Antipsychotics are used to treat most forms of psychosis, including schizophrenia, in humans. They do not have the same significance in animal behavior therapy and are usually most appropriately used on a short-term, intermittent basis. The first antipsychotic, chlorpromazine, was developed in 1950. Individual antipsychotic drugs show a wide range of physiological effects, resulting in tremendous variation in side effects. The most consistent pharmacological effect is an affinity for dopamine receptors. In humans, antipsychotics produce a state of relative indifference to stressful situations. In animals, antipsychotics reduce responsiveness to a variety of stimuli, exploratory behavior, and feeding behavior. Conditioned avoidance responses are lost in animals that are given antipsychotics.
Antipsychotic agents are divided into two groups based on side effect profiles (low-potency and high-potency drugs) or by structural classes (Table Classes of antipsychotic drugs). Low-potency antipsychotics have a lower affinity at D2 receptor sites, higher incidence of anticholinergic effects (sedation), stronger alpha-adrenergic blockade (cardiovascular side effects), and require larger doses (1-3 mg/kg), but have a lower incidence of extrapyramidal side effects. High-potency antipsychotics show a greater affinity for D2 receptor sites, fewer autonomic effects, less cardiac toxicity, a higher incidence of extrapyramidal signs, and are effective in smaller doses (0.5-1 mg/kg). The phenothiazine neuroleptics are antipsychotics that are commonly used in veterinary medicine for sedation and restraint.
Table Classes of antipsychotic drugs
|Azaperone (Stresnil, Suicalm)|
Antipsychotic agents block the action of dopamine, a catecholamine neurotransmitter that is synthesized from dietary tyrosine. Dopamine regulates motor activities and appetitive behaviors. Dopamine depletion is associated with behavioral quieting, depression, and extrapyramidal signs. Excess dopamine is associated with psychotic symptoms and the development of stereotypies. A large proportion of the brain’s dopamine is located in the corpus striatum and mediates the part of the extrapyramidal system concerned with coordinated motor activities. Dopaminergic neurons project to the basal ganglia and extrapyramidal neuronal system. Side effects associated with blockade of this system are called extrapyramidal responses. Dopamine is also high in some regions of the limbic system.
The nigrostriatal pathway consists of cell bodies originating in the substantia nigra and mediates motor activities. The mesolimbic pathway consists of neuronal cell bodies that originate in the ventral tegmental area, project to ventral striatum and limbic structures, and mediate appetitive behaviors. Dopamine is broken down by monoamine oxidase inside the presynaptic neuron or by catechol-O-methyltransferase outside the presynaptic neuron. There are five dopamine receptor subtypes. Traditional antipsychotics are D2 receptor antagonists and block 70-90% of D2 receptors at therapeutic doses.
Antipsychotics have a wide spectrum of physiological actions. Traditional antipsychotics have antihistaminic activity, dopamine receptor antagonism, alpha-adrenergic blockade, and muscarinic cholinergic blockade. Blockade of dopamine receptors in the basal ganglia and limbic system produces behavioral quieting, as well as depression of the reticular-activating system and brain regions that control thermoregulation, basal metabolic rate, emesis, vasomotor tone, and hormonal balance. Antipsychotics produce ataraxia: a state of decreased emotional arousal and relative indifference to stressful situations. They suppress spontaneous movements without affecting spinal and pain reflexes.
Overview of Indications
Antipsychotic agents are most often used in veterinary practice when chemical restraint is necessary. Antipsychotic agents are used for restraint or the temporary decrease of motor activity in cases of intense fear or stereotypic behavior. A complete behavioral and medical history is necessary to determine which pharmacological agents will be the most beneficial for any given case. A comprehensive treatment plan that includes behavior modification exercises and environmental modifications, along with drug therapy, has the best chance for success.
Antipsychotic agents have poor anxiolytic properties and should not be the sole treatment for any anxiety-related disorder. Therefore, while they can be useful in preventing self-injury or damage to the environment by an animal exhibiting a high-intensity fear response, they are not appropriate for long-term therapy and treatment of phobias.
Antipsychotic agents are indicated for the treatment of intense fear responses requiring heavy sedation to prevent self-injury or property damage. Sedation to the point of ataxia may be necessary to control frantic responses in storm-phobic dogs, but owners often report that their dogs still appear to be frightened.
Antipsychotic agents have also been used in game capture operations and to allow physical examination in intractable animals. Antipsychotics can also be used as antiemetics and for the treatment and prevention of motion sickness. When used as preanesthetic agents, antipsychotics may induce a state of indifference to a stressful situation.
Antipsychotic agents produce inconsistent results for the treatment of aggressive behavior, and in some cases have induced aggressive behavior in animals with no history of aggressiveness.
Antipsychotic agents have a high hepatic extraction ratio. Metabolites are generally inactive compounds and excreted in the urine. Maximal effect occurs about 1 hour after administration. Duration of action ranges from 4 to 24 hours. Half-lives range from 10 to 30 hours in humans. These agents are highly lipid soluble and highly protein bound.
Contraindications, Side Effects, and Adverse Events
Significant side effects can occur with acute antipsychotic use because of decreased dopaminergic activity in the substantia nigra. Side effects may include motor deficits or Parkinsonian-like symptoms, such as difficulty initiating movements (akinesis), muscle spasms (dystonia), motor restlessness (akathisia), and increased muscle tone resulting in tremors or stiffness.
Behavior effects include indifference (ataraxia), decreased emotional reactivity, and decreased conditioned avoidance responses. Antipsychotic agents may also cause a suppression of spontaneous movements, a decrease in apomorphine-induced stereotypies, a decrease in social and exploratory behaviors, a decrease in operant responding, and a decrease in responses to non-nociceptive stimuli.
Tardive dyskinesia occurs as a result of upregulation of dopamine receptors with chronic antipsychotic use. An increase in postsynaptic receptor density due to dopamine blockade can result in the inability to control movements or torticollis, and hyperkinesis. The dopaminergic system is unique in that intermittent use of antipsychotic medications can result in up-regulation of postsynaptic receptors. Chronic side effects may occur after three months of treatment. At least 10-20% of human patients treated with antipsychotics for more than one year develop tardive dyskinesia, and the symptoms are potentially irreversible even after the medication is discontinued.
Bradycardia and transient hypotension due to alpha-adrenergic blocking effects can occur. Syncope has been reported, particularly in brachycephalic breeds. Hypertension is possible with chronic use.
Endocrine effects include an increase in serum prolactin, luteinizing hormone, follicle-stimulating hormone suppression, gynecomastia, gallactorhea, infertility, and weight gain. Parasympatholytic autonomic reactions are possible. Other side effects include lowered seizure threshold, hematological disorders (thrombocytopenia), hyperglycemia, and electrocardiographic changes. Priapism has been reported in stallions.
Antipsychotic agents should be used with caution, if at all, in patients with seizure disorders, hepatic dysfunction, renal impairment, or cardiac disease, and in young or debilitated animals, geriatric patients, pregnant females, giant breeds, greyhounds, and boxers.
Neuroleptic malignant syndrome is a rare, but potentially fatal, complex of symptoms associated with antipsychotic use. It results in muscular rigidity, autonomic instability, hyperthermia, tachycardia, cardiac dysrhythmias, altered consciousness, coma, increased liver enzymes, creatine phosphokinase, and leukocytosis. Mortality reaches 20-30% in affected humans. Treatment includes discontinuation of the antipsychotic medication, symptomatic treatment, and medical monitoring.