Antipsychotics


http://evolve.elsevier.com/Edmunds/NP/




DRUG OVERVIEW


image


image Top 100 Icon; image key drug. Key drug selected because it was the first and is still in use.



 



INDICATIONS




• Management of psychotic disorders: Schizophrenia

• Antiemetic (see Chapter 23)

Specific drugs:


• thorazine: Conduct disorders in children, bipolar affective disorder, hiccups, intractable, mania, nausea, porphyria, acute intermittent, vomiting, tetanus, adjunct

• prochlorperazine: Generalized anxiety disorder, nausea, vomiting

• trifluoperazine: Generalized anxiety disorder

• thioridazine: Depression, behavior disorder

• haloperidol: Conduct disorders in children, Tourette’s syndrome, psychosis in the intensive care unit

• clozapine: Used in schizoaffective disorder to decrease risk of chronic suicidality

• risperidone: Bipolar affective disorder, mania, psychosis

• olanzapine: Bipolar affective disorder, mania, agitation, psychomotor, agitation secondary to schizophrenia, agitation secondary to bipolar affective disorder

• quetiapine: Bipolar affective disorder, schizophrenia

• ziprasidone: Bipolar affective disorder, psychomotor agitation, bipolar maintenance and bipolar depression

• aripiprazole: Bipolar affective disorder, mania, bipolar maintenance and bipolar depression

• haloperidol, olanzapine (Zyprexa), risperidone (Risperdal): Acute manic episode mood stabilizers



Unlabeled Uses



• Behavioral/psychologic symptoms of dementia (BPSD): thorazine, haloperidol

• Parenteral antipsychotics for combative patients or other serious manifestations of acute psychosis


• chlorpromazine: Control of severe nausea and vomiting, intractable: thorazine

• prochlorperazine: Migraine headache

• risperidone: Chronic tic syndrome, Tourette’s syndrome

• olanzapine: Anorexia nervosa, apathy, borderline personality disorder, nausea

• ziprasidone: Autism, Tourette’s syndrome

• quetiapine: Insomnia

Antipsychotics, also known as major tranquilizers or neuroleptics, are used commonly in the treatment of a variety of psychotic disorders. Their use in schizophrenia and in the management of behavioral and psychologic symptoms is discussed in this chapter. Primary care providers offer general or acute care for patients who may be taking these antipsychotic drugs. This chapter provides some very general information for them. These drugs are specialty drugs, and providers who prescribe these drugs routinely will require prescribing information with much greater detail. Providers who see geriatric patients, especially in the hospital or a nursing care facility, should be prepared to use this category of drugs; they too may need more detailed information.


There is growing documentation of prescribing off-label antipsychotic drugs, particular in nursing homes to calm patients with dementia. Medicare has threatened to institute penalties for this use of antipsychotic drugs. Research suggests antipsychotic medications are overprescribed in the older demented patient population. The use of these medication off-label, particularly quetiapine for treating insomnia in patients with no psychotic disorders, is also under current criticism from the medical community as being not standard practice.


The first antipsychotic on the market, chlorpromazine, was introduced in the early 1950s. This is the key drug among the phenothiazine first-generation antipsychotic agents. Currently, antipsychotics are divided into two generations. The first generation includes the older, “typical” drugs that treat the positive but not the negative symptoms associated with a psychotic state. Second-generation drugs have far fewer extrapyramidal symptoms (EPS) and tardive dyskinesia (TD), and they are used to treat both positive and negative symptoms of schizophrenia. With the exception of risperidone, they are prolactin sparing.



Extrapyramidal Symptoms


Although antipsychotic drugs often are effective, almost all are associated with adverse effects. The most important adverse effects associated with antipsychotic drugs include EPS, some of which may be irreversible. EPS include parkinsonian syndrome, akathisia, dystonia, neuroleptic malignant syndrome, and TD.


TD (abnormal involuntary movements) may be progressive and irreversible, even after the drug is discontinued. It is characterized by rhythmic involuntary movement of the tongue, face, mouth, or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). These may be accompanied by involuntary movements of the extremities. TD has been the major limitation of first-generation antipsychotics because symptoms of TD can be disabling, preventing the patient from returning to society, even after the schizophrenia is controlled.


Neuroleptic malignant syndrome (NMS): Symptoms usually occur weeks after initiation of treatment with antipsychotics. NMS is an idiosyncratic reaction to an antipsychotic or neuroleptic drug; symptoms typically develop over a period of hours to days, and the condition is life threatening. Major symptoms include fever, catatonic stupor, muscle rigidity, autonomic instability, tachycardia, delirium, and myoglobinemia.


Parkinsonian symptoms typically occur more commonly in the elderly and with higher-potency antipsychotics, except risperidone. Symptoms include masked facies, tremor, bradykinesia, rigidity, cogwheeling, drooling, and festination.


Akathisia may be difficult to differentiate from anxiety because the two appear to be so similar. Symptoms include an intensely unpleasant need to move, restlessness, and agitation. Because of the discomfort that is felt, akathisia is often a big factor in noncompliance regarding medications.


Acute dystonia: Symptoms include muscular rigidity, usually of the tongue, neck, face, or trunk. It is most likely to occur within the first week of antipsychotic drug treatment. Acute dystonia can be frightening, extremely uncomfortable, and life threatening if laryngeal dystonia occurs.



Therapeutic Overview


It is important to understand that psychosis is not a disease. Psychosis is the term that is used to describe a general symptom complex in which gross impairment of reality is demonstrated. It has many causes—both organic and psychiatric. Box 49-1 lists symptoms that are commonly associated with the presentation of a clinical psychosis. Table 49-1 shows the most common medical disorders that may present with psychiatric symptoms, but not all of these represent psychotic symptoms. A large number of diverse and even common medications can cause psychotic symptoms (Table 49-2). Table 49-3 lists different psychiatric disorders that may present with psychosis. Therefore, it is difficult to talk about treating the general symptoms of psychosis; it is more productive to talk about specific psychotic disorders such as schizophrenia.


 



BOX 49-1   Symptoms of Clinical Psychosis



Positive Axis



Delusions

Depersonalization

Hallucinations

Illusions

Loss of reality

Paranoia

Thought disorder


Negative Axis



Deficits of attention

Lack of grooming

Impoverished thought

Anhedonia

Lack of initiative

Alogia (absence of speech due to confusion)

Blunted affect


TABLE 49-1


Medical Conditions Associated with Psychiatric Symptoms














































































































































































Causes Example
Metabolic and endocrine Addison’s disease
  Calcium imbalance
  Carcinoid syndrome
  Cushing’s syndrome
  Electrolyte abnormalities
  Hepatic failure
  Hyperparathyroidism
  Hyperthyroidism
  Hypoglycemia
  Hypothyroidism
  Hypoxia
  Magnesium imbalance
  Pheochromocytoma
  Porphyria
  Renal failure
  Serotonin syndrome
  Wilson’s disease
Electrical Complex partial seizures
Peri-ictal states (depression, hallucinations) Postictal states (depression, dissociation, or disinhibition)
  Temporal lobe status epilepticus
Neoplastic Carcinoid syndrome
  Carcinoma of the pancreas
Metastatic brain tumors Primary brain tumor
  Remote effects of carcinoma
Arterial Arteriovenous malformations
  Hypertensive lacunar state
  Inflammation (cranial arteritis, lupus)
  Migraine
Multi-infarct states Subarachnoid bleeds
  Subclavian steal syndrome
  Thromboembolic phenomena
  Transient ischemic attacks
Mechanical Concussion
  Normal pressure hydrocephalus
  Subdural or epidural hematoma
  Trauma
Infectious Abscesses
  AIDS
  Hepatitis
  Meningoencephalitis (including tuberculosis, fungal, herpes)
  Multifocal leukoencephalopathy
  Subacute sclerosingpanencephalitis
  Syphilis
Nutritional Vitamin B12 deficiency
  Folate deficiency
  Niacin deficiency
  Pyridoxine (vitamin B6) deficiency
  Thiamine deficiency
Degenerative and neurologic Aging
  Alzheimer’s disease
  Heavy metal toxicity
  Huntington’s disease
  Jakob-Creutzfeldt disease
  Multiple sclerosis
  Parkinson’s disease
  Pick’s disease

Modified from Gabbard GO: Gabbard’s treatment of psychiatric disorders,ed 4, New York, 2007, American Psychiatric Publishing.



TABLE 49-2


Medications That Can Cause Psychotic Symptoms


Acyclovir


Amantadine


Amphetamine-like drugs


Anabolic steroids


Anticholinergics and atropine


Anticonvulsants


Antidepressants, all


Baclofen


Barbiturates


Benzodiazepines


α-Adrenergic blockers


Calcium channel blockers


Cephalosporins


Corticosteroids


Dopamine receptor agonists


fluoroquinolone antibiotics


Histamine H1-receptor blockers


Histamine H2-receptor blockers


HMG-CoA reductase inhibitors (statins)


NSAIDs


Opioids


Procaine derivatives


Salicylates


Sulfonamides


Data from The Medical Letter: Some drugs that cause psychiatric symptoms, Med Lett 44:1134, 2002, and Gabbard GO: Gabbard’s treatment of psychiatric disorders, ed 4, New York, 2007, American Psychiatric Publishing.



TABLE 49-3


Psychiatric Disorders That May Present with Psychosis




































Type of Psychiatric Disorder Examples
Chronic psychosis (severe) Schizophrenia
  Schizoaffective disorder, bipolar type (with prominent episodes of mania)
  Schizoaffective disorder, depressed type (with prominent depressive episodes)
  Schizophreniform (<6 months’ duration)
Chronic psychosis (less severe or bizarre) Delusional disorder
  Shared psychotic disorder
Episodic psychosis Depression with psychotic features
  Bipolar disorder (manic or depressed)
  Brief psychotic disorder
  PTSD; borderline personality disorder

Modified from Stern TA et al: Massachusetts General Hospital handbook of general hospital psychiatry,ed 5, St Louis, 2004, Mosby.


Many elderly patients are particularly vulnerable to the development of psychotic symptoms. The confluence of medical disorders, psychiatric disorders, and medications may easily provoke psychotic symptoms, particularly when patients move from an unfamiliar environment to a strange setting, or when a change disturbs the tenuous balance they are maintaining while coping with medical and psychiatric problems. Geriatric patients with dementia may exhibit behavioral and psychologic symptoms, which may or may not represent psychosis. These symptoms commonly include agitation, physical aggression, delusions, and hallucinations. Other behaviors, such as refusing personal care, being unable to communicate or perform daily activities, wandering, being restless, and participating in self-destructive acts, may require the use of some of these medications, sometimes for brief intervals. Research has demonstrated that the risk of developing metabolic syndrome in children and adolescents increases sharply after 3 to 12 months of antipsychotic treatment.



Schizophrenia


One of the diseases that may present with psychotic symptoms is schizophrenia. Schizophrenia is a disease that is heterogeneous and complex. The pathophysiology of schizophrenia is poorly understood. Early theories involved the dopaminergic system. Recently, serotonergic pathways have been implicated. Newer theories focus on the interplay between dopaminergic and serotonergic systems, along with the involvement of muscarinic, α-adrenergic, and histaminergic systems and the presence of genetic Y chromosome disease.



Assessment


Schizophrenia is diagnosed by history after the patient is assessed in three areas:



1. Characteristic symptoms: Two of more of the following:


a. Positive symptoms


Delusions

Hallucinations

Disorganized speech (e.g., incoherence)

Grossly disorganized or catatonic behavior

b. Negative symptoms


Impoverished thought

Deficits of attention

Blunted affect

Lack of initiative

2. Social or occupational dysfunction, notably problems with work, school, interpersonal relations, or self-care

3. Duration of symptoms of 6 months or longer

Antipsychotic drugs should not be used unless the practitioner has performed a thorough physical and psychiatric assessment, the diagnosis has been ascertained, and other therapy has been ruled out. Key diagnostic questions that should be asked include the following:



1. Has a reversible organic or substance-induced cause of psychosis been ruled out?

2. Are cognitive deficits prominent? (i.e., delirium or dementia)

3. Is the psychotic illness continuous or episodic? Have psychotic symptoms (active phase) been present for at least 4 weeks? Has evidence of the illness been present for at least 6 months? Is a decline in level of functioning evident? Are negative symptoms present?

4. Are mood episodes prominent? Have episodes of major depression or mania occurred? Do psychotic features occur only during affective episodes?

Before antipsychotic drugs are initiated, take baseline vital signs. Baseline laboratory tests that should be completed include liver function tests, CBC, ECG, and UA. These tests should be repeated periodically, as dictated by the drug that is taken and the comorbidities of the patient. History of previous responses to medications, especially antipsychotics, should be noted.



Mechanism of Action


The exact mechanism of antipsychotic drug action is unknown. These drugs are thought to work by blocking postsynaptic dopamine receptors in the hypothalamus, basal ganglia, limbic system, brainstem, and medulla, and to some extent serotonin receptors. Much work has been done to elucidate which receptors each drug affects. How this receptor blocking causes specific changes in behavior and cognition is not known. See Table 49-4 for specific neurotransmitter-receptor blocking actions of individual medications. Each neurotransmitter is associated with specific side effects. However, the correlation between the two is not completely understood. A very complicated and overlapping set of mechanisms interact to produce a wide variety of effects. Another complication is that these drugs produce different effects from patient to patient. Most cause sedation in some people and agitation in others (Box 49-2). Some antipsychotic drugs cause metabolic side effects such as obesity and diabetes by activating the SMAD3 protein, which plays a role in the transforming growth factor beta pathway—a cellular mechanism responsible for inflammation and insulin signaling, among other processes.


 



BOX 49-2   Neurotransmitter and Adverse Effects



Jan 1, 2017 | Posted by in PHARMACY | Comments Off on Antipsychotics

Full access? Get Clinical Tree

Get Clinical Tree app for offline access