Showing papers in "Journal of Clinical Psychopharmacology in 1996"
TL;DR: The existence of a broad bipolar spectrum between the extremes of psychotic manic-depressive illness and strictly defined unipolar depression is reaffirmed.
Abstract: Based on the author's work and that of collaborators, as well as other contemporaneous research, this article reaffirms the existence of a broad bipolar spectrum between the extremes of psychotic manic-depressive illness and strictly defined unipolar depression. The alternation of mania and melancholia beginning in the juvenile years is one of the most classic descriptions in clinical medicine that has come to us from Greco-Roman times. French alienists in the middle of the nineteenth century and Kraepelin at the turn of that century formalized it into manic-depressive psychosis. In the pre-DSM-III era during the 1960s and 1970s, North American psychiatrists rarely diagnosed the psychotic forms of the disease; now, there is greater recognition that most excited psychoses with a biphasic course, including many with schizo-affective features, belong to the bipolar spectrum. Current data also support Kraepelin's delineation of mixed states, which frequently take on psychotic proportions. However, full syndromal intertwining of depressive and manic states into dysphoric or mixed mania--as emphasized in DSM-IV--is relatively uncommon; depressive symptoms in the midst of mania are more representative of mixed states. DSM-IV also does not formally recognize hypomanic symptomatology that intrudes into major depressive episodes and gives rise to agitated depressive and/or anxious, dysphoric, restless depressions with flight of ideas. Many of these mixed depressive states arise within the setting of an attenuated bipolar spectrum characterized by major depressive episodes and soft signs of bipolarity. DSM-IV conventions are most explicit for the bipolar II subtype with major depressive and clear-cut spontaneous hypomanic episodes; temperamental cyclothymia and hyperthymia receive insufficient recognition as potential factors that could lead to switching from depression to bipolar I disorder and, in vulnerable subjects, to predominantly depressive cycling. In the main, rapid-cycling and mixed states are distinct. Nonetheless, there exist ultrarapid-cycling forms where morose, labile moods with irritable, mixed features constitute patients' habitual self and, for that reason, are often mistaken for "borderline" personality disorder. Clearly, more formal research needs to be conducted in this temperamental interface between more classic bipolar and unipolar disorders. The clinical stakes, however, are such that a narrow concept of bipolar disorder would deprive many patients with lifelong temperamental dysregulation and depressive episodes of the benefits of mood-regulating agents.
510 citations
TL;DR: Reports of withdrawal symptoms in a retrospective chart review of 352 patients treated in an outpatient clinic with the nonselective serotonin reuptake inhibitor clomipramine or with one of the selective SSRIs, fluoxetine, fluvoxamine, paroxettine, or sertraline suggest a role has been suggested for serotonin in coordinating sensory and autonomic function with motor activity.
Abstract: We studied reported withdrawal symptoms in a retrospective chart review of 352 patients treated in an outpatient clinic with the nonselective serotonin reuptake inhibitor clomipramine or with one of the selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, or sertraline. In 171 patients who were supervised during medication tapering and discontinuation, the most common symptoms were dizziness, lethargy, paresthesia, nausea, vivid dreams, irritability, and lowered mood. When patients with at least one qualitatively new symptom were defined as cases, these symptoms occurred significantly more frequently in patients who had been treated either with one of the shorter half-life SSRIs, fluvoxamine or paroxetine (17.2%), or with clomipramine (30.8%), than in patients taking one of the SSRIs with longer half-life metabolites, sertraline or fluoxetine (1.5%). The rate was not significantly different between the different shorter half-life treatments. Cases treated with fluvoxamine or paroxetine had received a significantly longer period of treatment (median 28 weeks) than noncases (16 weeks), but there were no significant associations with age or with diagnostic grouping. There was a trend toward an association with male sex. The majority of cases occurred despite slowly tapered withdrawal. Symptoms persisted for up to 21 days (mean = 11.8 days) after onset. These symptoms were relieved within 24 hours by restarting the medication, but were not relieved by benzodiazepines or by moclobemide. A role has been suggested for serotonin in coordinating sensory and autonomic function with motor activity. We suggest that this may lead to useful hypotheses about the pathophysiology of withdrawal symptoms from serotonin reuptake inhibitors.
268 citations
TL;DR: Treatment with ICI 204,636 was well tolerated, although it was associated with mild transient increases in alanine aminotransferase and a higher incidence of somnolence and anticholinergic effects compared with placebo, and preclinical predictions that ICi 204, 636 is an atypical antipsychotic were confirmed.
Abstract: ICI 204,636 is a new, potentially atypical antipsychotic. In early phase II trials, the antipsychotic was well tolerated and results suggested efficacy in the treatment of the positive and negative symptoms of schizophrenia. The efficacy and safety of ICI 204,636 were evaluated on a larger scale in a 6-week, multicenter, double-blind trial. Hospitalized patients who met DSM-III-R criteria for chronic or subchronic schizophrenia with acute exacerbation, as well as other criteria, were randomized to ICI 204,636 (75 to 750 mg daily) (N = 54) or placebo (N = 55). Patients were assessed weekly by use of the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression Scale (CGI) for efficacy and the Simpson Scale and Abnormal Involuntary Movement Scale for extrapyramidal side effects (EPS). Significant differences (p < or = 0.05) between treatment groups, which favored ICI 204,636, were identified throughout the trial. Endpoint differences were significant (by analysis of covariance) for BPRS factor IV (activation) and SANS scores and were marginally significant for total BPRS, BPRS factor III (thought disturbance), BPRS positive-symptom cluster, and CGI Severity of Illness item scores (p = 0.07, 0.09, 0.06, and 0.09, respectively). ICI 204,636 was well tolerated, although it was associated with mild transient increases in alanine aminotransferase and a higher incidence of somnolence and anticholinergic effects compared with placebo. In the dose range studied, treatment with ICI 204,636 did not induce EPS as determined by analysis of Simpson Scale total scores and lack of treatment-emergent acute dystonic reactions. Furthermore, ICI 204,636 did not produce sustained levels of prolactin; the mean change from baseline at endpoint (-7.2 micrograms/L) was comparable (p = 0.44) to that for placebo (-8.2 micrograms/L). These findings distinguish ICI 204,636 from standard antipsychotics and confirm preclinical predictions that ICI 204,636 is an atypical antipsychotic.
268 citations
TL;DR: Assessment of rectal temperature, blood cell counts, and cytokine and soluble cytokine receptor plasma levels during 6 weeks of clozapine treatment in 27 schizophrenic patients concluded that clozAPine has consistent in vivo immunomodulatory effects.
Abstract: The antipsychotic drug clozapine frequently induces fever during the first weeks of administration. In addition, it has been shown that clozapine increases plasma soluble interleukin-2 receptor (sIL-2r) levels as early as 1 week after treatment is started. These findings suggest that clozapine has immunomodulatory effects. To investigate this issue in more detail, we assessed the time course of rectal temperature, blood cell counts, and cytokine and soluble cytokine receptor plasma levels during 6 weeks of clozapine treatment in 27 schizophrenic patients. Clozapine increased the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, and sIL-2r. These increases were independent of prior or concurrent medication and did also occur in patients who did not experience clozapine-induced fever. However, increases in TNF-alpha and sIL-2r levels were more pronounced in patients with clozapine-induced fever who showed in addition increased plasma IL-6 levels and granulocyte counts. Plasma IL-1 receptor antagonist levels and monocyte and lymphocyte counts were not affected by clozapine treatment. It is concluded that clozapine has consistent in vivo immunomodulatory effects. The results presented suggest that clozapine-induced fever is mediated by pyrogenic cytokines.
224 citations
TL;DR: It can be concluded that Li addition to CIT is effective in patients not responding to C IT alone without any evidence of an accentuation or provocation of adverse events.
Abstract: Sixty-nine depressive patients (DSM III criteria: 296.2, 296.3, 296.5, 300.4) were treated with 40 to 60 mg citalopram (CIT) daily for 4 weeks. Among them, 45 responded to treatment (improvement > 50% on the 21-item Hamilton Rating Scale for Depression [HAM-D]) and continued their treatment for another week before being released from the study. The 24 nonresponders were randomized and comedicated under double-blind conditions with lithium carbonate (Li) (2 x 400 mg/day) (CIT-Li group) or with placebo (CIT-Pl group) from days 29 to 35. For days 36 to 42, the patients of both subgroups were treated openly with Li (800 mg/day) in addition to the ongoing CIT treatment. On day 35, 6 of 10 patients responded to the CIT-Li combination, whereas 2 of 14 patients only responded to the CIT-Pl combination. This group difference reached significance (p < 0.05) on day 35 with lower HAM-D total scores in the CIT-Li group. No evidence was seen of a pharmacokinetic interaction between CIT and Li, and this combination was well tolerated. Patients were phenotyped with dextromethorphan and mephenytoin at baseline and at day 28. As evaluated at baseline, three patients (responders) were poor metabolizers of dextromethorphan and six patients (three responders and three nonresponders) of mephenytoin. On day 28, the ratio CIT/N-desmethylCIT (DCIT) in plasma was significantly higher in poor than in extensive metabolizers of mephenytoin (p = 0.0001), and there was a significant positive correlation between the metabolic ratio of dextromethorphan and the ratio DCIT/N-didesmethylCIT in plasma (p < 0.001). These findings illustrate the role of CYP2D6 and CYP2C19 in the metabolism of CIT. It can be concluded that Li addition to CIT is effective in patients not responding to CIT alone without any evidence of an accentuation or provocation of adverse events.
168 citations
TL;DR: Patients in both medication groups showed significant and substantial improvements over time in areas of psychosocial functioning, as assessed by the Addiction Severity Index, rates of urinalysis tests positive for opioids, and self-reports of opioid withdrawal symptoms, illicit opioid use, and cocaine use.
Abstract: This article reports results for patients who completed the 16-week maintenance phase of a double-blind clinical trial comparing buprenorphine (N = 43; average dose = 9.0 mg/day sublingually) with methadone (N = 43; average dose = 54 mg/day orally) in the outpatient treatment of opioid dependence. In addition to pharmacotherapy, treatment during the clinical trial included individual counseling, weekly group therapy, and on-site medical services. Patients in both medication groups showed significant and substantial improvements over time in areas of psychosocial functioning, as assessed by the Addiction Severity Index, rates of urinalysis tests positive for opioids, and self-reports of opioid withdrawal symptoms, illicit opioid use, and cocaine use. Buprenorphine and methadone produced very similar outcomes on the wide array of outcome measures assessed, and improvements for both groups were large and occurred rapidly after treatment entry. A trend toward continued improvement in opioid-positive urines over time was noted for the buprenorphine but not the methadone group. These results provide further evidence of the efficacy of buprenorphine in the treatment of opioid dependence and provide a characterization of the time course of effects for buprenorphine and methadone. In addition, these results demonstrate the benefits of drug abuse treatment, both for drug and alcohol use and in other areas of psychosocial functioning. (J Clin Psychopharmacol 1996;16:58-67).
141 citations
TL;DR: It is suggested that relapse rates are high if medication is discontinued early and that further study is needed to determine (1) the optimal duration of maintenance pharmacotherapy for social phobia and (2) if specific psychotherapeutic interventions before medication discontinuation may prevent relapse.
Abstract: We conducted an 11-week forced-escalation open-label study of paroxetine in the treatment of 36 patients with generalized social phobia. At the mean dosage of 47.9 +/- 6.2 mg/day, 23 of 30 completers (77%) were deemed responders on the basis of a clinician rating of either "very much improved" or "much improved" on the Clinical Global Impressions scale. Duke Social Phobia Scale ratings declined from 35.5 +/- 13.1 at baseline to 19.7 +/- 17.4 at week 11 (p < 0.0005), and Liebowitz Social Anxiety Scale ratings declined from 75.1 +/- 25.4 at baseline to 37.2 +/- 32.5 at week 11 (p < 0.0005). Sixteen responders were randomized to an additional 12 weeks of either paroxetine (with no dosage change) or placebo (after a taper period) on a double-blind basis. To the best of our knowledge, this is the first controlled medication-discontinuation study in social phobia. One of eight patients randomized to continue paroxetine relapsed versus five of eight patients randomized to placebo. These findings call for a double-blind, placebo-controlled treatment study of paroxetine in generalized social phobia. They also suggest that relapse rates are high if medication is discontinued early and that further study is needed to determine (1) the optimal duration of maintenance pharmacotherapy for social phobia and (2) if specific psychotherapeutic interventions before medication discontinuation may prevent relapse.
137 citations
TL;DR: Clinical information about 11 patients who developed mania during treatment with SRIs, found to have personal or family histories of hypomania or mania, but these disorders were not usually recognized at the time of the patients' initial treatment for depression.
Abstract: Serotonin reuptake inhibitors (SRIs) are now considered the first-line treatment for depression, but they have not been well studied in bipolar disorder. Recently, some authors have recommended that patients at risk for antidepressant-induced mania be treated with SRIs rather than tricyclic antidepressants (TCAs). Clinical information about 11 patients who developed mania during treatment with SRIs is described. These patients were found to have personal or family histories of hypomania or mania, but these disorders were not usually recognized at the time of the patients' initial treatment for depression. The SRI-induced manic episodes were also quite severe, having psychotic features or requiring patients to be secluded for extreme agitation, but patients responded completely to antimanic treatment. The risk of treatment-emergent mania with SRIs is not trivial, especially among patients at risk for bipolar disorder. Additional research is needed to compare the actual rate of drug-induced mania with SRIs and TCAs in patients with different bipolar subtypes, while controlling for concurrent antimanic drug use.
129 citations
TL;DR: Planned pharmacokinetic drug interactions at the level of P450s have been proposed to reduce cyclosporine dosage requirements, to reduce variability of TCA levels, and to manipulate the contribution of alternative metabolic pathways to minimize toxic effects.
Abstract: The SSRIs have been used as an example to show how one might interpret the available evidence to draw conclusions about the relationships between drugs and P450s. Under what circumstances might one apply the knowledge of such relationships? First, the clinical implications must be considered when drugs with a narrow therapeutic index are coprescribed with other drugs that may affect P450s. For example, good clinical practice demands that before a TCA is coprescribed with another drug, the physician be aware of the potential for the second drug to interact with CYP2D6. Second, it may be helpful to consider P450 enzymes when adverse events occur during polypharmacy. It may happen that a known side effect of one drug occurs. Rather than attributing this to patient sensitivity, the physician should consider the possibility that a pharmacokinetic drug interaction increased plasma drug concentration, which in turn enhanced the probability of such an occurrence. Even when a pharmacokinetic drug interaction is considered as a possible cause, an appreciation of the role of P450s may lead to the realization that an interaction was not only possible but that it was likely. Finally, copharmacy can be used intentionally to produce controlled interactions. Indeed, planned pharmacokinetic drug interactions at the level of P450s have been proposed to reduce cyclosporine dosage requirements, to reduce variability of TCA levels, and to manipulate the contribution of alternative metabolic pathways to minimize toxic effects. As long as pharmaceuticals are metabolized by the P450 system, interactions with the various isozymes will be inescapable. It is fortunate that understanding them is becoming more tractable.
123 citations
TL;DR: R risperidone is an effective antipsychotic and anxiolytic agent in schizophrenic patients and clinical improvement, defined a priori as a 20% reduction in total Positive and Negative Syndrome Scale scores at end point, was attained.
Abstract: The subjects were 62 patients hospitalized for acute exacerbations of schizophrenia and were randomly assigned to receive risperidone (mean dose, 7.4 mg/day), haloperidol (7.6 mg/day), or methotrimeprazine (100 mg/day) for 4 weeks. Clinical improvement, defined a priori as a 20% reduction in total Positive and Negative Syndrome Scale (PANSS) scores at end point, was attained by 81% of the risperidone patients, 60% of the haloperidol patients, and 52% of the methotrimeprazine patients (p < 0.05). The reductions in total PANSS and Clinical Global Impression Scale severity scores from baseline to end point were significantly greater in the risperidone patients than in the other two groups. Reductions in scores on the Psychotic Anxiety Scale were significantly greater in the risperidone patients than the methotrimeprazine patients; the difference between haloperidol and methotrimeprazine was not significant. Extrapyramidal symptoms (scores on the Extrapyramidal Symptom Rating Scale) were more severe in the haloperidol patients than in the other two groups, but few differences were apparent between risperidone and methotrimeprazine patients. It is concluded that risperidone is an effective antipsychotic and anxiolytic agent in schizophrenic patients.
115 citations
TL;DR: The tolerability and safety profiles of venlafaxine were similar to those previously reported for selective serotonin reuptake inhibitors and in the elderly did not differ significantly from that observed in younger patients.
Abstract: The tolerability and safety of venlafaxine hydrochloride, a new serotonin and norepinephrine reuptake inhibitor, are reviewed in this article. The data presented here are based on a pool of 3,082 patients who were treated with this agent during clinical trials. Of these patients, 2,897 received venlafaxine for depression; 455 of these patients were treated for more than 360 days. The tolerability and safety profiles of venlafaxine were similar to those previously reported for selective serotonin reuptake inhibitors. Patients receiving venlafaxine experienced nausea, insomnia, dizziness, somnolence, constipation, and sweating more often than did patients receiving placebo but reported anticholinergic events less frequently than did patients receiving tricyclics. This is accounted for by the fact that, unlike the tricyclics, venlafaxine lacks significant affinity for muscarinic cholinergic receptors. Resolution of venlafaxine-associated nausea occurred rapidly in the vast majority of the patients who reported it at the start of therapy. Serious adverse events were rare among venlafaxine-treated patients. A small percentage of the patients given venlafaxine experienced modest but significant increases in blood-pressure readings, similar to those observed among imipramine-treated patients. At mean daily venlafaxine dosages of up to 300 mg, the percentage of venlafaxine-treated patients who had sustained elevations in supine diastolic blood pressure during treatment ranged from 2% to 6%, compared with 2% and 5% among the placebo- and imipramine-treated patients, respectively. All of the 14 patients who took an overdose of venlafaxine recovered without sequelae. Tolerability and safety in the elderly did not differ significantly from that observed in younger patients.
TL;DR: It is demonstrated that late-afternoon ethanol intake in middle-aged men disrupts sleep consolidation, affects the sleep stage distribution, and alters the sleep EEG.
Abstract: The effect of a moderate dose of ethanol (0.55 g/kg of body weight), administered 6 hours before scheduled bedtime, on performance, nocturnal sleep, and the sleep electroencephalogram (EEG) was investigated in 10 healthy, middle-aged men (mean age: 61.6 +/- 0.9 years). By the beginning of the sleep episode, breath-ethanol concentrations had declined to zero in all subjects. Compared with the control condition (mineral water), sleep was perceived as more superficial. Sleep efficiency, total sleep time, stage 1, and rapid eye movement (REM) sleep were reduced. In the second half of the sleep episode, wakefulness exhibited a twofold increase. EEG power density in low delta frequencies was enhanced in non-REM sleep (1.25-2.5 Hz) and REM sleep (1.25-1.5 Hz). In slow wave sleep (i.e., stages 3 + 4), power density was increased not only in the low-frequency range (1.25-1.5, 2.25-4.0, 4.75-5.0 Hz) but also within the alpha (8.25-9.0 Hz) and sigma (12.25-13.0 Hz) band. The data demonstrate that late-afternoon ethanol intake in middle-aged men disrupts sleep consolidation, affects the sleep stage distribution, and alters the sleep EEG.
TL;DR: The synaptic effects of marketed antidepressant agents are reviewed to elucidate the anticipated side effects and drug-interaction potential of these agents.
Abstract: Catecholamines, especially norepinephrine (NE) and serotonin (5-hydroxytryptamine [5-HT]), have been implicated in the pathophysiology of depression. However, their exact roles and their interrelationship are not completely understood. Antidepressants have various effects on the body, including action at the neuronal synapses of the brain; the two most important of these effects are blockade of the reuptake of neurotransmitters, including NE, 5-HT, and dopamine, and blockade of certain neurotransmitter receptors. Currently available antidepressants may be classified as inhibitors of monoamine oxidase or as blockers of biogenic amine neurotransmitter reuptake, the latter best describing tricyclic antidepressants and selective 5-HT-reuptake inhibitors, because they block the reuptake of one or more neurotransmitters. However, recently introduced antidepressants, such as the 5-HT-NE-reuptake inhibitors, have synaptic effects that differ from those of older compounds. These synaptic effects are important in explaining certain side effects and drug-drug interactions associated with all classes of antidepresants. This article reviews the synaptic effects of marketed antidepressant agents to elucidate the anticipated side effects and drug-interaction potential of these agents.
TL;DR: Recommendations for treatment strategies based on the phase and stage of the illness are organized into algorithms that emphasize the use of mood-stabilizing medications as initial steps in a systematic, iterative approach to treatment.
Abstract: The chronic, complex, and episodic course of bipolar mood disorder presents a formidable challenge to the clinician making a treatment plan. Although numerous therapeutic agents are reported to be efficacious for one or more aspects of bipolar illness, treatment is seldom completely effective and is never curative. The goal of treatment is to modify the symptomatic expression of the illness with the result that fewer, briefer, and milder episodes occur. In pursuit of this goal, the use of multiple medications, polypharmacy, is the rule rather than the exception. This article offers recommendations for treatment strategies based on the phase and stage of the illness. The strategies are organized into algorithms that emphasize the use of mood-stabilizing medications as initial steps in a systematic, iterative approach to treatment. Practical issues related to the use of mood-stabilizing therapies are discussed.
TL;DR: The current clinical pharmacokinetic database for these atypical antipsychotics suggests that much can be learned with additional study that would be of value in individualizing their dosage regimens.
Abstract: The current literature describing the pharmacokinetics of the atypical antipsychotics clozapine and risperidone is reviewed, and discussion on the clinical significance of these data is presented. These drugs are well absorbed when taken orally but are poorly bioavailable because of presystemic elimination. They are highly cleared by hepatic metabolism involving specific P450 isozymes. Risperidone elimination produces a potent active metabolite. Neither of the drugs has received extensive study related to drug-drug interactions, but several are potentially important because a purported therapeutic plasma concentration range is proposed for clozapine and a possible curvilinear dose response relationship has been reported for risperidone. The current clinical pharmacokinetic database for these atypical antipsychotics suggests that much can be learned with additional study that would be of value in individualizing their dosage regimens.
TL;DR: An overview of clinical presentations that predict general and differential response to mood stabilizers is provided and the only predictors that seem to differentially favor divalproex, and possible, carbamazepine over lithium are mixed states and rapid cycling.
Abstract: Although lithium remains the preferred treatment of bipolar disorder, only 60 to 80% of patients with the classic presentation have an adequate response to this drug. When the response rate to lithium is considered across the entire spectrum of bipolar disorders, this rate probably decreases to 50%. Natural history, illness subtype, and comorbidity are all important general predictors of response to treatment. At present, the only predictors that seem to differentially favor divalproex, and possible, carbamazepine over lithium are mixed states and rapid cycling. An overview of clinical presentations that predict general and differential response to mood stabilizers is provided.
TL;DR: In this study, fluvoxamine and clomipramine were equally effective in reducing OCD symptoms over a 10-week treatment period but displayed different side effect profiles.
Abstract: The efficacy and tolerability of fluvoxamine (100-300 mg/day) and clomipramine (100-250 mg/day) were compared in a randomized, double-blind, parallel-group study of 79 patients with obsessive-compulsive disorder (OCD) without coexisting major depression. After a 2-week placebo lead-in period, patients were randomized to fluvoxamine (37 patients) or clomipramine (42 patients) for 10 weeks. Efficacy was evaluated with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the National Institute of Mental Health Obsessive-Compulsive scale, and Patient and Clinical Global Improvement scales. Hamilton Rating Scale for Depression scores and somatic symptoms were also assessed. Seventy-eight percent of fluvoxamine patients and 64% of clomipramine patients completed the study. At the end of treatment, 56% of fluvoxamine patients were classified as responders (> or = 25% decrease in Y-BOCS score), compared with 54% of clomipramine patients. Both groups showed steady improvement throughout the study; no statistically significant differences were observed between the groups for any efficacy variable at any time. A similar percentage of patients in both groups withdrew because of adverse events. No serious adverse events related to drug occurred with either drug. Insomnia, nervousness, and dyspepsia were more statistically frequent with fluvoxamine; dry mouth and postural hypotension were more frequent with clomipramine. In this study, fluvoxamine and clomipramine were equally effective in reducing OCD symptoms over a 10-week treatment period but displayed different side effect profiles.
TL;DR: In vitro and in vivo data indicate that venlafaxine either does not significantly inhibit or weakly inhibits the activity of isoenzymes CYP2C9, CYD2D6, CYP1A2, or CYP3A3/4, which is a major role in the metabolism of many commonly used drugs.
Abstract: Selection of an antidepressant is influenced by many factors, including the patient's current drug regimen and the drug's potential for drug-drug interactions. Many psychotropic agents are known to be involved in drug-drug interactions because they are metabolized by various cytochrome pigment 450 (CYP) isoenzymes. In vitro testing with human hepatic microsomal preparations and monoclonal antibody techniques has allowed for the identification and investigation of many of these isoenzymes. Also, screening of substrates (both drug and probe) at the level of the various enzymes expressed in the human liver has allowed for the development of models that predict the risk for drug-drug interactions in vivo. Antidepressants are metabolized by and are competitive inhibitors of several isoenzymes: CYP1A2, CYP2D6, CYP3A3/4, CYP2C8/9, CYP2C19, and others. Of these, CYP2D6 has been the most thoroughly investigated and is the most extensively characterized, whereas CYP3A3/4 are more abundant and play a major role in the metabolism of many commonly used drugs. CYP2D6, but not CYP3A3/4, is subject to genetic polymorphism, which has been identified through the administration of a probe drug (sparteine, debrisoquin, or dextromethorphan). This analysis allows for the determination of an individual's "metabolizer status." This article discusses the CYP isoenzyme system in general terms and presents selected in vitro information that has been used to determine the likelihood of in vivo drug-drug interactions with various antidepressants. Of the marketed antidepressants, venlafaxine seems to have one of the most favorable drug-interaction profiles, and data specific to it are highlighted. In vitro and in vivo data indicate that venlafaxine either does not significantly inhibit or weakly inhibits the activity of isoenzymes CYP2C9, CYP2D6, CYP1A2, or CYP3A3/4.
TL;DR: Preliminary data suggest that trazodone may be effective in reducing the three primary clusters of symptoms of PTSD, and should be confirmed by using a larger sample in a double-blind, placebo-controlled study.
Abstract: Six patients with combat-related posttraumatic stress disorder (PTSD) entered a multiple-baseline trial of trazodone, beginning with 50 mg/day and increasing to 400 mg/day until response was maximal. Total Clinician-Administered PTSD Scale scores decreased from a mean of 92 at baseline to 79 at end point, and self-reported PTSD symptoms as measured by the Davidson Trauma Scale paralleled these results (mean of 102 at baseline to 88 at end point). Based on clinician global improvement scores, four patients were rated as much improved and two were rated to be minimally improved. Improvement in social and occupational functioning, and depression was minimal. Available follow-up scores for PTSD symptoms indicated that gains were maintained. Sleep was the first symptom to improve at 2 to 3 months. No dropouts during the treatment period occurred, and reported side effects were quite low. These preliminary data suggest that trazodone may be effective in reducing the three primary clusters of symptoms of PTSD. These findings should be confirmed by using a larger sample in a double-blind, placebo-controlled study.
TL;DR: Zolpidem, triazolam, and temazepam produced orderly dose- and time-related impairment of learning, recall, and performance, and increased subject- and observer-rated estimates of strength of drug effect.
Abstract: Zolpidem is an imidazopyridine hypnotic that is biochemically distinct from classic benzodiazepine agonists in that it may be selective for the BZ1 receptor subtype and shows a different pattern of distribution of binding sites. The present study compared the learning, recall, performance, subject-rated and observer-rated effects of zolpidem, triazolam, and temazepam in 11 healthy humans. Placebo, zolpidem (5, 10, and 20 mg/70 kg), triazolam (0.125, 0.25, and 0.50 mg/70 kg), and temazepam (15, 30, and 60 mg/70 kg) were administered orally in a randomized, double-blind, cross-over design. Zolpidem, triazolam, and temazepam produced orderly dose- and time-related impairment of learning, recall, and performance, and increased subject- and observer-rated estimates of strength of drug effect. The absolute magnitude of these effects at peak effect were comparable across the three compounds. The time to maximal drug effect was faster with zolpidem (0.5-1.0 hours) than with triazolam (1.5-2.0 hours) or temazepam (2-3 hours). These results suggest that despite the somewhat unique benzodiazepine receptor-binding profile of zolpidem, its behavioral and subject-rated effects are similar to those of benzodiazepine hypnotics (i.e., triazolam and temazepam).
TL;DR: In a double-blind, placebo-controlled study of 72 patients with bulimia nervosa treated successfully with inpatient psychotherapy, the efficacy of fluvoxamine in maintaining improvement was tested as discussed by the authors.
Abstract: In a double-blind, placebo-controlled study of 72 patients with bulimia nervosa treated successfully with inpatient psychotherapy, the efficacy of fluvoxamine in maintaining improvement was tested. Fluvoxamine and placebo, respectively, were given over a period of about 15 weeks (2-3 weeks inpatient titration phase, 12 weeks outpatient relapse-prevention [maintenance] phase). The variables assessed concerned bulimic behavior and other aspects of eating disorders, global status, depression, anxieties, obsessive-compulsive behavior, and other aspects of psychopathology. Because the dropout rate was relatively high (N = 27 [33%]) and because it was considerably higher in the fluvoxamine group (19 out of 37 subjects), analyses were performed on the intent-to-treat sample (ideally including all 72 subjects). Results of the completer sample analyses (including only those subjects who finished the study) are briefly presented for comparison. In both the intent-to-treat and the completer analyses, the following scales showed fluvoxamine to have a significant effect in reducing the return of bulimic behavior: (1) self-ratings: Eating Disorder Inventory (EDI)-bulimia, urges to binge in previous week and the number of actual binges in the previous week; (2) expert ratings: Psychiatric Status Rating Scales for Bulimia nervosa, Structured Interview for Anorexia and Bulimia nervosa (SIAB)-"total score," SIAB-subscale "fasting," and SIAB-subscale "vomiting." Two further variables (EDI-total score and SIAB-subscale "bulimia") showed the superior relapse prevention effects of fluvoxamine compared with placebo for the completer sample, while they did not reach significance for group-by-time interactions in the intent-to-treat sample. During a final, short (4-week) off-medication phase, no effect of the discontinuation of medication was observed.
TL;DR: An in vitro-in vivo scaling model predicted a large and potentially hazardous impairment of terfenadine clearance by ketoconazole and, to a slightly lesser extent, by itraconazole, but fluconazoles and the six selective serotonin reuptake inhibitors (SSRIs) at usual clinical doses were not predicted to impair terfendine clearance to a degree that would be of clinical importance.
Abstract: Biotransformation of the H-1 antagonist terfenadine to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations of human liver. These metabolic reactions are presumed to be mediated by Cytochrome P450-3A isoforms. The azole antifungal agent ketoconazole was a highly potent inhibitor of both reactions, having mean inhibition constants (Ki) of 0.037 and 0.34 microM for desalkyl- and hydroxy-terfenadine formation, respectively. Itraconazole also was a potent inhibitor, with Ki values of 0.28 and 2.05 microM, respectively. Fluconazole, on the other hand, was a weak inhibitor. Six selective serotonin reuptake inhibitor antidepressants tested in this system were at least 20 times less potent inhibitors of terfenadine metabolism than was ketoconazole. An in vitro-in vivo scaling model used in vitro Ki values, typical clinically relevant plasma concentrations of inhibitors, and presumed liver:plasma partition ratios to predict the degree of terfenadine clearance impairment during coadministration of terfenadine with these inhibitors in humans. The model predicted a large and potentially hazardous impairment of terfenadine clearance by ketoconazole and, to a slightly lesser extent, by itraconazole. However, fluconazole and the six selective serotonin reuptake inhibitors (SSRIs) at usual clinical doses were not predicted to impair terfenadine clearance to a degree that would be of clinical importance. Caution is nonetheless warranted with the coadministration of SSRIs and terfenadine when high doses of SSRIs (particularly fluoxetine) are administered. Also, some individuals may be unusually susceptible to metabolic inhibition for a variety of reasons.
TL;DR: Spectral analysis of HR and BP fluctuations suggested that both parasympathetic and sympathetic mechanisms are involved, specifically during OC, and confirmed the preexisting autonomic cardiovascular dysfunctions were not normalized by antidepressant drugs.
Abstract: Spectral analysis of fluctuations in heart rate (HR) and blood pressure (BP) was applied to assess sympathetic and parasympathetic cardiovascular control mechanisms in patients with unipolar affective disorder before and after treatment with imipramine (IMI) or mirtazapine (MIR).In a double-blind ra
TL;DR: The outcome of studies of lithium, divalproex, and carbamazepine in the acute treatment of episodes of mania and bipolar depression and in the maintenance treatment of bipolar disorder and the implications of these studies to clinical practice are reviewed.
Abstract: Outcome studies of bipolar disorder, the majority of which were conducted before the use of lithium, divalproex, and carbamazepine, generally found that only 50 to 60% of patients achieved good recovery 6 to 12 months after a manic episode. Over the past decade, a number of new pharmacologic studies have provided further information regarding the acute and long-term outcome of patients with bipolar disorder treated with these medications. In addition, better operational criteria to define outcome have been advanced, allowing for easier extrapolation of the results of clinical trials to clinical practice. We review the outcome of studies of lithium, divalproex, and carbamazepine in the acute treatment of episodes of mania and bipolar depression and in the maintenance treatment of bipolar disorder and the implications of these studies to clinical practice.
TL;DR: To evaluate subject selection biases in clinical trials, demographic characteristics of subjects at different phases of evaluation for a multicenter maintenance trial in schizophrenia were examined and showed that selection biases would rarely change overall study outcomes to a clinically relevant degree.
Abstract: To evaluate subject selection biases in clinical trials, demographic characteristics (gender, race, and age) of subjects at different phases of evaluation for a multicenter maintenance trial in schizophrenia were examined. Six thousand twelve diagnostically appropriate subjects were screened for the study; of these, 1,320 met eligibility criteria and 528 (9% of the screened sample) entered the study. Women, blacks, and older subjects were more likely not to meet eligibility criteria; women and older subjects were more likely and blacks were less likely to refuse study participation. Overall, compared with the screened population, the sample of subjects who entered the study contained proportionately fewer women (33 vs. 43%), more blacks (48.5 vs. 41%), and fewer older subjects (mean age of the entered sample was 29.4 +/- 7.4 vs. 34.8 +/- 11.3 years for the screened population). Having identified these selection factors, a second goal was to assess the potential clinical relevance of selection biases of these magnitudes on clinical trials using models of hypothetical studies with different degrees of selection bias. These showed that selection biases would rarely change overall study outcomes to a clinically relevant degree. However, in our models, selection biases did limit the ability to make inferences about results for select small subgroups of the study population. Investigators should consider collecting data on the recruitment process to allow estimation of the effects of selection biases on the generalizability of their findings.
TL;DR: These cases illustrate that severe and potentially life-threatening catatonia can develop in the wake of benzodiazepine withdrawal and older individuals may be particularly vulnerable to this side effect.
Abstract: The use of benzodiazepine medication is associated with a variety of acute and well-recognized withdrawal syndromes including anxiety, agitation, insomnia, and confusion. Catatonia has not previously been described. We report five patients who became catatonic after withdrawal of benzodiazepines. All five were older individuals (53-88 years) who had acutely become immobile, mute, and rigid with refusal or inability to eat or drink. Each of the five showed pronounced and rapid improvement after administration of low-dose lorazepam, which has previously been reported to be effective in the treatment of catatonia. Careful review of the records showed that each of the patients had been taking benzodiazepine medication for anywhere from 6 months to 15 years and that it had been rapidly tapered or abruptly discontinued 2 to 7 days before the onset of catatonia. These cases illustrate that severe and potentially life-threatening catatonia can develop in the wake of benzodiazepine withdrawal. Older individuals may be particularly vulnerable to this side effect.
TL;DR: Research into the psychobiology of premenstrual dysphoric disorder finds alterations in markers associated with serotonergic neurotransmission, and work showing that patients with PDD respond to some agents that block the reuptake of serotonin is supported.
Abstract: Research into the psychobiology of premenstrual dysphoric disorder (PDD) finds alterations in markers associated with serotonergic neurotransmission.Supporting this is work showing that patients with PDD respond to some agents that block the reuptake of serotonin. In this open trial, patients were t
TL;DR: This finding implies that individuals who repeatedly administer the drug to maintain certain levels of subjective effects may increase plasma drug levels and physiologic effects to toxic levels.
Abstract: This is a descriptive report on the relationship between the pharmacokinetics and pharmacodynamics of d-amphetamine in healthy, normal volunteers. Six men, aged 22 to 31, attended two experimental sessions during which they received single oral doses of 20 mg of d-amphetamine. Plasma levels of drug and measures of drug effect were collected predrug and at regular intervals for 24 hours after drug administration. Plasma drug levels peaked at 4 hours and remained at detectable levels for 24 hours after drug administration. Subjective ratings, including "feel drug" and "feel high" peaked at 1 1/2 to 2 hours and returned to baseline levels by 3 to 4 hours. Evaluation of phase plots (i.e., drug effect vs. drug concentration) indicated that acute tolerance developed to the subjective but not to the cardiopressor effects of d-amphetamine. This finding implies that individuals who repeatedly administer the drug to maintain certain levels of subjective effects may increase plasma drug levels and physiologic effects to toxic levels.
TL;DR: It is demonstrated that in patients severely dependent on benzodiazepines, additional psychoactive substance use and mental disorders are prominent, and the pattern of drug use and psychiatric comorbidity differentiates these patients from therapeutic-dose Benzodiazepine users.
Abstract: This study aimed to evaluate the concurrent and lifetime psychiatric comorbidity and drug use patterns in patients admitted to the hospital for detoxification from benzodiazepines.Psychiatric assessments using the Structured Clinical Interview for DSM-III-R with a psychosis screening module (SCID-P and II) were conducted in 30 inpatients admitted to the medical unit treatment unit of the Clinical Research and Treatment Institute of the Addiction Research Foundation for the treatment of severe benzodiazepine dependence. Patients (mean age, 36 years; range, 22-58; number of DSM-III-R criteria met for benzodiazepine substance dependence, greater or equal to 7 out of 9 [73%], all 9 criteria [40%]) used benzodiazepines and other drugs over prolonged periods of time at high doses, and their daily functioning was substantially impaired (Mean Global Assessment of Functioning Score, 48; range, 31-60). The most common lifetime psychiatric diagnoses were major depression (33%), other psychoactive drug dependence (100%) (opioids, 77%; alcohol, 53%), and panic disorder (30%). Current psychiatric diagnoses in addition to benzodiazepine dependence included other psychoactive substance use disorders (83%) (opioids, 67%; cocaine, 13%; multiple concurrent substance use, 17%), panic disorder (13%), and generalized anxiety disorder, (20%). Personality disorders included antisocial (42%), avoidant (25%), and borderline (17%). These findings demonstrate that in patients severely dependent on benzodiazepines, additional psychoactive substance use and mental disorders are prominent. The pattern of drug use and psychiatric comorbidity differentiates these patients from therapeutic-dose benzodiazepine users. (J Clin Psychopharmacol 1996;16:51-57).