Residency Psychiatry-Recent Updates- Brexpiprazole And Trofinetide

Brexpiprazole

Brexpiprazole is a D2 partial agonist, 5HT1A partial agonist, 5HT2A antagonist, and ?1,?2 antagonist. It shares many chemical and physiological similarities with aripiprazole.

Compared to aripiprazole, brexpiprazole has comparatively greater D2 partial agonist activity as well as 5HT2A antagonism, 5HT1 partial agonism, and ?1 antagonism.

Brexpiprazole is thought to have a lower potential for causing motor adverse effects, such as akathisia, than aripiprazole.
Because of the antagonistic relationship between 5HT 2A and ?1, there is an increase in the pyramidal glutaminergic neurons that innervate the considerable niagra. Following this, there is a drop in GABA tone, which causes the dopamine neurons in the substantia nigra to disperse. Brexpiprazole hence has a lower rate of drug-induced parkinsonism.

Psychotic medications including clozapine, quetepine, and iloperidone have a lower tendency to generate EPS because of their comparable effects on 5HT partial antagonism and ?1 antagonism.

Brexpiprazole was initially licensed by the FDA in 2015 for use as an adjuvant therapy to antidepressants in adults with major depressive disorders. It was also approved for the treatment of adult schizophrenia.

As a result, the medication was made available for use in 2021 to treat schizophrenia in adolescents older than 13 years old.

Brexpiprazole has a statistically significant treatment effect in reducing agitation over a 12-week period, according to several phase 3 12-week randomized placebo-controlled studies. Its safety profile is similar to that of other treatments for adults with major depressive disorder and schizophrenia.

The FDA approved a medication in 2023 to treat agitation brought on by dementia from Alzheimer's disease.

The cortex innervates in a top-down manner. In order to help the thalamus filter out emotional input, the pyramidal glutaminergic neurons in the striatum release glutamate, which is then followed by the production of GABA in the thalamus. The amygdala, the locus coeruleus, the cortex, and the ventral tegmental region are all recipients of thalamic output.

The loss of pyramidal neurons in Alzheimer's disease affects the top-down innervation. As a result, there is less inhibition of the GABA input to the thalamus. Agitation in Alzheimer's disease is caused by an increase in the emotional input to the amygdala, locus coeruleus, cortex, and ventral tegmental region, as a result of partial thalamic filtering out.

Brexpiprazole acts on a number of receptors; • It is helpful in reducing agitation. Brexpiprazole and ?2 antagonistism exist. Brexpiprazole and norepinephrine from the local coeruleus operate antagonistically. Thus, the level of arousal has decreased.

Brexpiprazole and 5HT2A antagonistic interactions exist. Thus, raphe serotonin is blocked. Because of its partial agonist effect, it reduces limbic agitation and increases 5HT inhibition.

  Early research on the combination of brexpiprazole and sertraline, two SSRIs, appears promising for treating PTSD, particularly in cases where ⍺1 antagonism is present.

Pharmacokinetics

After a single dose, the peak plasma concentration typically happens four hours later. It is highly bound—more than 99%—to albumin and ⍺1 glycoprotein.

Metabolism & Elimination

The primary enzymes involved in the metabolism of brexpiprazole are CYP3A4 and CYP2D6. • The terminal elimination half-life (T1/2) of brexpiprazole is 91 hours, whereas the T1/2 of its primary metabolite, DM3411, is 86 hours. 

Dosage Strength

Brexpiprazole pills come in strengths of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg.  0.5 mg once daily is the recommended dosage for agitation related to dementia from day 1 to day 7.  The suggested dosage is 1 mg once daily for days 8 through 14, and 2 mg for days 15 and beyond.

After at least 14 days, the dose can be increased to the maximum recommended amount of 3 mg once daily, depending on clinical response and tolerability.

A dose of 2 mg once daily is the maximum advised for patients with moderate to severe hepatic impairment and renal impairment with a Crcl of less than 60 ml/min.

Side-Effects 

Brexpiprazole frequently causes headache, vertigo, nasopharyngitis, urinary tract infections, and sleep issues like somnolence and sleeplessness.

The boxed warning states that there is a higher risk of death for elderly individuals receiving antipsychotic strength treatment for psychosis due to dementia.

Additionally, when children, adolescents, and young adults older than or equal to 24 years old use antidepressants for major depressive disorder or other purposes, they are more likely to experience suicide thoughts and behaviors when compared to a placebo.

Warning & Precautions

Brexpiprazole comes with cautions and warnings about cardiovascular adverse effects in older individuals with neuroleptic metabolic syndromes, tardive dyskinesia, psychosis associated to dementia, and metabolic abnormalities.In addition, syncope, leukopenia, neutropenia, agranulocytosis, orthostatic hypotension, pathological gambling, and other obsessive behaviors could happen.

Seizures, the possibility of falls, particularly in the elderly, dysphagia, dysregulation of body temperature, and cognitive and motor impairment are further cautions and warnings.

Contraindications

Any known sensitivity to brexpiprazole or any of its ingredients is contraindicated.

Trofinetide

Trofinetide, an artificial analogue of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor-1, is a tripeptide.

The FDA will begin to approve trofinetide in 2023 for the treatment of Rett syndrome in adults and pediatric patients who are older than or equal to two years.

It is classified as a Rett syndrome orphan medication.

The precise function of trofinetide has not yet been determined; the current consensus recommendations for the treatment of Rett syndrome center on supportive care strategies for progressing multisystem symptoms.

Adverse Effects

The adverse effects of trofinetide are diarrhea and vomiting.

Warnings & Precautions

Patients who have diarrhea are encouraged to stop using laxatives before starting trofinetide, and they should also let their doctor know if they do.  When there is severe diarrhea or a suspicion of dehydration, it is advised to reduce, stop, or alter the dosage.

If weight loss occurs, weight should be tracked while receiving treatment.  If there is a noticeable drop in weight, it is advised to stop taking the medication altogether, reduce it, or stop entirely.

Dosage & Administration

 An oral solution containing 200 mg/ml of trofinetide is offered.
One possible way to administer it is via a gastrotomy tube.

G-Port is required to administer the dosage via a gastrojejunal tube.  Meals can be consumed or not when taking it.

If a dose is missed, it should be skipped and the subsequent dose should be taken on a regular basis; if a dose is vomited, it should not be taken again.  Adult patients older than two years old who are classified as pediatric patients receive a weight-based dosage administered twice a day in the morning and evening.

For weights ranging from 9 to less than 12 kg, the dosage is 5000 mg twice daily.  For people weighing 12 to less than 20 kg, the dosage is 6000 mg twice daily.

For individuals weighing 20 to less than 35 kg, the dosage is 8000 mg twice daily.  For individuals weighing 35 to less than 50 kg, the dosage is 10,000 mg twice a day.  For weights greater than or equal to 50 kg, the dosage is 12000 mg twice daily.

Severe diarrhea, marked weight loss, or suspected dehydration should all be treated with a dose reduction, interruption, or discontinuation.  Patients with moderate to severe renal impairment should not use it.

Pharmacokinetics

The highest plasma concentration was reached two to three hours after oral treatment. Excretion of the medicine occurs mostly as an unmodified substance in urine, up to 80% of it, and very little in feces. There is a 1.5-hour t1/2.

Storage

The remedy is oral in nature. It should therefore be kept between 2 and 8 degrees. It ought not to be kept frozen.

After opening the bottle, you should throw away any leftover trofinetide solution within 14 days.

Also Read: Recent Updates In Lecanemab

Hope you found this blog helpful for your Psychiatry residency Neurology and General Medicine preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.