https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(03)12520-2.pdf

Population stratification and spurious allelic association.

OBJECTIVE: The term “mood stabilizer” is widely used in the context of treating bipolar disorder, but the U.S. Food and Drug Administration (FDA) does not officially recognize the term, and no consensus definition is accepted among investigators. The authors propose a “two-by-two” definition by which an agent is considered a mood stabilizer if it has efficacy in treating acute manic and depressive symptoms and in prophylaxis of manic and depressive symptoms in bipolar disorder. They review the literature on the efficacy of agents in any of these four roles to determine which if any agents meet this definition of mood stabilizer. METHOD: The authors conducted a comprehensive review of English-language literature describing peer-reviewed, U.S. Agency for Healthcare Research and Quality class A controlled trials in order to identify agents with efficacy in any of the four roles included in their definition of a mood stabilizer. The trials were classified as positive or negative on the basis of primary outcom...

/pdf/what-is-a-mood-stabilizer-an-evidence-based-response-26crczq72d.pdf

What Is a “Mood Stabilizer”? An Evidence-Based Response

Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism.

Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450–metabolized drugs

After a single dose, lithium, usually given as carbonate, reaches a peak plasma concentration at 1.0-2.0 hours for standard-release dosage forms, and 4-5 hours for sustained-release forms. Its bioavailability is 80-100%, its total clearance 10-40 mL/min and its elimination half-life is 18-36 hours. Use of the sustained-release formulation results in 30-50% reductions in peak plasma concentrations without major changes in the area under the plasma concentration curve. Lithium distribution to the brain, evaluated using 7Li magnetic resonance spectroscopy, showed brain concentrations to be approximately half those in serum, occasionally increasing to 75-80%. Brain concentrations were weakly correlated with serum concentrations. Lithium is almost exclusively excreted via the kidney as a free ion and lithium clearance is considered to decrease with aging. No gender- or race-related differences in kinetics have been demonstrated. Renal insufficiency is associated with a considerable reduction in renal clearance of lithium and is considered a contraindication to its use, especially if a sodium-poor diet is required. During the last months of pregnancy, lithium clearance increases by 30-50% as a result of an increase in glomerular filtration rate. Lithium also passes freely from maternal plasma into breast milk. Numerous kinetic interactions have been described for lithium, usually involving a decrease in the drug's clearance and therefore increasing its potential toxicity. Clinical pharmacology studies performed in healthy volunteers have investigated a possible effect of lithium on cognitive functions. Most of these studies reported a slight, negative effect on vigilance, alertness, learning and short-term memory after long-term administration only. Because of the narrow therapeutic range of lithium, therapeutic monitoring is the basis for optimal use and administration of this drug. Lithium dosages should be adjusted on the basis of the serum concentration drawn (optimally) 12 hours after the last dose. In patients receiving once-daily administration, the serum concentration at 24 hours should serve as the control value. The efficacy of lithium is clearly dose-dependent and reliably correlates with serum concentrations. It is now generally accepted that concentrations should be maintained between 0.6 and 0.8 mmol/L, although some authors still favour 0.8-1.2 mmol/L. With sustained-release preparations, and because of the later peak of serum lithium concentration, it is advised to keep serum concentrations within the upper range (0.8-1 mmol/L), rather than 0.6-0.8 mmol/L for standard formulations. It is controversial whether a reduced concentration is required in elderly people. The usual maintenance daily dose is 25-35 mmol (lithium carbonate 925-1300 mg) for patients aged 60 years. The initial recommended dose is usually 12-24 mmol (450-900 mg) per day, depending on age and bodyweight. The classical administration schedule is two or three times daily, although there is no strong evidence in favour of a three-times-daily schedule, and compliance with the midday dose is questionable. With a modern sustained-release preparation, the twice-daily schedule is well established, although one single evening dose is being recommended by a number of expert panels.

Lithium: updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring.

SUMMARY

Background: In clinical trials of acute mania, a number of measures have been used to assess the severity of illness and its response to treatment. Rating instruments need to be validated in order for a clinical study to provide reliable and meaningful estimates of treatment effects.



Objective: To critically assess rating scales used in measuring mania.



Method: A systematic search of the literature, retrieval of reports of clinical trials of drugs used in mania and the rating scales and a critical and systematic appraisal of their quality.



Results: Eight symptom-rating scales were identified. The Mania Rating Scale (MRS) was the most commonly used for assessing treatment response. Two more recently developed scales are the Manchester Nurse Rating Scale for Mania (MNRS-M) and the Clinician-Administered Rating Scale for Mania (CARS-M). The latter appears well validated but its in-use reliability needs to be explored further. The translation of observed changes in instrumental ratings into clinically meaningful change has to be established further. In particular, the relative weighting to be attached to the individual items needs further study. The advantage of the MRS is that there is a relatively extensive database of studies based on it and this will no doubt ensure that it remains a gold standard for the foreseeable future.



Conclusion: Useful rating scales are available for measuring mania but further cross-validation and validation against clinically meaningful global changes are required.

Measuring mania and critical appraisal of rating scales.

A method has been proposed for extracting numerical data when only graphical results are presented. Reports with both graphical and tabular data were identified and the graphs were electronically scanned. The coordinates of each point were read using the cross-hair facility of Adobe Photoshop 7.0. To improve the precision of these coordinates, each point was read at 1600% magnification. The agreement between the observers was almost perfect (R > 0.99). The proposed method makes possible use of data in meta-analyses that, would otherwise be discarded.

Extracting numerical data from published reports of pharmacokinetics investigations: method description and validation

Objective: To evaluate the efficacy of lithium in the treatment of acute mania.



Method: Systematic overview of the literature and meta-analysis of randomised controlled trials. Estimation of (i) the differences in the reduction in mania severity scores, and (ii) the ratio and difference in improvement response rates.



Results: A total of 658 patients from 12 trials were included. Treatment periods ranged from 3 to 4 weeks. The response rate ratio for lithium against placebo was 1·95 (95%CI 1·17–3·23). The mean number needed to treat was five (95%CI 3–20). Patients were twice as likely to obtain remission with lithium than with chlorpromazine (rate ratio = 1·96, 95%CI 1·02–3·77). The mean number needed to treat was four (95%CI 3–9). Neither carbamazepine nor valproate was more effective than lithium. The response rate ratios were 1·01 (95%CI 0·54–1·88) for lithium compared to carbamazepine and 1·22 (95%CI 0·91–1·64) for lithium against valproate. Haloperidol was no better than lithium on the basis of improvement based on assessment of global severity. The differences in effects between lithium and risperidone were –2·79 (95%CI –4·22 to –1·36) in favour of risperidone with respect to symptom severity improvement and –0·76 (95%CI –1·11 to –0·41) on the basis of reduction in global severity of disease. Symptom and global severity was as well controlled with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate.



Conclusion: The clinical trial evidence suggests that lithium should remain the first line treatment for acute mania.

Systematic overview of lithium treatment in acute mania.

Response to drugs can vary between individuals and between different ethnic populations. The biological (age, gender, disease and genetics), cultural and environmental factors which contribute to these variations are considered in this review. The most important aspect is the genetic variability between individuals in their ability to metabolize drugs due to expression of 'polymorphic' enzymes. Polymorphism enables division of individuals within a given population into at least two groups, poor metabolisers (PMs) and extensive metabolisers (EMs) of certain drugs. The two most extensively studied genetic polymorphisms are those involving cytochrome P450 2D6 (CYP2D6) and CYP2C19. CYP2D6 metabolizes a number of antidepressants, antipsychotics, beta-adrenoceptor blockers, and antiarrhythmic drugs. About 7% of Caucasians and 1% of Asians are PMs of CYP2D6 substrates. CYP2C19 enzyme participates in the metabolism of omeprazole, propranolol and psychotropic drugs such as hexobarbital, diazepam, citalopram, imipramine, clomipramine and amitriptyline. The incidence of PMs of CYP2C19 substrates is much higher in Asians (15-30%) than in Caucasians (3-6%). Variations in metabolism of psychotropic drugs result in variations in their pharmacokinetic parameters. This may lead to clinically significant intra- and inter-ethnic differences in pharmacological responses. Such variations are discussed in this review. Differential receptor-mediated response may play a role in ethnic differences in responses to antipsychotics and tricyclic antidepressants, but such pharmacodynamic factors remain to be systematically investigated. The results of studies of ethnic differences in response to psychopharmacotherapy appear to be discrepant, most probably due to limitations of study design, small sample size, inadequately defined study sample, and lack of control of confounding factors. The clinical value of understanding pharmacogenetics is in its use to optimize therapeutic efficacy, to prevent toxicity of those drugs whose metabolism is catalysed by polymorphic isoenzymes, and to contribute to the rational design of new drugs. Finally, applications and impact of pharmacogenetics in the field of psychopharmacotherapy are discussed.

Pharmacogenetics and psychopharmacotherapy.

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Papers

Measuring mania and critical appraisal of rating scales.

Extracting numerical data from published reports of pharmacokinetics investigations: method description and validation

Systematic overview of lithium treatment in acute mania.

Pharmacogenetics and psychopharmacotherapy.