dextromethorphan and Depressive-Disorder

In neurochemistry there are advantages in determining how patients are likely to react to psychoactive drugs prior to the commencement of drug therapy. Explanations of a patient's nonresponse, or unexpected adverse reactions to drugs are required. In many instances, a knowledge of the drug metabolism status of a patient can be helpful in the selection of a drug and its dosage regimen, and in the prediction of possible drug/drug interactions when two or more drugs have to be administered concomitantly. Important information on these topics may be obtained by phenotyping patients prior to drug therapy. The metabolism of various antidepressant and neuroleptic drugs is catalyzed by CYP2D6, a cytochrome P450 isozyme (also named P450IID6), whereas the metabolism of other drugs may involve different cytochromes P450. The properties of CYP2D6 and four other isozymes (CYP1A1, CYP1A2, CYP2C8/9 and CYP3A4) are described, and substrates identified. Phenotyping of patients for CYP2D6 activity and mephenytoin hydroxylase activity is described.

Topics: Clomipramine; Cytochromes; Dealkylation; Depressive Disorder; Desipramine; Dextromethorphan; Drug Interactions; Female; Humans; Hydroxylation; Imipramine; Isoenzymes; Male; Mephenytoin; Nortriptyline; Phenotype; Polymorphism, Genetic

Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of thioridazine and metabolites were measured in 21 patients who were receiving 100 mg thioridazine for 14 days and who were comedicated with moclobemide (450 mg/day). Two patients were poor metabolizers of dextromethorphan and one was a poor metabolizer of mephenytoin. Cytochrome P450IID6 (CYP2D6) is involved in the formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO. Significant correlations between the mephenytoin enantiomeric ratio and concentrations of thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute to the biotransformation of thioridazine into yet-unknown metabolites, other than thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO. An enantioselectivity and a large interindividual variability in the metabolism of thioridazine have been shown: measured (R)/(S) ratios of thioridazine, thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE), thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80), 0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/- 0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019 (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively. CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)-thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)-thioridazine 5-SO(SE).

Topics: Adult; Aged; Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Antitussive Agents; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Depressive Disorder; Dextromethorphan; Double-Blind Method; Female; Humans; Male; Mephenytoin; Mesoridazine; Middle Aged; Mixed Function Oxygenases; Phenothiazines; Stereoisomerism; Thioridazine

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.

Topics: Adult; Antidepressive Agents; Aryl Hydrocarbon Hydroxylases; Citalopram; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Depressive Disorder; Dextromethorphan; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Female; Humans; Lithium Carbonate; Male; Mephenytoin; Middle Aged; Mixed Function Oxygenases; Selective Serotonin Reuptake Inhibitors

Cytochrome P450 IID6 has got typical features (genetical polymorphism, competitive inhibition, saturability) which can be at the origin of pharmacokinetic modifications of molecules using it for their metabolism. In the field of pharmacology, many molecules are substrates or inhibitors of this cytochrome. They are presented. The results of a study of the dextromethorphan variation test performed before and after 28 days of clomipramine therapy with depressed patients are explained. They show a significant decreasing of the cytochrome P450 IID6 oxidation capacities between both of these times. A patient has passed from the phenotype "effective metabolizer" to the one of "poor metabolizer" with clomipramine.

Topics: Adolescent; Adult; Aged; Clomipramine; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Depressive Disorder; Dextromethorphan; Humans; Middle Aged; Mixed Function Oxygenases; Phenotype; Psychiatric Status Rating Scales

Dextromethorphan (DXM) is one of the common drugs abused by adolescents. It is the active ingredient found in cough medicine which is used for suppressing cough. High dosage of DXM can induce euphoria, dissociative effects and even hallucinations. Chronic use of DXM may also lead to depressive-related symptoms. Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of ageing-related neurodegenerative diseases. A recent study has shown the potential beneficial effect of Lycium barbarum to reduce depression-like behavior. In the present study, we investigated the role of Lycium barbarum polysaccharide (LBP) to alleviate DXM-induced emotional distress. Sprague Dawley rats were divided into 4 groups (n=6 per group), including the normal control (vehicles only), DXM-treated group (40 mg/kg DXM), LBP-treated group (1 mg/kg LBP) and DXM+ LBP-treated group (40 mg/kg DXM and 1 mg/kg LBP). After two-week treatment, the DXM-treated group showed increased depression-like and social anxiety-like behaviors in the forced swim test and social interaction test respectively. On the other hand, the adverse behavioral effects induced by DXM were reduced by LBP treatment. Histological results showed that LBP treatment alone did not promote hippocampal neurogenesis when compared to the normal control, but LBP could lessen the suppression of hippocampal neurogenesis induced by DXM. The findings provide insights for the potential use of wolfberry as an adjunct treatment option for alleviating mood disturbances during rehabilitation of cough syrup abusers.

Topics: Animals; Antitussive Agents; Anxiety Disorders; Depressive Disorder; Dextromethorphan; Disease Models, Animal; Drugs, Chinese Herbal; Hippocampus; Male; Neurogenesis; Neurons; Neuroprotective Agents; Psychotropic Drugs; Random Allocation; Rats, Sprague-Dawley; Social Behavior; Substance-Related Disorders

Dextromethorphan (DM) is an antitussive with rapid acting antidepressant potential based on pharmacodynamic similarities to ketamine. Building upon our previous finding that DM produces antidepressant-like effects in the mouse forced swim test (FST), the present study aimed to establish the antidepressant-like actions of DM in the tail suspension test (TST), another well-established model predictive of antidepressant efficacy. Additionally, using the TST and FST, we investigated the role of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in the antidepressant-like properties of DM because accumulating evidence suggests that AMPA receptors play an important role in the pathophysiology of depression and may contribute to the efficacy of antidepressant medications, including that of ketamine. We found that DM displays antidepressant-like effects in the TST similar to the conventional and fast acting antidepressants characterized by imipramine and ketamine, respectively. Moreover, decreasing the first-pass metabolism of DM by concomitant administration of quinidine (CYP2D6 inhibitor) potentiated antidepressant-like actions, implying DM itself has antidepressant efficacy. Finally, in both the TST and FST, pretreatment with the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide) significantly attenuated the antidepressant-like behavior elicited by DM. Together, the data show that DM exerts antidepressant-like actions through AMPA receptors, further suggesting DM may act as a safe and effective fast acting antidepressant drug.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Depression; Depressive Disorder; Dextromethorphan; Disease Models, Animal; Excitatory Amino Acid Antagonists; Hindlimb Suspension; Imipramine; Ketamine; Male; Mice; Quinidine; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Swimming

Coricidin HBP, a cold medication containing dextromethorphan, has become a popular agent abused among adolescents. This retrospective chart review examines the potential psychiatric manifestations of Coricidin HBP misuse and patterns of use among patients treated in an inpatient child and adolescent psychiatric unit. Coricidin HBP use was documented in 47 patient. The data revealed that Coricidin HBP use was associated with: (a) predominantly depressive symptomatology; (b) transient substance-induced psychosis; (c) cardiac toxicity; and (d) greater quantities used per episode by Caucasians. Clinicians treating adolescents need to be aware of the abuse potential and psychiatric manifestations of this dextromethorphan-containing product.

Topics: Acetaminophen; Adolescent; Age Factors; Alcoholism; California; Child; Chlorpheniramine; Comorbidity; Cross-Sectional Studies; Depressive Disorder; Dextromethorphan; Dose-Response Relationship, Drug; Drug Combinations; Drug Overdose; Female; Heart Block; Hospitalization; Humans; Male; Mental Disorders; Phenylpropanolamine; Psychiatric Department, Hospital; Psychoses, Substance-Induced; Retrospective Studies; Sex Factors; Substance-Related Disorders; Suicide, Attempted; Tachycardia, Ventricular

Dextromethorphan is a commonly used antitussive agent that can be purchased over the counter. It is metabolized primarily by the cytochrome P450 (CYP) 2D6 isozyme. Methadone has been found to inhibit CYP2D6, indicating a potential for interaction with dextromethorphan.. An 83-year-old woman was evaluated for delirium, hypersomnia, confusion, lethargy, impaired concentration, and poor food intake. Symptoms resolved soon after discontinuing dextromethorphan.. Vulnerability to delirium was potentially caused by coadministration of methadone, which can inhibit the CYP2D6 isozyme.. Evaluation of delirium should include close investigation of the patient's medications for potential interactions with dextromethorphan.

Topics: Aged; Analgesics, Opioid; Antitussive Agents; Cough; Delirium; Depressive Disorder; Dextromethorphan; Drug Interactions; Female; Humans; Methadone; Pain; Selective Serotonin Reuptake Inhibitors; Sertraline

The clinical relevance of the CYP2D6 oxidation polymorphism in the treatment of depression with desipramine (DMI) was studied prospectively in depressed outpatients.. After CYP2D6 phenotype determination with dextromethorphan, 31 patients were treated with oral DMI at a dosage of 100 mg per day for 3 weeks. At the end of the 3rd week of treatment, severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale and steady-state plasma concentrations of DMI and its metabolite 2-hydroxydesipramine (2-OH-DMI) were measured by high-performance liquid chromatography (HPLC).. Plasma DMI levels were significantly correlated with dextromethorphan metabolic ratio. The two patients with the poor metabolizer phenotype showed the highest plasma concentrations of DMI and complained of severe adverse effects, requiring dosage reduction. No significant correlation was found between plasma levels of either DMI or DMI plus 2-OH-DMI and antidepressant effect.. These findings indicate that the dextromethorphan metabolic ratio has a great impact on steady-state plasma levels of DMI in depressed patients and may identify subjects at risk for severe concentration-dependent adverse effects. On the other hand, this index of CYP2D6 activity does not seem to predict the degree of clinical amelioration.

Topics: Adult; Antidepressive Agents, Tricyclic; Cytochrome P-450 CYP2D6; Depressive Disorder; Desipramine; Dextromethorphan; Female; Humans; Male; Middle Aged; Oxidation-Reduction; Phenotype; Polymorphism, Genetic; Prospective Studies

A depressive patient, a non-responder to trimipramine (TRI), was comedicated first with citalopram (CIT) and then with fluvoxamine (FLUV). Both the TRI-CIT and TRI-FLUV combination treatments led to a worsening of the depressive state and to the appearance of panic attacks. The addition of FLUV to TRI resulted in a twofold increase of the plasma levels of TRI and to a slight increase of its N-demethylated and 2-hydroxylated metabolites. These results suggest that the interaction between FLUV and TRI occurred at the level of cytochrome P-450IID6 and cytochrome P-450meph in this patient, phenotyped as an extensive metabolizer of both dextromethorphan and mephenytoin. The adverse effects were possibly due to (a) a pharmacokinetic interaction between CIT and FLUV with TRI and/or (b) alterations in serotonergic and/or dopaminergic neurotransmission.

Topics: Aged; Citalopram; Depressive Disorder; Dextromethorphan; Drug Interactions; Female; Fluvoxamine; Humans; Mephenytoin; Phenotype; Trimipramine

Topics: Adult; Central Nervous System; Clomipramine; Depressive Disorder; Dextromethorphan; Drug Interactions; Drug Overdose; Emergencies; Female; Humans; Phenelzine; Serotonin; Syndrome