Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition.

Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (-76%; confidence interval (CI), -83%, -66%; P < 0.001) and aripiprazole (-52%; CI, -62%, -39%; P < 0.001), but not for olanzapine (-9%; CI, -28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.

Does level of care, sex, age, or choice of drug influence adherence to treatment with antipsychotics?

Rates of nonadherence during treatment with antipsychotics have been found to vary in a wide range from 20% to 90%. The aim of the present study was to investigate the influence of inpatient versus outpatient status on the adherence to treatment with olanzapine and clozapine. In the period from 1999 to 2007, olanzapine and clozapine were the 2 most frequently analyzed antipsychotics at the Department of Clinical Pharmacology at St. Olavs University Hospital, Trondheim, Norway, with more than 24,000 and more than 18,000 samples, respectively. In total, 111 patients on olanzapine and 95 patients on clozapine had provided samples in both the inpatient and outpatient settings and were included in the study. The primary outcome variable was the serum concentration-to-dose ratio (C/D ratio), that is, the serum drug concentration per milligram of drug given. For olanzapine, the C/D ratio in the outpatient setting was 10.7% lower than in the inpatient setting (P = 0.013). No such difference was found for clozapine. The difference in the olanzapine group was exclusively attributed to a lower outpatient ratio in females. For clozapine, no sex influence was found. No effect of age on the C/D ratios was found either for olanzapine or for clozapine. The lower C/D ratio in females using olanzapine in the outpatient setting might imply that they, in contrast to males, are less adherent to their medication when outside hospital. For clozapine, there were no indications of differences in adherence between inpatients and outpatients.

[Irreversible, non-selective monoamine oxidase inhibitors]. / Irreversible, uselektive monoaminoksidasehemmere.

Irreversible, non-selective monoamine oxidase (MAO) inhibitors were among the first antidepressants. No drugs in this group are currently marketed in Norway, but many physicians will see patients using them, as they can be prescribed on a named patient basis after application to the Norwegian Medicines Agency. This article presents adverse effects, interactions and precautions related to the use of these drugs.

Prescribing patterns and the use of therapeutic drug monitoring of psychotropic medication in a psychiatric high-security unit.

The aim of this study was to investigate the use of psychotropic medication and therapeutic drug monitoring in a high-security psychiatric unit and to compare the doses and serum concentrations both with the recommended intervals and with the doses and serum concentrations in a control group. One hundred thirty-two patients were admitted in the period from January 2000 to December 2005. All available samples were used when comparing serum concentrations and doses with the recommended ranges. For the comparison of doses and serum concentration-to-dose (C:D) ratios with the control group only 1 sample from each patient was used. A total of 459 analyses of 27 different drugs in samples from 8 women and 73 men were included. The median number of therapeutic drug monitoring analyses per patient was 4 (range 1-29). Thirty-seven of the 81 patients (46%) used 2 or more antipsychotics at the same time. Clozapine, lamotrigine, olanzapine, quetiapine, ziprasidone, and zuclopenthixol were often given in doses above the recommended. The serum levels were frequently above those recommended for clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zuclopenthixol. The serum levels were significantly higher in the study group than in the control group for clozapine, lamotrigine, quetiapine, and zuclopenthixol. The given dose was significantly higher in the study group than in the control group for clozapine, lamotrigine and zuclopenthixol. The C:D ratio was significantly lower in the study group than in the control group for olanzapine but higher for quetiapine. The non-evidence based practice of high-dose polypharmacy with several antipsychotics is widely used in this unit. The use of higher doses in the study group than in the control group was not due to differences in metabolism or adherence to treatment between the 2 groups. The frequent use of therapeutic drug monitoring did not seem to have a great impact on the prescribed doses.

Quetiapine and drug interactions: evidence from a routine therapeutic drug monitoring service.

OBJECTIVE: The objective of the present study was to investigate the effect of age, gender, and various comedications on the pharmacokinetics of quetiapine in a naturalistic setting. METHOD: In total, 2111 serum samples analyzed for quetiapine during the period from June 2001 to December 2004 were included in the study. The samples had been collected for routine therapeutic drug monitoring purposes from 1179 patients treated with quetiapine. A log-linear mixed model was used to identify factors influencing the dose-corrected quetiapine serum concentration, expressed as the quetiapine concentration-to-dose (C/D) ratio. Variables included in the analysis were age, gender, and concomitant treatment with a total of 41 drugs most often used in combination with quetiapine. RESULTS: Age >or= 70 years (p = .001) and comedication with alimemazine (p = .002), fluvoxamine (p = .001), citalopram/escitalopram (p = .041), or clozapine (p < .001) significantly increased the serum concentrations of quetiapine, while age < 18 years (p = .044) and comedication with lamotrigine (p = .024), levomepromazine (p = .011), oxazepam (p < .001), or carbamazepine (p < .001) significantly decreased the serum concentrations. The effects were most pronounced for fluvoxamine (+159%), clozapine (+82%), age >or= 70 years (+67%), and carbamaze-pine (-86%). In 18% of the samples, the daily dose exceeded the currently recommended maximum of 800 mg/day. CONCLUSION: Due to the increased serum levels of quetiapine, a lower dose than usual should be considered when quetiapine is administered to elderly patients and to patients comedicated with clozapine or fluvoxamine. As the inducing effect of carbamazepine on quetiapine metabolism is very potent, cotreatment with carbamazepine cannot be recommended. On the basis of our data and pharmacokinetic considerations, the majority of drugs commonly used in psychiatry can safely be given in combination with quetiapine.

Adverse drug reactions of antidepressants and antipsychotics: experience, knowledge and attitudes among Norwegian psychiatrists.

Efficient prevention of adverse drug reactions (ADRs) requires knowledge about their severity and pharmacological mechanisms and is dependent on reliable data on their frequencies and possible risk factors. The study was conducted to investigate the prescribers' experience and understanding of the ADRs of psychotropic drugs, and their attitude towards reporting these. In a questionnaire, physicians treating adult psychiatric patients were asked which ADRs that they regarded bothersome for some of the most widely used antidepressants and antipsychotics. Questions about the relationship between blockade of drug receptors and ADRs, and about the physicians' personal experience of and attitudes towards reporting of ADRs were also included. In total, 70 of 91 questionnaires (78%) were returned. The mean number of ADRs regarded bothersome ranged from 2.4 to 9.3 for the various drugs/drug classes. Qualified psychiatrists stated a significantly higher number of bothersome ADRs than did the residents. The percentage of physicians associating blockade of a receptor with a specific ADR varied from 76% (histamine receptor blockade and sedation) to 37% (alpha(1)-adrenergic blockade and tachycardia). Thirty-nine per cent of the physicians had never reported an ADR to the Norwegian Medicines Agency. The number of ADRs considered bothersome was relatively high. The pattern of these ADRs generally mirrored the typical ADR profiles of the drugs. The knowledge of the underlying mechanisms of ADRs was more or less incomplete. The reporting rate of ADRs to the national regulatory authorities was low.

Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline.

Drugs with long terminal half-lives, such as terbinafine, have a potential for involvement in both long-lasting drug-drug interactions and interactions appearing weeks after discontinuation. We present a case report on a 37-year-old white woman with normal CYP2D6 metabolic capacity who was treated with amitriptyline, valproate, and olanzapine when terbinafine was introduced. Shortly thereafter she experienced extreme dryness of the mouth, nausea, and dizziness accompanied by a large increase in the serum concentrations of amitriptyline and nortriptyline. Terbinafine therapy was discontinued, and the amitriptyline dose was reduced. Surprisingly, the serum concentrations of amitriptyline and nortriptyline did not return to baseline until approximately 6 months later. Studies have shown that terbinafine is a highly potent competitive inhibitor of CYP2D6. CYP2D6 is an important intermediate enzyme in metabolism of amitriptyline to nortriptyline. Nortriptyline is further metabolized to 10-hydroxy metabolites, mainly by CYP2D6. It is, therefore, likely that the concomitant use of terbinafine was the major cause of the increased serum concentrations of amitriptyline and nortriptyline. Very different terbinafine elimination half-lives (17-400 hours) are stated in the physicians' reference guides. If the shortest estimates are used when adjusting the dose of interacting drugs, the risk of underestimating the duration of the interaction is large. Based on our data there is a risk of clinically significant drug-drug interactions for at least 3 months after stopping terbinafine intake.

Serum concentrations of risperidone and 9-hydroxyrisperidone after administration of the long-acting injectable form of risperidone: evidence from a routine therapeutic drug monitoring service.

There is limited documentation on the pharmacokinetics of long-acting intramuscular risperidone in a naturalistic setting. The objective of this study was to investigate the concentrations of risperidone and its active metabolite 9-hydroxyrisperidone as well as the concentration/dose (C/D) ratios achieved after intramuscular depot administration in a routine therapeutic drug monitoring setting. Thirty samples were collected from 10 female and 20 male patients receiving depot injections of risperidone. For 6 of the patients, the results could be compared with corresponding data available after previous oral administration of risperidone. In addition, data from a group of 278 patients using oral risperidone were retrieved. The median serum concentrations of risperidone plus 9-hydroxyrisperidone were 38 nmol/L 12-14 days after a intramuscular dose of 25 mg/14 days, 67 nmol/L after a dose of 37.5 mg/14 days, 99 nmol/L after a dose of 50 mg/14 days, and 148 nmol/L after a dose of 75 mg/14 days. The median C/D ratio for risperidone plus 9-hydroxy-risperidone was 22.2 (nmol/L)/(mg/d). In the group on oral medication, the median C/D ratio was 18.6 (nmol/L)/(mg/d). In the 6 patients previously using oral risperidone, switching to depot injections gave an average increase of 33% (range 12%-68%) in the C/D ratio. In conclusion, the authors' data indicate that there are great interindividual differences in the extent to which the daily dose has to be reduced when switching from oral to intramuscular depot administration to achieve the same serum concentrations of risperidone plus 9-hydroxyrisperidone. Because the degree of dose adjustment required for the individual patient so far cannot be predicted, guidance by therapeutic drug monitoring might be helpful.