Other Warnings/Precautions

• If signs of neuroleptic malignant syndrome develop, treatment should be immediately discontinued

• Use with caution in patients with respiratory disorders, glaucoma, or urinary retention

• Use cautiously in patients with alcohol withdrawal or convulsive disorders because of possible lowering of seizure threshold

• Use with caution if at all in Parkinson’s disease or Lewy body dementia

• Avoid extreme heat exposure

• Antiemetic effect can mask signs of other disorders or overdose

• Do not use epinephrine in event of overdose as interaction with some pressor agents may lower blood pressure

• Because mesoridazine may dose-dependently prolong QTc interval, use with caution in patients who have bradycardia or who are taking drugs that can induce bradycardia (e.g., beta blockers, calcium channel blockers, clonidine, digitalis)

• Because mesoridazine may dose-dependently prolong QTc interval, use with caution in patients who have hypokalemia and/or hypomagnesemia or who are taking drugs that can induce hypokalemia and/or magnesemia (e.g., diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide)

• Mesoridazine can increase the QTc interval, potentially causing torsades de pointes-type arrhythmia or sudden death

Do Not Use

• If there is a history of QTc prolongation or cardiac arrhythmia, recent acute myocardial infarction, uncompensated heart failure

✽ If QTc interval greater than 450 msec or if taking an agent capable of prolonging the QTc interval

• If patient is in a comatose state or has CNS depression

• If there is a proven allergy to mesoridazine

• If there is a known sensitivity to any phenothiazine

MESORIDAZINE: SPECIAL POPULATIONS

Renal Impairment

• Use with caution

Hepatic Impairment

• Use with caution

Cardiac Impairment

• Mesoridazine produces a dose-dependent prolongation of QTc interval, which may be enhanced by the existence of bradycardia, hypokalemia, congenital, or acquired long QTc interval, which should be evaluated prior to administering mesoridazine

• Use with caution if treating concomitantly with a medication likely to produce prolonged bradycardia, hypokalemia, slowing of intracardiac conduction, or prolongation of the QTc interval

• Avoid mesoridazine in patients with a known history of QTc prolongation, recent acute myocardial infarction, and uncompensated heart failure

✽ Risk/benefit ratio may not justify use in cardiac impairment

Elderly

• Lower doses should be used and patient should be monitored closely

• Although conventional antipsychotics are commonly used for behavioral disturbances in dementia, no agent has been approved for treatment of elderly patients with dementia-related psychosis

• Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo, and also have an increased risk of cerebrovascular events

Children and Adolescents

• Safety and efficacy not established

Pregnancy

• Risk Category C [some animal studies show adverse effects; no controlled studies in humans]

• There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester; symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding

• Reports of extrapyramidal symptoms, jaundice, hyperreflexia, hyporeflexia in infants whose mothers took a phenothiazine during pregnancy

• Psychotic symptoms may worsen during pregnancy and some form of treatment may be necessary

• Atypical antipsychotics may be preferable to conventional antipsychotics or anticonvulsant mood stabilizers if treatment is required during pregnancy

• Mesoridazine should generally not be used during the first trimester

• Should evaluate for an antipsychotic with a better risk/benefit ratio if treatment is required during pregnancy

Breast Feeding

• Some drug is found in mother’s breast milk

• Effects on infant have been observed (dystonia, tardive dyskinesia, sedation)

✽ Recommended either to discontinue drug or bottle feed

MESORIDAZINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Only for patients who respond to this agent and not other antipsychotics

Potential Disadvantages

• Vulnerable populations such as children or elderly

• Patients on other drugs

Primary Target Symptoms

• Positive symptoms of psychosis in patients who fail to respond to treatment with other antipsychotics

• Motor and autonomic hyperactivity in patients who fail to respond to treatment with other antipsychotics

• Violent or aggressive behavior in patients who fail to respond to treatment with other antipsychotics

Pearls

✽ Generally, the benefits of mesoridazine do not outweigh its risks for most patients

✽ Because of its effects on the QTc interval, mesoridazine is not intended for use unless other options (at least 2 antipsychotics) have failed

• Mesoridazine has not been systematically studied in treatment-refractory schizophrenia

• Patients with inadequate responses to atypical antipsychotics may benefit from a trial of augmentation with a conventional antipsychotic or switching to a conventional antipsychotic

• However, long-term polypharmacy with a combination of a conventional antipsychotic with an atypical antipsychotic may combine their side effects without clearly augmenting the efficacy of either

• For treatment-resistant patients, especially those with impulsivity, aggression, violence, and self-harm, long-term polypharmacy with 2 atypical antipsychotics or with 1 atypical antipsychotic and 1 conventional antipsychotic may be useful or even necessary while closely monitoring

• In such cases, it may be beneficial to combine 1 depot antipsychotic with 1 oral antipsychotic

• Although a frequent practice by some prescribers, adding 2 conventional antipsychotics together has little rationale and may reduce tolerability without clearly enhancing efficacy

Suggested Reading

Frankenburg FR. Choices in antipsychotic therapy in schizophrenia. Harv Rev Psychiatry 1999;6:241–9.

Gardos G, Tecce JJ, Hartmann E, Bowers P, Cole JO. Treatment with mesoridazine and thioridazine in chronic schizophrenia: II. Potential predictors of drug response. Compr Psychiatry 1978;19:527–32.

Gershon S, Sakalis G, Bowers PA. Mesoridazine – a pharmacodynamic and pharmacokinetic profile. J Clin Psychiatry 1981;42:463–9.

METHYLFOLATE (L)

METHYLFOLATE (L): THERAPEUTICS

Brands

• Deplin

see index for additional brand names

Generic?

No

Class

• Medical food (bioavailable form of folate)

• Trimonoamine modulator

Commonly Prescribed for

(bold for FDA approved as medical food indications)

• Suboptimal folate levels in depressed patients (adjunct to antidepressant)

• Hyperhomocysteinemia in schizophrenia patients (adjunct to antipsychotic)

• Enhancement of antidepressant response at the initiation of treatment

• Cognitive or mood symptoms in patients with MTHFR (methylene tetrahydrofolate) deficiency

How the Drug Works

• Folate is a water-soluble B vitamin (B9) that is essential for cell growth/reproduction, breakdown/utilization of proteins, formation of nucleic acids, and other functions

• L-methylfolate, or 6-(S)-5-methyl-tetrahydrofolate, is derived from folate and is the form that enters the brain and works directly as a methyl donor and monoamine synthesis modulator

• That is, it regulates tetrahydrobiopterin (BH4), a critical enzyme cofactor for trimonoamine neurotransmitter synthesis

• Methyl donor for DNA methylation and thus an epigenetic regulator