Pharmacotherapy of Psychosis

Ananda K Pandurangi

Pharmacotherapy of PsychosisCHAPTER 1

Ananda K Pandurangi

INTRODUCTION

Psychotic disorders, especially schizophrenia cause significant distress to the individual and family and, can be debilitating. Antipsychotic drugs are the mainstay of treatment. Brief and acute psychotic disorders are expected to resolve completely. Schizophrenia and schizoaffective disorder however often lead to persistent disability of varying degrees. About 30% of schizophrenia is resistant to currently available therapies.

In this chapter, we provide a brief description of psychotic disorders. This is followed by antipsychotic drug development, principles of pharmacotherapy of psychotic disorders and review of specific antipsychotic agents and long acting preparations. The chapter also presents treatment in special populations and management of common as well as serious adverse effects.

Effective treatment is available for psychotic disorders although there are serious limitations to current antipsychotic agents, both in efficacy and adverse effects. Physicians should appreciate the burden of psychosis on the patient and family, use antipsychotics judiciously, follow established algorithms, and combine pharmacotherapy with psychosocial interventions. New drugs with different mechanisms of action are needed for progress in the field.

PSYCHOSIS AND PSYCHOTIC DISORDERS

Psychosis refers to a sustained mental state of impaired touch with reality, manifested by hallucinations, delusions, disordered communication, catatonia and/or disorganized behaviors, referred to as positive symptoms. Transient perceptual alterations or desired religious/spiritual experiences are not considered psychosis. Primary psychotic disorders are conditions with psychosis as the major manifestation and which cause distress, dysfunction and disability. Psychosis may also be secondary to another mental or physical disorder. Alogia, apathy, blunted affect, anhedonia, avolition and amotivation2 are referred to as negative symptoms, and are often part of a chronic psychotic disorder. Negative symptoms may also be part of a prodromal or residual state of schizophrenia, or personality disorders related to schizophrenia.

Evaluation of a suspected psychotic condition includes (1) assessment of the nature and severity of the positive, negative, general psychiatric and physical symptoms, (2) establishing the presence of psychosis, currently and/or historically, (3) assessing comorbid physical, psychiatric and substance use disorders, (4) tests such as blood studies, psychometry, electroencephalography (EEG), brain imaging, cerebrospinal fluid (CSF), etc. as indicated, (5) arriving at a working diagnosis, (6) placing the symptoms/behaviors in appropriate developmental and psychosocial context, and (7) development of an ongoing management plan to build a therapeutic relationship, educate significant others and judicious use of psychotropics and psychosocial therapies to achieve optimal outcome. Table 1 provides a comprehensive list of psychotic disorders including the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and the International Classification of Diseases, 10th revision, (ICD-10) categories.^1,2

DEVELOPMENT OF ANTIPSYCHOTIC DRUGS

The first-generation antipsychotic (FGA) chlorpromazine was discovered in 1952. Historically, reserpine is truly the first antipsychotic whose action was later shown to be depletion of synaptic dopamine. Since it significantly reduces blood pressure and sometimes caused suicidal ideation, its use faded away. Chlorpromazine was discovered serendipitously to reduce psychosis during the quest to find an agent to prevent surgical shock. This was subsequently verified by Drs Delay and Deniker of France.³ Thioridazine (another phenothiazine derivative, once popular because of its low extrapyramidal symptom (EPS) burden but now discontinued because of QT prolongation), fluphenazine, trifluoperazine and others followed. Subsequently, it was demonstrated that the likely antipsychotic action of these agents was dopamine receptor blockade in the brain. Thus, a functional way of classifying these drugs is based on their respective ability to block dopamine receptors. Chlorpromazine and thioridazine have low potency, and fluphenazine and trifluoperazine have high potency as dopamine antagonists. The search for more powerful antipsychotic drugs (APDs) continued and in the late 1950s, haloperidol, a high potency butyrophenone was discovered by Paul Janssen in Belgium. It became the most widely prescribed FGA between 1970 and 1990 and continues to be prescribed worldwide.3

Table 1 Disorders with psychosis.

Disorder	Course and duration	Features and diagnosis	Outcome/Comments
Category I—schizophrenia spectrum disorders (Rule out disorders listed in Category II of this table before making diagnosis)
Brief psychotic disorder	Acute, days to <4 weeks, rarely longer	Often precipitated by stress. Dramatic and fluctuating psychosis	Full resolution of symptoms and return of function
Schizophreniform disorder	Acute, >4 weeks but <6 months	Schizophrenia-like symptoms	May progress to schizophrenia
Schizophrenia	Chronic, years	>1 month of psychotic symptoms, >6 months of behavior change. Some functional decline is typical	Persistent symptoms in 30–60% of patients. Some recovery is possible in most
Schizoaffective disorder	Chronic, years	Symptoms of psychosis and mood disorder are equally prominent. >2 weeks of psychosis without mood symptoms needed for diagnosis	Outcome is usually better than schizophrenia
Delusion disorder	Chronic, >1 month to years	Nonbizarre delusion(s). No hallucinations or minimal	Personality is usually preserved. Function often preserved
Catatonia	Variable	Catatonic stupor, excitement or both	May be associated with another mental medical disorder or be independent
Cycloid psychoses	Episodic, brief, variable chronicity	Three types: akinetic-hyperkinetic, anxiety-blissfulness and confusion psychosis	Outcomes better than schizophrenia, and similar to brief psychotic disorders
Schizotypal personality disorder	Chronic, lifelong	Mild perceptual aberrations and mild disorder in thinking/communication	Mild functional impairment. Mild periodic psychosis possible4
Psychosis risk syndrome	Younger age group 30–40% convert to psychosis	Inattention, varying degrees of asociality, soft neurological signs	Conversion to psychosis could be reduced or prevented by early psychosocial and medications treatments
Category II—psychoses in other psychiatric disorders
Depression with psychosis	Recurrent, >2 weeks of symptoms in each episode	Depression is primary. Content of psychosis often congruent with mood	Outcome better than schizophrenia. Responds well to electroconvulsive therapy (ECT)
Mania with psychosis	Episodic, >1 week of symptoms	Mania is primary. Content of psychosis often congruent with mood	Outcome better than schizophrenia
Substance-induced psychoses	Variable. Depends on substance and length of use	Visual and tactile hallucinations and paranoia are common. Alcohol and amphetamine psychosis may mimic schizophrenia	Usually resolves with abstinence but could persist days to weeks even after abstinence
Delirium with psychosis	Brief duration (days)	Disturbed consciousness. Fragmentary and fleeting delusions. Visual and tactile hallucinations may be seen	May require frequent parenteral antipsychotics in small doses
Psychosis due to general medical conditions	Varies with underlying condition	Verified by diagnosis of the medical disorder. Visual hallucinations often seen. May be part of delirium
Dementia with psychosis (Alzheimer, vascular, etc.)	Intermittent or chronic	Inferred by behavior. Delusions are fragmentary and not well elaborated	Low doses of antipsychotics may be sufficient
Psychosis in autism spectrum disorders and intellectual disability	Intermittent or chronic	Delusions are often poorly formed and fragmentary. Visual hallucinations may be seen. Not to be confused with overlearned fears and fantasies	Higher doses of medications often not well tolerated. Higher risk of tardive dyskinesia

Realizing that the available APDs while being effective carried a significant burden of neurological side effects, another class of FGAs was developed in the late 1970s with the claim of less EPS. These drugs have medium potency dopamine antagonism and include loxitane, molindone and thiothixene and other thioxanthene derivatives. However, the claim of low EPS has never been proven by vigorous trials. It appears that EPS is largely dose-dependent and when used in the lower range of their therapeutic dose, all FGAs produce less EPS.

Clozapine is the first drug among second-generation antipsychotics (SGAs). It was synthesized in 1960 and used for various psychiatric conditions including schizophrenia, but was discontinued due to agranulocytosis in about 1% of the patients. It was later brought back in 1987 under strict hematological monitoring due to its superior clinical benefits in refractory schizophrenia.⁴ In the 1990s, more SGAs were developed such as risperidone, olanzapine and quetiapine. The SGAs differ from the FGAs in two major ways. They exhibit both DA2 and 5-HT2 antagonism, cause less EPS than FGAs and were thought to benefit both positive and negative symptoms, although the latter has not borne out. Even the promise of SGAs as safe APDs was belied as it became evident that most of them cause metabolic side effects, especially weight gain and hyperglycemia. There are now more than 10 SGAs available to clinicians, although not all are available in every country. Table 2 shows the representative APDs.

Few selected APDs and their clinical use are mentioned here because of one or more unique features.

Chlorpromazine: Antipsychotic dose is between 300 mg and 900 mg. It can be rapidly tranquilizing and useful in managing agitated psychosis. It can cause side effects such as acute and tardive EPS, orthostatic hypotension, increased QT interval of approximately 10 ms, modest weight gain and possible skin pigmentation over the long-term use. It is available in various short-acting formulations but not as a long-acting preparation
Haloperidol: It is a high potency DA2 blocking agent from the butyrophenone class. Its dose ranges from 0.5 mg to 20 mg. Studies suggest a therapeutic window with serum levels of 5–15 ng/mL. It causes considerably more EPS than other APDs. It can also cause a more serious condition called neuroleptic malignant syndrome (NMS)

Clozapine: Clozapine is a dibenzodiazepine with superior efficacy in refractory schizophrenia. Clozapine has modest D2 and significant 5-HT2 antagonism and a wide range of other receptor actions whose relevance to its antipsychotic activity remains unknown, such as DA1, 5-HT1A, 5-HT1C and 5-HT3 agonism and DA4, 5-HT6, M1, α1 and α2 noradrenergic receptor antagonism.6

Table 2 Antipsychotic drugs (selective list).

Antipsychotic drug (APD; popular brand name)	Equivalent units for 100 mg of chlorpromazine (CPZ)	Initial dose (mg/day)	Therapeutic dose range (mg/day)	Maximum dose (mg/day)	Half-life (in hours)	Metabolism through cytochrome P450 (CYP)
First-generation antipsychotic drugs
Chlorpromazine (Thorazine, Largactil)	100	50–100	300–1,000	1,000	30	1A2, 2D6, 3A4
Fluphenazine (Prolixin)	15	2.5–5	10–20	60	15	2D6, 3A4
Flupentixol (oral) (Depixol, Fluanxol)	1–2	1–2	2–10	20	35	2D6
Haloperidol (Haldol)	2	0.5–2	5–20	60	14–20	2D6, 3A4
Second-generation antipsychotic drugs
Amisulpride (Solian)	90–100	200	400–800	1,200	12–20	Minimal liver metabolism
Aripiprazole (Abilify)	NA	5	15–30	30	75–146	2D6, 3A4
Cariprazine (Vraylar, Reagila)	NA	1.5	1.5–6	6		3A4, 2D67
Clozapine (Clozaril)	100	25	300–600	900	16–24	1A2, 3A4
Lurasidone (Latuda)	8–10	20–40	40–80	120	12–18	3A4
Olanzapine (Zyprexa)	3–4	5	15–20	30	20–50	1A2, 2C19, 2D6
Paliperidone (Invega)	1–2	3–6	3–12	12	24	Minimal liver metabolism
Quetiapine (Seroquel)	100	100	300–600	900	6–8	3A4
Risperidone (Risperdal)	1–2	0.5–1	1–6	16	3–6	2D6, 3A4
Ziprasidone (Geodon)	15–20	40	40–160	160	4–10	3A4, 1A2, 2D6

A rigorous randomized controlled trial proved its efficacy in refractory schizophrenia.⁴ Its toxicities include seizures, agranulocytosis and myocarditis. It has helped many patients turn around their lives after suffering from schizophrenia. It also has proven efficacy in reducing suicidal ideation and self-harm in patients with schizophrenia.⁵

Clozapine use requires hematological monitoring to avoid agranulocytosis. The monitoring protocol has evolved over the years and varies between countries. Currently, weekly monitoring of the absolute neutrophil count (ANC) for 3–6 months followed by monthly monitoring is the standard.⁶ Typically, clozapine should not be continued if ANC drops below 1,500 cells/mL. Benign ethnic neutropenia is not a contraindication for clozapine. Therapeutic blood level of clozapine and norclozapine combined is around 350 ng/mL. It is a third- or fourth-line agent, reserved for refractory schizophrenia. While more than 30% of persons with schizophrenia may qualify to receive this drug, only 2–10% are receiving it. Physician and patient reluctance about the blood tests, the drugs ability to induce other serious side effects albeit rarely and lack of promotion by the industry may be the reasons for its underutilization

Risperidone: It is an SGA that became available in 1994. It has strong DA2 and 5-HT2 blocking actions. At doses between 0.5 mg/day and 2 mg/day, the risk of EPS is low, but at doses of 4 mg and above, the EPS becomes more evident. It also induces prolactinemia which can be problematic. Paliperidone is an active metabolite of risperidone and is also marketed separately as an APD. Both risperidone and paliperidone are also available in long-acting formulations that work from 2 weeks to 12 weeks
Amisulpride: It is a strong presynaptic dopamine antagonist and may have site selective actions sparing the nigrostriatal receptors, thus causing little EPS. It has been shown to have superior efficacy in schizophrenia as monotherapy as well as in augmentation studies of clozapine. It is available in Europe and Asia but not in North America
Aripiprazole: This is a partial dopamine agonist with approximately 30% dopamine agonism steering toward normal dopamine activity. EPS and metabolic burden low. It does not cause hyperprolactinemia unlike most other APDs. This is especially useful in young women
Long-acting injections (LAIs): Whereas until the year 2000, there were only 2–3 long-acting formulations, now there are as many as 9 formulations. Among FGAs, haloperidol decanoate, fluphenazine decanoate and enanthate have been used effectively for many decades. Among SGAs, risperidone Consta was the first long-acting SGA. It uses an9 innovative compounding method of crushing risperidone into encapsulated microspheres that reside in a diluent and are slowly released into the systemic circulation over 2 weeks. Other LAIs include paliperidone palmitate, olanzapine pamoate and aripiprazole monohydrate. These are effective for about 4–6 weeks and aripiprazole lauroxil and another version of paliperidone palmitate seem to be effective for 8–12 weeks. There are specific advantages to LAIs including improved compliance and more steady levels of drug over a longer period of time to reduce relapse. There are also disadvantages such as the intrusiveness of an injection, local pain and possible induration. The irreversible nature of the injection in case of serious side effects such as NMS is a challenge. However, the benefits outweigh the disadvantages, in avoiding relapse and improving quality of life.^7,8

MECHANISM OF ACTION OF ANTIPSYCHOTIC DRUGS

Several mechanisms of actions have been hypothesized for the action of APDs. One of the most important ones among them is the dopamine hypothesis (schematically shown in Fig. 1). The hypothesis suggests that the positive symptoms of psychosis occur due to the overactivity of the mesolimbic dopamine pathway. The “deficit” state of psychosis which manifests as negative and cognitive symptoms are due to the underactivity of the mesocortical pathway. The effect of antipsychotics in the form of blockage of dopamine receptors results in the EPS due to action on the nigrostriatal pathway. The effect on tuberoinfundibular pathway results in hyperprolactinemia. Serotonin receptors at the terminals of the axons modulate the dopamine release, but differentially across the four pathways.

Fig. 1: Schematic diagram of the dopamine pathway.

Fig. 2: Representation of the blocking actions of antipsychotics.

Another important hypothesis that has found traction is the excitotoxicity through the glutamate receptor. Development perspective of schizophrenia suggests that excitotoxic effect through the aberrant glutamate receptor over prolonged periods of time may result in altered or excessive synaptic pruning, which results in the genesis of symptoms.

Antipsychotics can have effect on the various receptors (as in Fig. 2). Each of the antipsychotics has different profile of activity on the different receptors. The dopamine receptor blocking effect is responsible for reducing positive psychotic symptoms. It is also responsible for certain side effects like EPSs and hyperprolactinemia. The muscarinic cholinergic blocking properties of antipsychotics result in dry mouth, blurred vision and constipation. Blockade of histamine H1 receptor by antipsychotics results in weight gain and drowsiness. Blockade of α1 receptor results in dizziness, decreased blood pressure and drowsiness. SGAs also have an effect on serotonin receptor and inhibit dopamine release.

TREATMENT GUIDELINES AND ALGORITHMS

Numerous drug trials have established the acute and long-term efficacy, tolerability and relative safety of APDs.^9–11 Various organizations and professional societies provide guidelines on treatment of schizophrenia. The better known algorithm/guidelines include (see Table 3 for a selective summary):

The Texas Medication Algorithm Project (TMAP) for psychosis¹²
The National Institute for Health and Care Excellence (NICE) guidelines for use of APDs¹³
The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of schizophrenia (acute treatment and long-term treatment)¹⁴
The World Psychiatric Association¹⁰
Schizophrenia Patient Outcomes Research Team (PORT, 2009)¹⁵

Table 3 Algorithms from guidelines.

Step	Medications
	TMAP¹²	APA¹⁶	ANZRCP¹⁷
1	SGA	SGA	SGA (Not olanzapine)
2	Different SGA	Different SGA or FGA	Different SGA or FGA (Not olanzapine)
3	Different SGA or FGA	Different SGA or FGA or clozapine	Olanzapine
4	Clozapine	Clozapine	Clozapine
5	Clozapine + FGA or SGA or ECT	ECT	Clozapine
6	Different SGA or FGA		CBT to be added at any step as tolerated by patient. LAI may be used at any step if patient and provider agree. ECT may be used at any stage if rapid response desired
7	Any two antipsychotic drugs
8	Any antipsychotic drug + ECT or augmentor*
*Augmentors include valproate, carbamazepine, lithium, lamotrigine, pregabalin, topiramate, benzodiazepines, glycine, serine, cycloserine, propranolol. (ANZRCP: Australian and New Zealand Royal College of Psychiatrists; APA: American Psychiatric Association; CBT: cognitive behavior therapy; ECT: electroconvulsive therapy; FGA: first-generation antipsychotic; LAI: long-acting injection; SGA: second-generation antipsychotic; TMAP: Texas Medication Algorithm Project)

The American Psychiatric Association (APA) practice guidelines for schizophrenia: Treatment Reference Guide (2014)¹⁶
The Australian and New Zealand Royal College of Psychiatrists (ANZRCP) guidelines.¹⁷

The NICE (UK) and the WFSBP provide reviews of the APD drug literature in different phases of the illness. They do not however provide a step by step algorithm. Instead, evidence-based good clinical practice guidelines are provided.^13,14

The following summary statements may be made about APD therapy in schizophrenia:

Overall, APDs improve positive symptoms in 60–70% of patients^1,9,11
Nearly 75% of patients tend to discontinue their first APD due to various reasons such as lack of efficacy or side effects¹⁸12
As a class, there is no significant difference between FGA and SGA in efficacy although individual differences exist based on patient populations and study designs¹⁹
Clozapine is clearly superior to other APDs in refractory schizophrenia. Olanzapine may possibly be superior to other APDs. Both have significant side effects²⁰
Discontinuation or noncompliance with APD results in high relapse totaling nearly 80% with most relapses occurring in the first year after stopping the drug. The first 6 months are the most vulnerable^11,21
There are no effective treatments for the negative symptoms or cognitive impairments of schizophrenia. A small group of patients estimated around 10–20% may experience only one episode of psychosis and/or may do well without APDs or after APD discontinuation.

TREATMENT OF SCHIZOPHRENIA

General principles of treatment of schizophrenia are highlighted in Box 1.

Treatment plans have been best developed for schizophrenia and then extrapolated to other psychotic disorders.

BOX 1 : General principles of treatment of schizophrenia.

Treatment should begin as soon as possible. Longer the duration of untreated psychosis more challenging the treatment and more long-term negative consequences
Patient and family input should be sought at each stage
Consent by patient or proxy consent by family or other appropriate party based on local laws should be obtained. Involuntary treatment should be avoided whenever possible
Psychiatric diagnosis, comorbid disorders, allergies, age, gender, drug interactions, treatment setting, cost and availability are to be considered in choice and dosing of antipsychotic drug (APD)
Second-generation antipsychotics are preferred first-line treatments for psychosis due to their initial lower side effects
Treatment should begin with the lowest effective dose of the APD. There is no correlation between how florid or quiet the psychosis is and dose of APD needed
Rate of titration depends on the setting and response. Very rapid escalation may risk intolerable side effects. First episode patients are especially vulnerable to side effects. Rapid neuroleptization within a day is not recommended. Too slow uptitration may unnecessarily prolong the psychosis
Antipsychotic polypharmacy is to be avoided
Antipsychotic drugs should not be used to solely treat nonpsychotic symptoms, such as insomnia or anxiety. APDs may be combined with antidepressant medications and mood stabilizers
Maintenance dosing is typically 50% or more lower than acute dosing. Dose of APD should be reviewed every 3 months at a minimum
Clozapine should be considered if 2–3 APDs have failed
Long-acting injections should be considered no more than 2 years after firm diagnosis. Patients disengaging from treatment have a high risk of suicide

After the assessment and diagnosis of schizophrenia, the physician may select the antipsychotic medication. The patient and practitioner's experience and side effects largely determine which medication is prescribed. Although genetic assays are available and increasingly used, this is currently helpful only to understand hepatic metabolism and atypical responses. While SGAs are the first-line agents because of low EPS, the relative frequency with which FGA and SGAs are prescribed and to whom, is often a function of cost, availability and access.

Dosing will vary according to stage of illness and treatment setting. Higher doses are needed in acute care and lower maintenance dosing is appropriate in outpatient and long-term care. About 15–25% of patients have severe schizophrenia and may need long-term hospital care of 3 months to several years. Patient and family members should be involved in the care plans as much as possible. Subjective experience of medication effects, sexual side effects and cost are often not addressed by clinicians but are common reasons for nonadherence. Patient should be educated on the symptoms and causes of relapse and that schizophrenia is a medical condition and not anyone's fault. The patient should feel engaged in the treatment plan and own it. Family therapy may be needed to avoid excess expressed negative or critical emotions. The patient should be encouraged to lead as much of a productive life as possible. Social skills training may be needed. Therapies should be customized to match patient's stage of recovery.²² Wraparound services should be provided as much as feasible including access to health care, housing, education and vocational support. A basic program with required elements and a complete program with a full range of services should be conceptualized by providers and governments.²³

SPECIAL POPULATIONS

Some of the special populations like child and adolescent, pregnancy and lactation and medically ill patients are covered in other chapters.

Catatonia Patients

Catatonia occurs in mood disorders, psychotic disorders, medical conditions and independently. Diagnosis may be unclear in the beginning. Patients have poor hydration, infections and injuries, may need physical restraint and have high creatine kinase (CK) with vulnerability to NMS and aspiration. Intravenous lorazepam is helpful to resolve catatonia, at least transiently, with monitoring of vital signs and pulse oximetry when available.²⁴ It is best not to exceed 24 mg of lorazepam in a 24-hour period on medical units and approximately 12 mg on psychiatry units. Intramuscular or oral14 lorazepam may be used but is not as effective. Intravenous fluids, nasogastric tube feeding and bladder catheterization may be necessary. If lorazepam therapy fails, electroconvulsive therapy (ECT) should be instituted. It is the best treatment for catatonia with greater than or equal to 80% response rates. Low doses of an SGA should be considered if ECT cannot be implemented. Other agents tried in catatonia with anecdotal evidence include amantadine, carbamazepine, divalproex sodium, levodopa (L-dopa), memantine, methylphenidate, etc. As the catatonia resolves, other medications may be needed based on the diagnosis, such as mood stabilizers or antidepressants.

Patients with Concomitant Substance Use

In patients with psychosis and concomitant use of substances, if the psychosis is moderate or less, it is prudent to wait and let the substance wash out. Vitamin C can acidify the urine and hasten this. If psychosis is florid, start an antipsychotic. Duration of antipsychotic treatment will vary. If substance caused psychosis, it could be only a few days. Longer treatment is needed if the substance only triggered the psychosis. This may never be clear. Withdrawal management should proceed in parallel. Alcoholic hallucinosis can be protracted and there might be hepatic impairment, seizures, or other medical complications. Antipsychotics cleared renally such as paliperidone or amisulpride may be better than those fully dependent on the liver. In stimulant-induced psychosis, there may be hypertension. Use of high potency antipsychotics such as haloperidol or risperidone is appropriate in such patients. In hallucinogen-induced acute psychosis, lorazepam can augment an antipsychotic. After stabilization, drug rehabilitation may be needed.

Patients with Intellectual Disability and Developmental Delay

Assessment of psychosis requires special skills and experience because of communication impediments. No prior medication history may be available. Diffuse behavior disorder or child-like fantasies and fears are hard to distinguish from psychosis. Psychosis may mask behind behaviors such as not eating, not communicating and irritability. Treatment is challenging as patients often have sensitivities to drugs including allergies, paradoxical responses and unusual adverse effects. A good clinical practice is to treat an adult with intellectual disability/developmental delay as a child, in dosing an antipsychotic.

Examine for stigmata of genetic/congenital disorders and consider genetic testing
High potency antipsychotic should be avoided as the risk of EPS, NMS and tardive dyskinesia (TD) is high15
Avoid loxitane and clozapine due to low seizure threshold in these patients
Avoid long-acting injectable as both dosing and prolonged side effects would be challenging to manage.

Patient with Predominant Cognitive and Negative Symptoms

It is now recognized that negative and cognitive symptoms create the core deficits of schizophrenia. In assessing the negative symptoms of schizophrenia, it is important to consider and treat negative symptoms secondary to paranoia, parkinsonism and depression. After excluding these, we may conclude the person has primary negative symptoms. Similarly, it is best to assess enduring cognitive impairments after the acute psychosis has subsided, rather than during psychosis. Current antipsychotics minimally benefit these symptoms. Sadly, there are no effective treatments for either of these although many agents have been tried.^25,26

Geriatric Patient

Assessment of psychosis is difficult in the face of cognitive and sensory impairments. Disorderly behavior of dementia may be hard to separate from core psychotic symptoms. Past history of psychosis prior to the onset of cognitive impairment may help. Whether to treat less than acute psychosis during end-stage dementia is an ethical question, with no fixed answer.

Antipsychotics have additional risks in the elderly dementia patient including a slightly higher risk of cerebrovascular accident and mortality. High potency drugs have the risk of EPS and low potency agents create the risk of hypotension and falls. The decision has to be individualized based on the symptom cluster that is most distressing to the patient. Justification for continued use of the APD should be reviewed regularly.²⁷

Prisoner-Patients

Prisoner-patients can be challenging due to limited information, substance abuse, legal issues, secondary gains, malingering, etc. Minority persons or antisocial behaviors may be mislabeled as psychosis. Guards may request antipsychotics to control behavior. The treatment may be court ordered and the traditional doctor-patient relationship may be weak or absent.

Availability of antipsychotics in jails is often limited to older agents. Monitoring of response and side effects may be limited. Dehydration may be common. Hard leather/iron restraints and physical fights may cause muscle injury and unleash rhabdomyolysis with risk of NMS. The physician will need to judiciously select and dose the antipsychotic. If oral compliance16 is an issue, alternatives such as olanzapine self-absorbing wafer, risperidone melting tablet, and loxitane inhaler should be considered.

ADVERSE EFFECTS OF ANTIPSYCHOTIC DRUGS AND MANAGEMENT

All APDs have the potential to cause significant adverse effects. The pharmacotherapy of psychosis includes awareness, assessment and treatment of these and validation of patient distress. The major adverse effects and their management have been shown in Table 4.

Allergy

Drug allergies should be inquired into and documented. If genuine allergy exists, the specific antipsychotic should not be prescribed. Antipsychotics within the same chemical class may have cross-allergy. Prior to a LAI, the oral form should be tested for allergy. Some practitioners inject a small amount of the LAI subcutaneously and observe for 24 hours before giving the full dose. An allergic reaction called drug reaction with eosinophilia and systemic symptoms (DRESS) has been seen with olanzapine, with rashes, fever and lymphadenopathy. Allergic reactions should promptly be treated with creams, tablets or injections of antihistamines, or rarely steroids.

Sedation

Chlorpromazine, clozapine and quetiapine are more sedating than other antipsychotics due to their stronger antihistaminic actions. Such antipsychotics could be taken as a single nightly dose, or small morning dose and larger bedtime dose. If sedation persists, reduce the dose or switch to an agent such as aripiprazole. Activities requiring quick responses are to be avoided such as driving or working with machinery when (1) the antipsychotic is new to the patient, (2) there is escalation in dose and (3) up to 4 hours after taking the medication. Multiple sedative drugs should be avoided.

Extrapyramidal Symptoms

The term neuroleptic denotes a noxious action on the nervous system, which results largely from blocking nigrostriatal DA2 receptors. Other mechanisms may also be involved in dystonia, akathisia and TD. With the advent of SGAs, the occurrence of severe EPS has reduced and this is a major achievement in psychopharmacology. EPSs comprise of (1) acute dystonia, (2) acute dyskinesia, (3) Parkinson symptoms of akinesia, hypokinesia, flat affect, resting tremors, pill-rolling movements, shuffling gait, retropulsion, etc. (4) akathisia or acathisia, (5) TD, and (6) tardive dystonia.17

Table 4 Adverse effects potential of select antipsychotic drugs.

Antipsychotic drug	Sedation	Extrapyramidal symptom (EPS)	Anticholinergic	QT	Weight	Metabolic
Predominant receptor involved	H1	D2	M1	Ionic Kr channel	H1	H1, 5-HT1A, 5-HT2C, M3
First-generation antipsychotic drugs
Chlorpromazine	+++++	+++	++++	++	++	++
Fluphenazine	++	++++	+++	++	++	++
Haloperidol	++	+++++	+++	+	++	++
Thiothixene	+	++	++	++	++	++
Loxapine	+++	++	++	++	++	++
Molindone	++	++	++	++	+	+
Second-generation antipsychotic drugs
Amisulpride	+++	+	+	++	++	++
Aripiprazole	+	+	+	++	+	+
Cariprazine	++	+	+	++	++	++
Clozapine	+++++	+	++++	++++	+++++	+++++
Lurasidone	+++	++	++	++	++	+++
Olanzapine	+++	++	+++	+	+++++	+++++
Quetiapine	+++++	++	+++	+++	+++	+++
Risperidone	++	+++	++	+++	+++	+++
Ziprasidone	+++	++	++	++++	+	+
(+ = low; ++ = low-to-moderate; +++ = moderate; ++++ = moderately to high; +++++ = high)

They affect both small and large muscles, predominantly in the voluntary musculature. Dystonia and dyskinesia of the laryngeal, esophageal and gastric muscles can occur, although rare. Assessment of EPS is a part of the standard physical examination in all psychiatry patients, especially those on APD. There are several scales available to assess EPS such as the Simpson-Angus Scale (SAS), the Extrapyramidal Symptom Rating Scale (ESRS), Udvalg for Kliniske Undersogelser (UKU) side effects rating scale, Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), etc.²⁸ A convenient way to remember the common EPS is to use a timeline of their occurrence, although this is not a hard and fast rule: Acute dystonia 1–3 days; akathisia 7–14 days; parkinsonism 14–28 days; and TD more than 12 weeks.

Treatment of Extrapyramidal Symptoms

Acute dystonia is best treated with intramuscular diphenhydramine, 25–50 mg promptly upon occurrence of the dystonia. Since the incidence is approximately 5–10%, it is not necessary to write a standing order for all patients. Anticholinergics are not typically helpful in dystonia
Parkinsonism: Anticholinergics work best with parkinsonism. Benztropine 0.5–6 mg/day, trihexyphenidyl 2–8 mg and procyclidine 7.5–15 mg are effective. Amantadine 100–300 mg/day may be used if anticholinergics are ineffective or cause their own side effects
Akathisia: Classic akathisia is described as anxiety with a feeling of jumping out of the skin, shuffling feet and inability to sit/stand in one place for long. It is not painful but extremely uncomfortable. It may be confused with psychotic or manic agitation. It may trigger psychiatric symptoms including suicidal impulses. Propranolol is effective in treating akathisia, implying underlying noradrenergic hyperactivity. The dose can vary from 10 mg two to three times a day to 80 mg two to three times a day with vital signs’ monitoring. Lorazepam also helps akathisia. Anticholinergics, diphenhydramine, buspirone, selective serotonin reuptake inhibitor (SSRI) antidepressants, clonidine, lithium, divalproex sodium, pregabalin, gabapentin have been tried with only sporadic case reports in their favor
Tardive dyskinesia: It is varies from very mild and occasional to severe and frequent. It may involve small orofacial muscles, fingers and toes and/or large muscles of the neck, trunk and limbs. TD is typically not painful and some patients with psychosis are not even aware of mild TD. However, many patients are aware and disturbed by it. The AIMS is a convenient tool to assess TD. SGAs are19 associated with less and milder TD compared to FGAs. TD is usually irreversible except for withdrawal dyskinesia. Persons with developmental disorders, mood disorders and brain injury are vulnerable to severe TD. There is now a resurgence of interest to treat TD because of newly approved drugs—deutetrabenazine and valbenazine. Other unapproved agents tried for TD with inconsistent benefits are—amantadine, benztropine, clonazepam, diazepam, diphenhydramine, L-dopa, lithium, propranolol, vitamin E, etc. The recommended approach is to reduce the antipsychotic dose and/or switch to clozapine, quetiapine or amisulpride. Neurological consultation may be appropriate in some cases to rule out other causes of movement disorder.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is likely due to rapid and massive dopamine blockade in the nigrostriatal and cortical tracts. The combination of diffuse muscle rigidity, muscle breakdown (high creatine kinase, myoglobinuria) and autonomic dysregulation (high fever, tachycardia) during neuroleptic treatment defines this syndrome. Disorientation and confusion may occur although not required for diagnosis. Creatine kinase can range from 1,000 to 100,000 units and temperature may reach to greater than or equal to 105°F. Recent incidence of NMS is approximately 0.03% with FGA and SGA exposures combined. Mortality rate is approximately 5% of the NMS cases. NMS incidence is significantly down as SGAs replace FGAs.²⁹

Management includes stopping the antipsychotic, intravenous fluids, temperature control with cold blankets and other symptomatic treatment. Bromocriptine to enhance dopamine activity and dantrolene to reduce muscle rigidity are recommended if NMS does not begin to resolve in 3–5 days with supportive care. Lorazepam may be used to treat any agitation. NMS may take 7–28 days to resolve. ECT is effective in some cases of prolonged NMS. NMS may cause muscle contractures, kidney injury and cognitive impairments. Rechallenge with an antipsychotic should wait greater than or equal to 14 days after NMS resolves. It is unsafe to rechallenge with the same antipsychotic as NMS recurs in more than 25% of such cases.

QT Prolongation

All antipsychotics prolong QT, variably from 5 ms to greater than 20 ms even in therapeutic doses. QTc greater than 500 ms has risk of ventricular tachyarrhythmias like torsade de pointes, and sudden death. Haloperidol and olanzapine cause shorter QT increase and ziprasidone the longest, with other antipsychotics in between (Table 4).20

The risk of QT increase can be reduced by ensuring normal levels of potassium and magnesium, avoiding multiple QT prolonging drugs and slow titration of the APD. Obtaining family history of sudden death (possible long QT syndrome), monitoring QT by electrocardiography (EKG), consulting the internist/cardiologist and informing patient/family are recommended in addressing this risk.

Weight Gain and Metabolic Risks

Second-generation antipsychotics have the potential to induce adverse metabolic changes and weight gain. Clozapine and olanzapine have the most significant risks (Tables 4 and 5). Although FGAs also cause weight gain, the magnitude was not alarming. The mechanisms for increased consumption, adiposity and weight gain by SGAs are unclear. Likely mechanisms are—H1 and 5-HT2C antagonism and through leptin metabolism. SGAs may induce insulin resistance and decrease the response of pancreatic beta-cells to glycemia, possibly by muscarinic 3 and 5-HT1A antagonism with average glucose increase of 5–10 mg/100 mL. Approximately 5–6% of people on long-term SGAs have a risk of clinically significant hyperglycemia.

Metabolic syndrome refers to a group of conditions including overweight with increased abdominal (visceral) fat, atherogenic dyslipidemia, insulin resistance and hypertension. These interact synergistically and increase the risk of prothrombotic and proinflammatory states and also predispose to diabetes mellitus, which further increase atherosclerotic risks. See Table 5 for guidelines on monitoring metabolic effects of antipsychotics.

Seizures

Antipsychotic drugs minimally lower seizure threshold. Only clozapine may induce seizures within the therapeutic dose. Loxitane has potential to do the same. For clozapine therapy, if a seizure is to occur, the addition of divalproex sodium is recommended.

Anticholinergic Symptoms

Many antipsychotics cause anticholinergic symptoms (Table 4). Common symptoms are:

Blurry vision: While the eye eventually accommodates to this, this effect can increase intraocular pressure in patients with narrow-angle glaucoma
Dryness of mouth or “cotton mouth” is common. Frequently sipping water and/or chewing sugarless gum can help

Table 5 American Diabetes Association (ADA) and American Psychiatric Association (APA) consensus guidelines for baseline assessment and monitoring of patients receiving atypical antipsychotic medications.³⁰*

	Baseline	4 weeks	8 weeks	12 weeks	Quarterly	Annually	Every 5 years
Personal/family history^†	X					X
Weight (body mass index)	X	X	X	X	X
Waist circumference	X					X
Blood pressure	X			X		X
Fasting plasma glucose	X			X		X
Fasting lipid profile	X			X			X
*More frequent assessments may be warranted based on clinical status. ^†Personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease.

Constipation: Proper hydration, eating bulky food and use of laxatives and stool softeners are helpful. Bethanechol, a cholinergic agent can improve peristalsis
Difficulty in micturition, especially in males with prostatic hypertrophy. If severe, bethanechol may be used to relax the detrusor muscle
Anticholinergic delirium: Symptoms include mydriasis, dry mouth, tachycardia and confusion with disorientation. For mild delirium, stop the offending antipsychotic for a few days, then resume at a lower dose and ensure no other anticholinergics are prescribed. If severe, physostigmine, a potent cholinergic agonist can be administered to reverse the anticholinergic toxicity with vital signs’ monitoring to avoid severe bradycardia.

Hypotension

This may occur with many antipsychotics and is mediated by alpha-adrenergic antagonism. Patients report feeling dizzy and weak. If severe, they may faint, especially with quick postural changes, due to orthostasis.

Endocrine and Sexual

Most antipsychotics cause hyperprolactinemia due to dopamine antagonism in the tuberoinfundibular pathway. Haloperidol and risperidone have a higher burden, and amisulpride and cariprazine have a lower burden. Aripiprazole and brexpiprazole are mostly free of this effect.

Management of the sexual side effects includes patient education, reducing antipsychotic dose, changing the antipsychotic, intermittent drug holidays of 1–2 days for sexual activity and use of medications such as cyproheptadine, bromocriptine, cabergoline, bethanechol and sildenafil or similar agents.

CONCLUSION

Treatment of psychotic disorders with antipsychotics is essential and provides tangible benefits including reduction of symptoms and distress, improved function, avoid or decrease hospitalization and enables the patient to remain part of the family and community. Despite these benefits, disappointingly, it does not appear that the long-term outcome in schizophrenia has been changed significantly over the last 70 years. Clozapine may be an exception but its total contribution to modifying pathology at an epidemiologic level is not sufficient to bend the curve. Antipsychotics have many side effects, some are more serious than others and in summary this is a group of drugs that are disliked by many patients.23

As a group, FGAs and SGAs are of similar efficacy with positive symptoms. Neither significantly benefits negative or cognitive symptoms of psychosis. Yet it is a very gratifying experience to see antipsychotics help patients improve from a chaotic psychosis and return to a semblance of normal life. Both FGAs and SGAs carry substantial adverse effects burden. The physician should maximize the benefit, minimize the side effects and optimize the treatment for his/her patient. This requires good training, continuing education and ongoing experience. In schizophrenia and other chronic psychotic disorders, antipsychotics are needed more or less lifelong. The physician should always choose the lowest effective dose with periodic review. Future research should include subjective patient experience as a major factor in drug development. Costs of drugs can be a substantial factor in selecting drugs, and the profession should strongly advocate for lower prices. Healthcare is not an appropriate sector to make heavy profits. Money should not be spent on developing more “me-too” drugs. New antipsychotics are needed with novel mechanisms of action. Breakthroughs in schizophrenia genetics informed by brain imaging and interdisciplinary studies are likely to lead to innovative compounds, and such efforts should be strongly supported by all stakeholders.

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Chapter Notes

Pharmacotherapy of PsychosisCHAPTER 1

BOX 1 : General principles of treatment of schizophrenia.