Drug Interactions

• Respiratory depression may occur when loxapine is combined with lorazepam

• Additive effects may occur if used with CNS depressants

• May decrease the effects of levodopa, dopamine agonists

• Some patients taking a neuroleptic and lithium have developed an encephalopathic syndrome similar to neuroleptic malignant syndrome

• Combined use with epinephrine may lower blood pressure

• May increase the effects of antihypertensive drugs except for guanethidine, whose antihypertensive actions loxapine may antagonize

Other Warnings/Precautions

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

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

• 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

• Use cautiously in patients with glaucoma, urinary retention

• Observe for signs of ocular toxicity (pigmentary retinopathy, lenticular pigmentation)

• Avoid extreme heat exposure

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

Do Not Use

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

• If patient has asthma or history of asthma, chronic obstructive pulmonary disease, other lung disease associated with bronchospasm, acute respiratory signs/symptoms, current use of medications to treat airways, history of bronchospasm following treatment with loxapine inhalation powder (inhalant only)

• If there is a proven allergy to loxapine

• If there is a known sensitivity to any dibenzoxazepine

LOXAPINE: SPECIAL POPULATIONS

Renal Impairment

• Use with caution

Hepatic Impairment

• Use with caution

Cardiac Impairment

• Use with caution

Elderly

• Some patients may tolerate lower doses better

• 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

• Generally, consider second-line after atypical antipsychotics

Pregnancy

• Renal papillary abnormalities have been seen in rats during pregnancy

• No studies in pregnant women

• 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

• 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

Breast Feeding

• Unknown if loxapine is secreted in human breast milk, but all psychotropics assumed to be secreted in breast milk

✽ Recommended either to discontinue drug or bottle feed

LOXAPINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Intramuscular formulation for emergency use

Potential Disadvantages

• Patients with tardive dyskinesia

Primary Target Symptoms

• Positive symptoms of psychosis

• Motor and autonomic hyperactivity

• Violent or aggressive behavior

Pearls

✽ Recently discovered to be a serotonin dopamine antagonist (binding studies and PET scans)

✽ Active metabolites are also serotonin dopamine antagonists with longer half-lives than parent drug, thus possibly allowing once daily treatment

✽ One active metabolite is an antidepressant (amoxapine, also known as N-desmethyl-loxapine)

• Theoretically, loxapine should have antidepressant actions, especially at high doses, but no controlled studies

• Theoretically, loxapine may have advantages for short-term use in some patients with psychotic depression

• Developed as a conventional antipsychotic; i.e., reduces positive symptoms, but causes extrapyramidal symptoms and prolactin elevations

• Lower extrapyramidal symptoms than haloperidol in some studies, but not fixed-dose studies and no low-dose studies

✽ Causes less weight gain than other antipsychotics, both atypical and conventional, and may even be associated with weight loss

• No formal studies of negative symptoms, but some studies show superiority to conventional antipsychotics for emotional withdrawal and social competence

• Best use may be as low-cost augmentation agent to atypical antipsychotics

✽ Enhances efficacy in clozapine partial responders when given concomitantly with clozapine

• For previously stabilized patients with “breakthrough” agitation or incipient decompensation, “top-up” the atypical antipsychotic with as-needed intramuscular or oral single doses of loxapine

• An inhalation powder for acute agitation is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ADASUVE REMS

• Due to the risk of bronchospasm, loxapine inhalation powder should be administered only in an enrolled health-care facility that has immediate onsite access to equipment and personnel trained to manage acute bronchospasm, including advanced airway management (intubation and mechanical ventilation)

• Patients have very similar antipsychotic responses to any conventional antipsychotic, which is different from atypical antipsychotics where antipsychotic responses of individual patients can occasionally vary greatly from one atypical antipsychotic to another

• Patients with inadequate responses to atypical antipsychotics may benefit from determination of plasma levels and, if low, a dosage increase even beyond the usual prescribing limits

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

• However, long-term polypharmacy with a combination of a conventional antipsychotic such as loxapine 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

Chakrabarti A, Bagnall A, Chue P, et al. Loxapine for schizophrenia. Cochrane Database Syst Rev 2007;17(4):CD001943.

Fenton M, Murphy B, Wood J, Bagnall A, Chue P, Leitner M. Loxapine for schizophrenia. Cochrane Database Syst Rev 2000;(2): CD001943.

Heel RC, Brogden RN, Speight TM, Avery GS. Loxapine: a review of its pharmacological properties and therapeutic efficacy as an antipsychotic agent. Drugs 1978;15(3): 198–217.

Zisook S, Click MA Jr. Evaluations of loxapine succinate in the ambulatory treatment of acute schizophrenic episodes. Int Pharmacopsychiatry 1980;15(6):365–78.

LURASIDONE

LURASIDONE: THERAPEUTICS

Brands

• LATUDA

see index for additional brand names

Generic?

No

Class

• Atypical antipsychotic (serotonin-dopamine antagonist; second generation antipsychotic; also a potential mood stabilizer)

Commonly Prescribed for

(bold for FDA approved)

• Schizophrenia

• Bipolar depression

• Acute mania/mixed mania

• Other psychotic disorders

• Bipolar maintenance

• Treatment-resistant depression

• Behavioral disturbances in dementia

• Behavioral disturbances in children and adolescents

• Disorders associated with problems with impulse control

How the Drug Works

• Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms

• Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognition and affective symptoms

• Potently blocks serotonin 7 receptors, which may be beneficial for mood, sleep, cognitive impairment, and negative symptoms in schizophrenia, and also in bipolar disorder and major depressive disorder

• Partial agonist at 5HT1A receptors, and antagonist actions at serotonin 7 and alpha 2A and alpha 2C receptors, which may be beneficial for mood, anxiety and cognition in a number of disorders

• Lacks potent actions at dopamine D1, muscarinic M1, and histamine H1 receptors, theoretically suggesting less propensity for inducing cognitive impairment, weight gain, or sedation compared to other agents with these properties