CATEGORIES OF NEUROLEPTICS AND ANTIDEPRESSANTS USED FOR BEHAVIORAL MODIFICATION

Neuroleptics, also referred to as antipsychotics in human medicine, include butyrophenones (haloperidol, azaperone), phenothiazines (perphenazine, fluphenazine), thioxanthenes (flupenthixol, zuclopenthixol), and substituted benzamides (sulpiride). These drugs cause a range of degrees of sedation, alpha-adrenoceptor blocking activity, extrapyramidal symptoms, and antimuscarinic effects.¹ These drugs generally tranquilize without affecting consciousness or excitement, but should not be regarded merely as “tranquilizers.” In humans, for the short term, they are used to calm disturbed patients, whatever the underlying psychopathology. Newer neuroleptics, such as risperidone, also called atypical antipsychotics, may be better tolerated because extrapyramidal symptoms occur less frequently (in humans).

Antidepressants may also be used to moderate abnormal animal behaviors, particularly the selective serotonin reuptake inhibitors (SSRIs), such as citalopram and fluoxetine (Prozac; Elly Lilly, U.S.A.), and the monoamine oxidase inhibitors (MAOIs), such as clomipramine.⁸ Interaction between these two groups may complicate switching from one drug to another; MAOIs are rarely used in human medicine because of the dangers of dietary and drug interactions. Other antidepressants should not be started for 2 weeks after treatment with MAOIs has stopped (3 weeks with clomipramine). Conversely, an MAOI should not be started until at least 2 weeks after anticyclic or related antidepressant (3 weeks with clomipramine) has stopped. For this reason, the selection of SSRIs or MAOIs for the treatment of zoo animals should be undertaken with great care because if one is not working, the time required to change drugs is prolonged, which may lead to an exacerbation of the welfare issue.

CAUTIONS, CONTRAINDICATIONS, AND SIDE EFFECTS OF NEUROLEPTICS

Neuroleptics should be avoided in patients with renal or hepatic impairment or cardiovascular disease. They are best avoided during pregnancy. Withdrawal after long-term therapy should always be gradual and carefully monitored to prevent acute withdrawal syndromes or rapid relapse. Antimuscarinic effects are a side effect of most neuroleptics and include dry mouth and constipation.

The most significant side effects are the extrapyramidal signs. These effects occur most often with the piperazine phenothiazines (perphenazine, fluphenazine), but also with the butyrophenones (haloperidol, azaperone). The phenothiazine group may be further divided in groups 1, 2, and 3. Group 3 phenothiazines include perphenazine, which is widely used in zoo animals, particularly ungulates,² because it is associated with fewer sedative effects than the other groups. However, perphenazine may produce more pronounced extrapyramidal effects. Extrapyramidal signs are easy to recognize but cannot be predicted because they depend on dose, type of drug, and individual susceptibility. Extrapyramidal signs include parkinsonian-like symptoms (including tremor), dystonia (abnormal face and body movements), akathisia (restlessness), and tardive dyskinesia (involuntary rhythmic movement of tongue, face, and jaw). The latter usually develops in humans who receive long-term therapy but may occur on short-term treatment and low doses or after withdrawal of the drug.

Neuroleptic malignant syndrome (hyperthermia, fluctuating level of consciousness, muscular rigidity, and autonomic dysfunction with pallor, tachycardia, labile blood pressure, sweating, and urinary incontinence) is a rare but potentially fatal side effect. Discontinuation of the drug is essential because no specific treatment exists for this syndrome, which usually lasts 5 to 7 days after cessation of therapy in humans.

Other side effects include drowsiness, insomnia, convulsions, dizziness, gastrointestinal disturbances, cardiovascular disturbances including sudden death, photosensitization, and corneal and lens opacities. Therefore, patients receiving any of these drugs should be carefully monitored by staff who are aware of the side effects of these drugs and who will ensure that any such signs are reported to the veterinarian as a matter of urgency.

Drug selection in human medicine is based on the degree of sedation required and the patient’s susceptibility to extrapyramidal effects. This susceptibility is generally unknown when dealing with great apes. Prescribing more than one antipsychotic at a time is not recommended unless under close medical supervision; this may increase the risks, and there is no evidence that side effects are minimized. Given the lack of data in great apes, a number of regimens will likely be tried before one suitable for the particular patient and condition is found. In particular, care should be taken to select the drug regimens in a certain order to avoid potentially dangerous drug interactions.

Therefore these drugs should be carefully selected for use in great apes because they do not pose a simple and safe solution to the behavioral management of zoo animals. When used carefully, however, neuroleptics may provide an extra tool for managing difficult patients who are unresponsive to behavioral therapy alone.

USE OF NEUROLEPTICS IN GORILLAS

Few published reports on the use of neuroleptic or behavior-modifying drugs in great apes exist. A survey on the use of psychoactive drugs in great apes included the use of haloperidol, with and without fluoxetine, or risperidone to control aggression in male gorillas.⁶

A case study on the control of aggression and abnormal behaviors in a group of two female gorillas and one male gorilla described the use of haloperidol and thioridazine in all three animals.⁵ Another paper has described the use of haloperidol in a female gorilla to treat self-mutilation.³ Zuclopenthixol has been used to reduce anxiety without sedation in a group of 10 gorillas transported by air from Europe to Australia.¹²

Perphenazine enanthate as a long-acting injectable product has been used to moderate aggression in an adult male gorilla intermittently over several months. On one occasion an extrapyramidal side effect similar to neuroleptic malignant syndrome was noted 3 days after injection, characterized by a hypertonic crisis five times in 1 hour.⁷ Oral zuclopenthixol has been used in a gorilla reacting aggressively to visiting public, using doses of 10 to 25 mg three times a day. The dose was gradually tapered to zero, with a decrease of 5 mg every week.⁷ Transportation of an adult male gorilla from Germany to South Africa was facilitated using 75 mg zuclopenthixol and 30 mg haloperidol; this dose resulted in deep sedation, however, making clinical assessment difficult.⁴

NEUROLEPTIC DRUGS TO MODERATE AGGRESSION AND FACILITATE INTRODUCTION IN A MALE GORILLA

A group of adult gorillas had been mixed together in the Gorilla Island complex at Bristol Zoo Gardens (Bristol, U.K.) in 2003. The group consisted of a 27-year-old multiparous female (female 1) who had been at the zoo since 1998, a 21-year-old female (female 2), and a 20-year-old male who arrived together in November 2001. Female 2 had congenital bilateral cataracts, which were removed in 2002, restoring full vision.

In summer 2003, adult males were exchanged with another zoo, and a period of introduction followed. This new male had a history of aggressive behavior resulting in injury to females. This male had been housed in a bachelor group for 9 years after removal from his natal group at 8 years old. He was then moved to another zoo to be with a group of four females. During integration with those females, there were several incidents of aggression, resulting in such severe injury to the females that the zoo stopped further attempts at introduction and offered the male for transfer through the breeding program of the European Endangered Species Program (EEP).

The receiving zoo had a larger gorilla facility and thus was able to maintain the male gorilla in isolation from the females for short periods. On assessment at the new zoo, the male appeared agitated and nervous, as evidenced by excessive sweating, “raspberry blowing” (pursing the lips and blowing), hooting, and exhibiting poor appetite. Despite his previous history, a normal but carefully monitored introduction program was planned to determine if his responses would be better now that he was in a different environment. During the first 7 days the male was in auditory, visual, and olfactory contact but physically separated from the females. Various management practices were attempted to integrate the male with the two females from day 8. The mixes with the male occurred during the day; the females were together overnight, but separated from the male.

On the first introduction the male attacked female 1. This behavior is expected in early gorilla introductions, but this episode was prolonged and severe, and the male appeared to ignore the female’s submissive gestures. Female 2 complicated this initial introduction by supporting the male in his attack. Female 2 had no experience of gorilla group dynamics and limited social skills because she recently had congenital cataracts removed, having been virtually blind since birth. She had also been previously housed in a small zoo with a male gorilla, so there had been limited interaction and no mating between the two animals. During this attack, female 1 sustained a severe injury to the arm necessitating surgical repair. Thereafter, female 2 was not mixed with the male at the same time as female 1 for several weeks in an attempt to integrate the male with one female at a time. Each female was introduced to the male for increasing periods during the day to a maximum of 6 hours per day. Keepers carefully monitored the animals and separated the male when signs of tension were observed. The daily routine involved separating all three animals in the late afternoon for a feed, and then the two females were housed together but separate from the male overnight.

This integration method seemed to be progressing well until day 19, when the male attacked female 1, without provocation, resulting in severe injuries. She had to be separated to permit surgery and healing, although she remained in auditory, olfactory, and visual contact with the male and was housed with the other female at night. The male was therefore mixed only with female 2 for 34 days for 6 hours daily, with only one aggressive incident. On day 23 he attacked her for several minutes but without injury; this was seen as normal behavior. On day 36 there was a mix with both females, and the male gorilla immediately attacked female 1, who sustained severe injuries, again requiring surgery. Given this history of repeated injurious behavior, an attempt to moderate the male’s aggression using medication was initiated, because further introductions were deemed to place the females at an unacceptable risk of harm.

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