Agents to Treat the Side Effects of Antipsychotic Medications

A Tale of Four Pathways

Psychosis is found in patients with schizophrenia, bipolar disorder, mood disorders, and drug abuse. These symptoms are often treated with antipsychotic medications (Sadock, Sadock & Ruiz, 2015). Antipsychotics are effective in treating the positive symptoms (i.e. hallucinations, delusions, racing thoughts) of psychosis by blocking a specific dopaminergic pathway, the mesolimbic pathway. There are four dopaminergic pathways: mesolimbic, mesocortical, tuberoinfundibular, and nigrostriatal. Antipsychotic medications are not sparing in terms of these pathways, and this is what requires more of a careful consideration to prescribe (Sadock et al., 2015).

Mesolimbic Pathway

The Mesolimbic pathway’s job is to guide motivational behaviors, memory, and the processing of information and other stimuli. Antipsychotics relieve positive symptoms by creating an antagonist effect on the mesolimbic pathway (Sadock et al., 2015). When a drug antagonizes a pathway, it may block it or reduce the effectiveness of that pathway. Typical antipsychotics are successful in reducing positive symptoms but not eliminating them. It is common that a schizophrenic patient will see around a third of all positive symptoms reduced (Stahl, Grady&Muntner, 2017).

Blocking the remaining pathways is not the goal of prescribing an antipsychotic medication. In fact, blockade of the other three pathways causes many problems as discussed below (Sadock et al., 2015).

Mesocortical Pathway

The mesocortical pathway is related to communication, stress response, and cognition. This pathway is already thought to be underactive in patients with schizophrenia. Blocking or decreasing activity in this pathway can create difficulties with thought and speech, apathy, reduction in a drive to be social, decreased motivation, and an inability to feel pleasure. These are known as negative symptoms.The dopaminergic antagonist effect on the mesocortical pathway creates mental deficiencies and a lack of emotions. Typical antipsychotics block this pathway more than atypical antipsychotics. This is because typical antipsychotics have a stronger affinity for dopamine receptors than do atypical antipsychotics. Also, atypicals have faster disassociation from dopamine receptors than typicals. This means typicals have more of an effect on dopamine pathways, and they do so for longer periods of time. Sometimes,atypical antipsychotics can even reduce the negative effects a disease can have on this pathway. This is because atypicals bind to multiple other receptor sites and often decrease reuptake in neurotransmitters other than dopamine.

Tuberoinfundibular Pathway

The tuberoinfundibular pathway is associated with the release of prolactin, so the dopaminergic antagonist effect on this pathway can cause hyperprolactinemia. Hyperprolactinemia is a condition where an individual has higher-than-ordinary dimensions of the hormone prolactin in the blood. The primary job of prolactin is to stimulate the production of breast milk after labor, so high prolactin levels are typical in pregnancy. Men who suffer from hyperprolactinemia often suffer sexual dysfunction and gynecomastia.

Nigrostriatal Pathway

The nigrostriatal pathway is associated with the extrapyramidal system, and controls motor function and movement. The dopaminergic effect on the nigrostriatal pathway results in movement disorders known asextrapyramidal symptoms (EPS). Not having enough dopamine in this pathway can lead to acute dystonia (spasms and muscle contractions), akathisia (motor restlessness), and parkinsonism (rigidity, tremor, bradykinesia, and postural instability).Too much dopamine in this pathway can lead to hyperkinetic movements (irregular, jerky movements). When the nigrostriatal pathway is chronically blocked, this creates dysfunction called tardive dyskinesia (TD). This disorder causes tongue and facial movements, such as constant chewing, tongue protrusions, and facial grimacing. TD can also cause involuntary limb movements that can be quick or jerky. This disorder can be irreversible, and is consistently the most difficult EPS to treat.

High potency typical antipsychotics like haloperidol (Haldol) produce stronger antipsychotic effects at lower doses, but they tend to cause more EPS and hyperprolactinemia (Sadock et al., 2015). The less selective low potency typical antipsychotics like Chlorpromazine (Thorazine) do not bind to dopamine receptors as tightly as high potency atypical antipsychotics and tend to have more of an effect on alpha1- adrenergic, histamine, and muscarinic receptors. In addition to blocking dopamine, antipsychotics also influence alpha-1 adrenergic, histamine, and muscarinic receptors, which account for additional side effects from their use (Sadock et al., 2015). Blockade of the alpha-1 adrenergic receptors can lead to a decrease in blood pressure.Blockade of muscarinic receptors can lead to anticholinergic symptoms like dry mouth, blurred vision, difficulty urinating, and constipation. Blockade of histamine receptors can lead to sedation and weight gain (Sadock et al., 2015).

The challenge with treating positive symptoms associated with psychosis is having an adequate percentage of dopamine blockade, while not blocking dopamine too much causing the unwanted side effects of antipsychotics (Sadock et al., 2015). Atypical antipsychotics do not cause as many side effects as typical antipsychotics, and this is due to their transient blockage of dopamine. Atypical antipsychotics have varying degrees of dopaminergic activity compared to typical antipsychotics (Stahl et al., 2017).

There are different ways to manage the side effects of antipsychotics, in particular EPS(Kusumi& Koyama, 1999). The provider could prescribe a different antipsychotic, lower the dose of the existing medication, or add a drug that is effective in treating EPS. Anticholinergics like Benztropine and Trihexyphenidyl are the first line treatment for acute dystonia.Patients that have acute dystonia exhibit a good response to a combination of an anticholinergic and a benzodiazepine. Anticholinergics, benzodiazepines, and beta blockers are successful in treating akathisia. Antihistaminergic medications like Diphenhydramine can also be beneficial in treating akathisia. To treat Parkinsonian symptoms the first line medications are anticholinergic medications like Trihexyphenidyl (Kusumi& Koyama, 1999).

TD usually affects patients that have been on long term therapy of antipsychotics, but in some cases, it can occur after shorter medication trials. The cause of how this works is not known for sure, but it is hypothesized that after years of being blocked by antipsychotics drugs, the result is that these receptors become very sensitive or they upregulate (Stahl et al., 2017). This means that there is an increase in number of the dopamine receptors. This is the brain’s attempt to make up for the dopamine receptors being chronically blocked A way to understand TD would be to think of a busy interstate. The traffic building up on the interstate causes a traffic jam that eventually leads to the cars all coming to a stop. In an effort to allow the cars to get to where they are going, many exits are built off of the main interstate that will allow cars to pass. Over time, there are so many exits that allow cars to pass that there is now too much traffic getting to the destinations where the cars are going. After chronically blocking dopamine receptors, the brain creates more receptors for the dopamine to adhere to. After years of the brain rewiring itself, there are now too many receptors for the dopamine to be in contact with.This can cause too much dopaminergic activity. Too much dopamine will cause hyperkinetic activity like TD (Stahl et al., 2017).TD can be more challenging to treat than other EPS. Valbenazine and Deutetrabenazine, which are in a class of medications called vesicular monoamine transporter 2 (VMAT2) inhibitors, have been shown in studies to be effective in treating TD.

Anticholinergic Agents

Trihexyphenidyl and Benztropineare examples of anticholinergic medications that are used to treat EPS. Anticholinergics reduce movement disorders by decreasing the excess acetylcholine activity caused by reduction of dopamine inhibition when dopamine receptors are blocked(Stahl et al., 2017). Dopamine normally regulates levels of acetylcholine, so when dopamine is blocked an excess of acetylcholine occurs. The onset of action for these medications can be anywhere from minutes to hours when treating EPS. Anticholinergic medications work by reducing the motor side effects that a patient has, but do not decrease the chance for the development of TD. If monotherapy with ananticholinergic medication does not work the next step would be to try a different anticholinergic medication, switch to a benzodiazepine medication, or an antihistamine medication. EPS that develops after long-term use of an antipsychotic medication have a lower chance of responding to treatment with an anticholinergic medication (Stahl et al., 2017).

Diphenhydramine can be classified as an anticholinergic agentand an antihistamine (Stahl et al., 2017). Like other agents with anticholinergic properties, diphenhydramine reduces movement disorders by decreasing the excess acetylcholine activity caused by reduction of dopamine inhibition when dopamine receptors are blocked. Diphenhydramine additionally treats EPS with its potent histamine 1 properties (Stahl et al., 2017). H1-antihistamines were developed from anticholinergic drugs, and act as inverse agonists instead of antagonists of histamine H1-receptors which are members of the G-protein family (Church & Church, 2013).Diphenhydramine has a similar onset and properties as other anticholinergic agents. If effective therapy is not reached with diphenhydramine the patient should take trihexyphenidyl, benztropine, or a benzodiazepine (Stahl et al., 2017).

Research suggests that anticholinergic agents are beneficial in treating EPS like dystonia, akathisia, and parkinsonianism, but chronic administration of anticholinergic agents can also increase the incidence and severity of TD(Bergman & Soares-Weiser, 2018). Antipsychotics decrease the accessibility of dopamine to dopaminergic striatal receptors, thus causing EPS (Klawans&Rubovits, 1974).Cholinergic pathways also effect the function of striatal receptors. Acetylcholine has been shown to have an opposite effect on the striatum than that of dopamine. For normal functioning to occur on the striatum there must be a balance between acetylcholine and dopamine. This relationship is the likely cause of increased incidence and severity of TD after the chronic administration of anticholinergic agents (Klawans&Rubovits, 1974). In addition, some evidence indicates that the administration of anticholinergic agents is associated with worsening cognitive performance either through acute delirium or with chronic mild cognitive impairment (Campbell et al., 2009).

Trihexyphenidyl

Brand Names: Artane, Apo-Trihex, Parkin, Pacitane

Adverse Effects: Serious reactions include glaucoma (angle-closure), blindness, anhidrosis, hyperthermia, heat stroke, neuroleptic malignant syndrome (NMS), tardive dyskinesia, psychosis (anticholinergic), bradycardia (paradoxical). Common reactions include xerostomia, blurred vision, dizziness, nausea, anxiety, confusion, parotitis, xeroderma, cycloplegia, constipation, drowsiness, urinary retention, tachycardia, and headache.

Dosing: (for EPS) 5-15 mg/day by mouth divided 3x/day-4x/day. Start 1 mg by mouth/day and repeat in several hours as needed. Maximum dose: 15 mg /day. Patient teaching: take with food; doses greater than 10 mg/day divide into 4 doses; taper dose gradually to discontinue.

Benztropine

Brand Name: Cogentin

Adverse Effects: Serious reactions include tachycardia, psychosis (anticholinergic), heat stroke. Common reactions include xerostomia, constipation, urinary retention, tachycardia, sedation, dyspnea, nausea, vomiting, flatulence, anorexia, abdominal pain, rash, pruritus, dizziness, headache, nervousness, tinnitus, edema, blurred vision.

Dosing: (for EPS) 1-4mg by mouth/intramuscular injection/intravenously per day - twice a day. For transient symptoms after the initiation of antipsychotic treatment, use 1-2mg by mouth twice a day/three times a day to prevent recurrence.

Diphenhydramine

Brand Names: Benedryl, Sominex

Adverse Effects: The blockade of histamine 1 receptors often causes sedation. Serious reactions include (rare) convulsions that are experienced sometimes at higher doses, urinary retention, tachycardia, confusion, paralytic ileus. Common reactions include sedation, dizziness, constipation, nausea, dry mouth, blurred vision

Dosing: (for EPS) 25-50 mg by mouth/IV/IM every 6-8 hours as needed. Injection: 25-50 mg intravenously at a rate not exceeding 25 mg/min or deep intramuscularly: can be dosed at 100 mg if required: maximum daily dose is 400 mg. Injection should only be used if oral therapy is contraindicated.

Beta Blockers

Beta blockers, like propranolol, have several uses in both medical and mental health disorders (Stahl et al., 2017). Propranolol are used to prevent migraines, hypertension, angina, cardiac arrythmias, myocardial infarction, anxiety, PTSD, and in the treatment of antipsychotic side effects like akathisia and parkinsonian tremors. Propranolol has many different mechanisms of action (MOA) that make it effective for treating cardiac disorders, but the MOA that enables it work to combat EPS is antagonism of beta 1 receptors. The medication causes a reduction in the tremor that the patient experiences, which allows them to have an increased level of functioning with activities and the ability to speak more clearly(Stahl et al., 2017).

Propranolol

Brand Names: Inderal, Inderal LA, InnoPran XL

Adverse effects: Serious side effects include blunt premonitory symptoms of hypoglycemia, mask signs of hyperthyroidism, and inhibition of bronchodilation (contraindicated in asthma and COPD patients). Common side effects include bradycardia, hypotension, hyper-or hypoglycemia, weight gain, bronchospasm, colf/flu symptoms, dizziness, vertigo, fatigue, depression, sleep disturbances, sexual dysfunction, and urinary retention

Dosing: For tremor the initial dose of 40mg twice per day: the dose may be gradually increased as needed to 120-320 mg per day in 2-3 divided doses.

Benzodiazepines

One of the most prominent EPS is akathisia, which is a state of agitation, distress, and restlessness. To understand the feeling a person feels when they suffer from akathisia try drinking eight shots of espresso and then attempt to sit still. Benzodiazepines like lorazepam are used to treat the symptom of akathisia. Lorazepam works by binding to benzodiazepine receptors at the GABA-A- ligand gated chloride channel complex (Stahl et al., 2017). GABA is the main inhibitory neurotransmitter of the brain. This action has earned GABA the name “breaks of the brain”. GABA is what enables person to slow down. Lorazepam enhances the effects of GABA, which helps to control EPS like akathisia.

Lorazepam

Brand Name: Ativan

Adverse effects: Serious side effects include respiratory depression, especially if the medication is taken with a CNS depressant. It can rarely cause hepatic dysfunction, renal dysfunction, and blood dyscrasias. Common side effects include sedation, fatigue, depression, dizziness, ataxia, slurred speech, weakness, confusion, and forgetfulness.

Dosing: Lorazepam can be dosed at 1 to 2 mg/day to treat acute akathisia.

Vesicular monoamine transporter 2 (VMAT2) inhibitors

Tardive dyskinesia (TD) is a group of hyperkinetic movement disorders that are associated with the use of dopamine receptor blocking agents like antipsychotics (Uhlyar& Rey, 2018).TD most commonly presents with involuntarymovements of the tongue, lips, face, and extremities. The Abnormal Involuntary Movement Scale (AIMS) is commonly used by providers who have prescribed antipsychotics to patients to assess the symptoms that are associated with TD. In 2017 the FDA approved Valbenazineto be the first medication for the treatment of TD in adults. Previously there had been no medication for TD treatment that had been studied adequately, and the only treatment options for providers were off label medications and supplements like gingko biloba, clozapam, and tetrabenazine. Valbenazineand deutetrabenazinetreat TD through the reversible inhibition of VMAT2. VMAT2 is found in the central nervous system and its job is transporting and storage of neurotransmitters like dopamine, serotonin, and norepinephrine across the synapse. Inhibiting VMAT2 causes augmentation of neurotransmitter degradation which results in a depletion of presynaptic neurotransmitters, most notably dopamine. The neurotransmission of dopamine is vital for motor control and hyperkinetic disorders like TD is often associated with the dysregulation of this process (Uhlyar& Rey, 2018).

This previously discussed dysregulation is a result of the brain’s attempt to compensate for chronically blocked dopamine receptors by creating an increased number of new receptors.

Tetrabenazine, which is also a VMAT2 inhibitor, is used to treat the movement disorder chorea that is caused by Huntington’s disease (Touma &Scarff, 2018). Tetrabenazine’s off label use in the treatment of TD was not effective due to the need for frequent dosing, plasma fluctuations, and serious adverse effects. Deutetrabenazine utilizes a nontoxic deuterium isotope instead of hydrogen, like tetrabenazine, which enables slower metabolization. It is believed that this slower metabolization process leads to a decrease in plasma fluctuations and adverse effects seen in the use of deutetrabenazine. Deutetrabenazine still has many serious side effects that are listed below (Touma &Scarff, 2018).

Valbenazine

Brand Name: Ingrezza

Adverse Effects: Serious side effects include somnolence and QT prolongation. Common side effects include balance problems, akathisia, headache, nausea, vomiting, and arthralgia.

Dosing: The initial dose of 40 mg once daily is administered for one week and then increased to80 mg once daily in the treatment of TD.

Deutetrabenazine

Brand Name: Austedo

Adverse Effects: Serious reactions include depression, suicidality, QT prolongation, neuroleptic malignant syndrome, somnolence, hyperprolactinemia, binding to melanin-containing tissues. Common side effects include diarrhea, dry mouth, fatigue, urinary tract infection, insomnia, anxiety, constipation, and contusion.

Dosing:6 mg PO BID, then can be increased at weekly intervals in increments of 6 mg/day to relieve symptoms of TD; not to exceed 48 mg/day.

References

Bergman, H., & Soares-Weiser, K. (2018). Anticholinergic medication for antipsychotic-induced tardive dyskinesia. The Cochrane database of systematic reviews, 1(1), CD000204. doi: 10.1002/14651858.CD000204.pub2

Campbell, N., Boustani, M., Limbil, T., Ott, C., Fox, C., Maidment, I., & Gulati, R. (2009). The cognitive impact of anticholinergics: a clinical review. Clinical interventions in aging, 4, 225–233.

Church, M. K., & Church, D. S. (2013). Pharmacology of antihistamines. Indian journal of dermatology, 58(3), 219–224. doi:10.4103/0019-5154.110832

Cummings, M. A., Proctor, G. J., & Stahl, S. M. (2018). Deuterium Tetrabenazine for Tardive Dyskinesia. Clinical Schizophrenia & Related Psychoses, 11(4), 214–220. https://doi.org/10.3371/CSRP.CUPR.010318

Klawans, H. L., &Rubovits, R. (1974). Effect of cholinergic and anticholinergic agents on tardive dyskinesia. Journal of neurology, neurosurgery, and psychiatry, 37(8), 941–947. doi:10.1136/jnnp.37.8.941

Kusumi, I., & Koyama, T. (1999). Algorithms for the treatment of acute side effects induced by neuroleptics. Psychiatry & Clinical Neurosciences, 53, S19–S22. Retrieved from http://search.ebscohost.com/login.aspx?direct=true&db=a2h&AN=23238321&site=eds-live&scope=site

Sadock, B. J., Sadock, V. A., & Ruiz, P. (2015). Kaplan &Sadocks synopsis of psychiatry: Behavioral sciences/clinical psychiatry. Philadelphia: Wolters Kluwer.

Stahl, S. M., Grady, M. M., &Muntner, N. (2017). Stahls essential psychopharmacology: Prescribers guide (6th ed.). Cambridge, United Kingdom: Cambridge University Press.

Touma, K. T. B., &Scarff, J. R. (2018). Valbenazine and Deutetrabenazine for Tardive Dyskinesia. Innovations in Clinical Neuroscience, 15(5/6), 13–16. Retrieved from http://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=130481106&site=eds-live&scope=site

Uhlyar, S., & Rey, J. A. (2018). Valbenazine (Ingrezza): The First FDA-Approved Treatment for Tardive Dyskinesia. P&T: A Peer-Reviewed Journal for Managed Care & Formulary Management, 43(6), 328–331. Retrieved from http://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=129799771&site=eds-live&scope=site

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