Postoperative cranial nerve dysfunction depended on the tumor type resected. Carotid body tumor surgery frequently required sympathetic chain resection (21%), with jugular and vagal paraganglioma removal frequently resulting in lower cranial nerve resection. These patients required various modes of postoperative rehabilitation, especially vocal cord medialization and swallowing therapy. CONCLUSIONS: The combined endovascular and surgical treatment of paragangliomas is acceptably safe and effective for treating these highly vascular neoplasms. Adequate resection may often require sacrifice of one or more cranial nerves, and appropriate rehabilitation is important in the treatment regimen.     

Characterization of the serotonin transporter in lymphocytes and platelets of schizophrenia patients treated with atypical or typical antipsychotics compared to healthy individuals.

A rapidly growing body of data suggests that abnormalities in serotonergic function might be involved in the pathophysiology of schizophrenia and that serotonergic mechanisms play a role in the therapeutic effects of antipsychotics. The activity of the serotonin transporter (5-HTT), as determined by [(3)H]5-HT uptake to blood lymphocytes, was measured in 38 medicated schizophrenia patients (15 of them treated with typical antipsychotics and 23 treated with atypical antipsychotics) and 15 healthy control subjects. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [(3)H]citalopram binding. There were no significant differences in the density (B(max)) of platelet [(3)H]citalopram binding sites between the three groups. Similarly, the dissociation constant (K(d)) values were indistinguishable. There were no significant differences in the maximal uptake velocity (V(max)) of [(3)H]5-HT to fresh lymphocytes between the three groups. The affinity (K(m)) values of 5-HT to the 5-HTT were significantly higher in schizophrenia patients treated with typical antipsychotics compared with control subjects. The K(m) values in schizophrenia patients treated with atypical antipsychotics were significantly lower compared with those observed in the group of schizophrenia patients treated with typical antipsychotics; however, they were comparable to values in the control group. The high values of K(m) associated with typical antipsychotic treatment may be relevant to the high risk of developing extrapyramidal side effects (EPS). The role of the various components of the serotonergic system in the etiopathology of schizophrenia and the mechanisms by which antipsychotics achieve their therapeutic effects need to be further evaluated.     

Serotonin transporter characteristics in lymphocytes and platelets of male aggressive schizophrenia patients compared to non-aggressive schizophrenia patients

A large body of literature indicates that disturbances of central serotonin (5-HT) function play an important role in aggressive behavior. Results from open-label and placebo-controlled trials as well as the reported inverse relationship between 5-HT function and aggression in human subjects, suggest that reduced 5-HT activity is associated with aggressive behavior. The activity of the 5-HT transporter (5-HTT), as determined by [³H]5-HT uptake to blood lymphocytes, was measured in 20 currently aggressive and 20 non-aggressive male schizophrenia patients. In addition, the pharmacodynamic characteristics of platelet 5-HTT were assessed by [³H]citalopram binding.

There were no significant differences in the density (B_max) of platelet [³H]citalopram binding sites between the two groups. Similarly, the dissociation constant (K_d) values were indistinguishable. The maximum uptake velocity (V_max) of [³H]5-HT to fresh lymphocytes and the K_m values of the 5-HT to the transporter were significantly higher in currently aggressive compared to the non-aggressive schizophrenia patients. The association of high V_max values with current aggressive behavior provides further support to the involvement of the 5-HTT in aggressive behavior as well as to the efficacy of 5-HTT blockers in the control of aggression. The role of the various components of the serotonergic system in the pathophysiology and treatment of aggressive behavior in schizophrenia needs to be further evaluated.