Ingeborg Wilting

Pharmacogenetics: From Bench to Byte

Despite initial enthusiasm, 1 , 2 , 3 the use of pharmacogenetics has remained limited to investigation in only a few clinical fields such as oncology and psychiatry. 4 , 5 , 6 , 7 , 8 The main reason is the paucity of scientific evidence to show that pharmacogenetic testing leads to improved clinical outcomes. 9 , 10 Moreover, for most pharmacogenetic tests (such as tests for genetic variants of cytochrome P450 enzymes) a detailed knowledge of pharmacology is a prerequisite for application in clinical practice, and both physicians and pharmacists might find it difficult to interpret the clinical value of pharmacogenetic test results. Guidelines that link the result of a pharmacogenetic test to therapeutic recommendations might help to overcome these problems, but such guidelines are only sparsely available. In 2001, an early step was taken to develop such guidelines for the therapeutic use of antidepressants, and these included CYP2D6‐related dose recommendations drawn from pharmacokinetic study data. 11 However, the use of such recommendations in routine clinical practice remains difficult, because they are currently outside the ambit of the clinical environment and are not accessible during the decision‐making process by physicians and pharmacists, namely the prescription and dispensing of drugs.

The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments

OBJECTIVES Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. METHODS These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. RESULTS General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. CONCLUSIONS These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice.

Is aspirin useful in patients on lithium? A pharmacoepidemiological study related to bipolar disorder☆

OBJECTIVES Administration to rats of mood stabilizers approved for bipolar disorder (BD) downregulates markers of the brain arachidonic acid (AA, 20:4n-6) metabolic cascade, including phospholipase A(2) (PLA(2)) and cyclooxygenase (COX) expression. We hypothesized that other agents that target the brain AA cascade, nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, also would ameliorate BD symptoms. METHODS Medication histories on subjects who had been prescribed lithium were collected from the Netherlands PHARMO Record Linkage System. Data were stratified according to drug classes that inhibit PLA(2) and/or COX enzymes, and duration of use. Incidence density (ID) of medication events (dose increase or substance change) was used as a proxy for clinical worsening. ID ratios in patients with the inhibitors plus lithium were compared to ratios in patients using lithium alone. RESULTS Low-dose acetylsalicylic acid (aspirin) significantly reduced the ID ratio of medication events, independent of use duration. The ID ratios of NSAIDs and glucocorticoids did not differ significantly from 1.0 if prescribed for > or =180 or > or =90 days, but exceeded 1.0 with shorter use. Selective COX-2 inhibitors had no significant effect and multiagent administration increased the ID ratio above 1.0. CONCLUSIONS Low-dose aspirin produced a statistically significant duration-independent reduction in the relative risk of clinical deterioration in subjects on lithium, whereas other NSAIDs and glucocorticoids did not. These tentative findings could be tested on larger databases containing detailed information about diagnosis and disease course, as well as by controlled clinical trials.

Changes in outpatient lithium treatment in the Netherlands during 1996–2005

BACKGROUND The objectives of the present study were to investigate in outpatients in the Netherlands between 1996 and 2005, changes in 1) the incidence and prevalence of lithium use and 2) lithium use patterns (discontinuation, add-on, and switch). METHODS Incidence and prevalence of lithium use were determined for each year between 1996 and 2005. In addition, we determined cumulative changes in lithium use (discontinuation, add-on, and switching) at three, six, 12 and 24 months for three separate time-cohorts (1998-1999, 2000-2001 and 2002-2003). Lastly, concomitant use of other drugs used in the treatment of bipolar disorders next to lithium during the 24 months after the first lithium prescription was determined for the three time-cohorts. RESULTS Incidence of lithium use was constant at approximately 0.2 per 1000 person-years, prevalence increased with 26% from 0.95 to 1.2 per 1000 persons. The percentage of patients receiving an add-on drug used in the treatment of bipolar disorders was constant over the three time-cohorts, with a significant decrease in use of tricyclic antidepressants. Within the patient group that stopped using lithium, more patients switched from lithium to another agent used in the treatment of bipolar disorders over calendar time, and fewer patients discontinued lithium. There was a significant increase in the use of atypical antipsychotics and valproic acid next to lithium. LIMITATIONS We did not know the specific diagnosis for which lithium treatment was instituted. CONCLUSION The changes were in line with the increase in alternatives during the last decade and in line with Dutch guidelines.

Association between lithium serum level, mood state, and patient-reported adverse drug reactions during long-term lithium treatment : a naturalistic follow-up study

OBJECTIVES To assess the association between mood state and the prevalence and the severity of lithium adverse drug reactions (ADRs). METHODS A 26-year follow-up study was conducted among patients > or =18 years treated at the outpatient lithium clinic of the University Medical Center Groningen, The Netherlands, between November 1973 and December 2000. At each monthly scheduled visit, patients were questioned by a research nurse in a standardized manner about the presence and the severity of nine specific ADRs that frequently occur as a consequence of lithium treatment and that can be identified by the patients themselves. In addition, lithium serum level was measured and mood state was rated at each visit. RESULTS A total of 186 patients participated and the median duration of follow-up was 5.7 years (interquartile range 2.2-11.8 years). We observed an increased prevalence and severity of ADRs with increased lithium serum level (p < 0.05), also when adjusting for mood state. The prevalence and the severity of ADRs increased with decreasing mood state into the depressive range and decreased with mood state increasing into the manic range (p < 0.05), also when adjusting for lithium serum level. Taking into account the intraindividual dependency of the data resulted in a statistically significant (p < 0.001) association between, respectively, lithium serum level, mood state, and the prevalence and severity of ADRs. CONCLUSIONS Both physicians and researchers need to be aware that lithium serum level and mood state are independently associated with patient reporting and severity scoring of ADRs, which may complicate objective assessment of ADRs.

The influence of lithium on calcium homeostasis in older patients in daily clinical practice.

Lithium can influence calcium homeostasis resulting in changes in parathormone set point and renal calcium handling. The clinical significance of these changes in older patients is unknown. The objective of this study was to investigate the possible association between duration of lithium treatment and corrected calcium, parathormone and 24‐h urinary calcium excretion in older psychiatric patients corrected for renal function and vitamin 25OH D and also to estimate the point prevalence of hypercalcemia and raised parathormone.

Valproic acid-induced hair-texture changes in a white woman

∗†Ingeborg Wilting, ‡Jan H. M. van Laarhoven, §Ingrid F. de Koning-Verest, and †‖Antoine C. G. Egberts ∗Department of Clinical Pharmacy, TweeSteden Hospital and St. Elisabeth Hospital, Tilburg; †Utrecht University, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology & Pharmacotherapy, Utrecht; ‡Department of Psychiatry, St. Elisabeth Hospital, and §Public Pharmacy de Blaak, Tilburg; ‖ Department of Clinical Pharmacy, Utrecht University Medical Center, Utrecht, The Netherlands

Differences in Lithium Use Patterns in the Netherlands: Comparing Middle-Aged and Older Patients in a Database Study

BACKGROUND Age-dependent changes in lithium pharmacokinetic and pharmacodynamic properties can influence lithium use in an aging population, especially as newer treatment options are available. OBJECTIVE We compared lithium use patterns between middle-aged and elderly outpatients in the Netherlands. METHODS Data for this study were obtained from the Dutch PHARMO Record Linkage System. Incident lithium users 40 years or older were identified in the period 1996-2008. The following lithium use patterns were defined: continuation, add on, switch, and discontinuation. Differences were assessed for the following age groups: 40 to 49 years, 50 to 59 years, 60 to 69 years, and 70 years or older. The youngest group was the reference group. Patient baseline characteristics and potential determinants of changes in lithium use patterns were assessed. RESULTS We identified 2081 incident lithium users. Use of antidepressants was not different at baseline between age groups, but elderly patients starting lithium treatment used baseline antipsychotics less frequently (P < 0.05). Older patients were less likely to receive psychotropic drugs as add on to ongoing lithium therapy (P < 0.05). Frequency of discontinuation and switch events did not differ between the age groups. In the whole study group, age was associated with any change in lithium use patterns. CONCLUSIONS Older patients are less likely to receive psychotropic drugs as add on to ongoing lithium therapy. Despite pharmacokinetic and pharmacodynamic changes in the elderly, lithium is not more often discontinued and not more often switched in older patients.

Evaluation of Available Treatment Guidelines for the Management of Lithium Intoxication

Intoxications with lithium carry considerable risk for long-term morbidity and even mortality. Consequently, any patient suspected of lithium intoxication requires immediate and appropriate care. The objectives of this study were to assess the completeness and the applicability of generally available treatment guidelines for the management of patients with a lithium intoxication and, hence, to provide general recommendations for improvement of existing treatment guidelines. Nineteen treatment guidelines originating from 7 different countries were gathered by searching the Internet, online databases, and textbooks and by contacting different poison information centers and university medical centers. A list of items was composed from the retrieved treatment guidelines and a further literature search. Most relevant items were present in the various guidelines. However, in some guidelines, essential information was missing or potentially hazardous information was provided. Clarity, presentation, and applicability of the guidelines, as assessed using parts of the Appraisal of Guidelines Research and Evaluation instrument, were relatively poor. Regular updates of treatment guidelines should be performed to incorporate new essential information. To improve applicability of guidelines, unambiguous key recommendations, alternative treatments, and special care requirements should be provided and authors are recommended to test treatment guidelines using a panel of less experienced caregivers in a hypothetical case scenario.

The association between concomitant use of serotonergic antidepressants and lithium-induced polyuria. A multicenter medical chart review study

BACKGROUND A previous study aimed at revealing the prevalence and determinants of lithium induced polyuria suggested an increased risk of polyuria (urine volume > or =3 L/24 h) in those using serotonergic antidepressants next to lithium. OBJECTIVE The objective of our study was to re-evaluate this secondary finding in another study population. METHODS We performed a multicenter medical chart review study in patients using lithium in whom a 24-hour urine volume had been determined. RESULTS We included 116 patients, twelve (26%)of the 46 patients with polyuria used serotonergic antidepressants compared to ten (14%) of the 70 patients without polyuria. We found an increased risk of polyuria in lithium users concurrently using serotonergic antidepressants (oddsratio 2.86; 95% confidence interval 1.00-8.21), adjusted for age, gender, use of antiepileptics and thyreomimetics. CONCLUSION Our results confirm the previous secondary finding of an increased risk of polyuria in patients using serotonergic antidepressants next to lithium. Physicians should take this into account when evaluating polyuria in patients using lithium and when choosing an antidepressant in patients using lithium.