Selective Serotonin Reuptake Inhibitors

8
Selective Serotonin Reuptake Inhibitors

Niwako Ogata¹, Leticia Mattos de Souza Dantas², and Sharon L. Crowell‐Davis²

¹ Purdue University, West Lafayette, IN, USA

² University of Georgia, Athens, GA, USA

Action

The selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that inhibit the reuptake of serotonin. This results in an increase in serotonergic neuro‐transmission by allowing serotonin molecules to act for extended periods of time. With prolonged use, there is also down‐regulation of serotonin receptors. Currently the Food and Drug Administration (FDA) has approved six of them in human medicine to treat depression: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva), and sertraline (Zoloft). Fluoxetine is also available as an FDA‐approved veterinary product named Reconcile^®.

Overview of Indications

The SSRIs are classified as antidepressants; however, they have anxiolytic, anticompulsive, and some antiaggressive effects (e.g. Charney et al. 1990; Coccaro et al. 1990; Kavoussi et al. 1994; Sanchez and Hyttel 1994; Stein and Stahl 2000; Walsh and Dinan 2001). It is primarily for these reasons that they are used in veterinary medicine. The onset of all effects is usually slow, and clients who have pets on treatment with SSRIs must be informed of this so that they do not have unrealistic expectations. While some response may be observed within a few days of initiation of treatment, improvement commonly does not occur for three to four weeks, or even longer. Thus, if an SSRI is recommended, caution the client that the pet’s response to the medication will not be evaluated until it has been on medication daily for at least one month. SSRIs should never be given on an “as‐needed” basis, because they will generally be ineffective if used this way. They can be used in cases of specific phobias (such as agoraphobia or storm phobia) and are particularly useful in cases of anxiety that occurs pervasively and frequently, as in the case of generalized anxiety disorder (e.g. Gorman 2002). Animals with generalized anxiety disorder exhibit an almost constant state of low‐level anxiety, regardless of their current environment, and are hyperreactive to a variety of fear‐inducing environmental stimuli.

Fluoxetine has been used in the treatment of behavior problems in domestic animals more commonly than any other SSRI. As a consequence, there is more information about safety, side effects, and efficacy in various species for this medication than any other. Following fluoxetine, paroxetine and sertraline have been used the most and are mentioned in various textbooks, even though there is a lack of clinical trials on their use for mental health treatment in veterinary medicine.

Common uses for behaviour problems in domestic animals include anxiety disorders, affective aggression, obsessive compulsive disorders, and urine marking. They can potentially be used for offensive and predatory aggression (Carrillo et al. 2009). However, medication should never be considered a substitute for adequate restraint and safety measures for patients with this or any other type of aggressive behavior. As discussed in Chapter 1, serotonin is involved in the control of aggression. Reisner et al. (1996) measured cerebrospinal fluid (CSF) levels of 5‐hydroxyindole acetic acid (5‐HIAA) in 21 dogs with a diagnosis of “dominance” aggression and 19 control dogs. The dogs with “dominance” aggression had significantly lower concentrations of CSF 5‐HIAA than did the 19 controls (Reisner et al. 1996). When used in the treatment of compulsive disorders, response to serotonin reuptake inhibitors (SSRIs) varies with the specific signs of the disorder and the duration of the problem (Irimajiri et al. 2009).

All SSRIs are metabolized in the liver and excreted through the kidneys. Therefore, premedication blood work to assess the function of these organs is recommended. It is also worth noting that SSRIs can cause urinary incontinence or retention through predominant serotonin receptor subtypes at the site of action. The excitatory effects on the bladder sphincter seem to be medicated by 5‐HT2 receptors, whereas the inhibitory effects on the bladder seem to be mediated by 5‐HT1 receptors (Espey et al. 1998; Lowenstein et al. 2007). There is an indication that the effect might be various among species (Thor et al. 2002).

Contraindications, Side Effects, and Adverse Events

Side effects observed in various species include sedation, tremor, constipation, diarrhea, nausea, anxiety, irritability, agitation, insomnia, decreased appetite, anorexia, aggression, mania, decreased libido, hyponatremia, and seizures. Mild sedation and decreased appetite are the most common side effects observed by the authors in dogs. Both are typically transient. If the appetite decrease is sufficient to cause concern about adequate food intake, temporarily increasing the palatability of the diet and/or hand feeding is usually sufficient to induce adequate food consumption until this phase passes.

SSRIs may also be contraindicated with other natural supplements given to animals, including St John’s Wort, cannabis-based substances like Rick Simpson Oil (RSO), and antidepressants like trazodone.

Serotonin syndrome is a phenomenon reported in humans. It is a consequence of taking excessive quantities of medications that increase serotonin levels and/or taking certain medications that are incompatible with SSRIs concomitantly. Signs and symptoms can be grossly grouped into mental changes, neuromuscular changes and autonomic changes. Treatment should include decontamination, anticonvulsants, thermoregulation, and fluid therapy (Mills 1995; Brown et al. 1996; Martin 1996). This phenomenon is discussed in further detail in Chapter 19 (Combinations).

When mothers are given various SSRIs (fluoxetine, sertraline, paroxetine, or one of the previous with clonazepam), the neonatal acute pain response is decreased and parasympathetic cardiac modulation during the recovery period is increased (Oberlander et al. 2002).

Adverse Drug Interactions

SSRIs are competitive inhibitors of a number of cytochrome P450 liver enzymes. Therefore, if a patient is placed on an SSRI and another medication that is metabolized by the P450 liver enzymes, elevated plasma levels may develop in the medications, potentially resulting in toxic side effects (Albers et al. 2002). To date, there is minimal data on variation between breeds and species in the P450 enzymes as it relates to the metabolism of various psychoactive drugs. Therefore, findings in humans must be substantially relied upon for the time being. Since there is substantial variation, even within the human population, it is expected that further studies will also reveal substantial variation in veterinary populations (DeVane 1994).

All of the SSRIs can increase levels of warfarin due to P450 interactions and due to competition for plasma protein binding sites. Fluoxetine and fluvoxamine are the strongest inhibitors of CYP1A2 and CYP2C9, P450 (both enzymes that metabolize warfarin) (Albers et al. 2002).

Fluoxetine, fluvoxamine, sertraline, and paroxetine cause significant inhibition of CYP2D6, which metabolizes amitriptyline, amphetamine, clomipramine, desipramine, haloperidol, imipramine, and nortriptyline (Crewe et al. 1992; Albers et al. 2002).

Fluvoxamine causes the greatest degree of inhibition of CYP3A4, which metabolizes alprazolam, buspirone, clomipramine, clonazepam, and imipramine (Albers et al. 2002).

Fluoxetine and fluvoxamine cause the greatest degree of inhibition of CYP2C19, which metabolizes amitriptyline, clomipramine, diazepam, imipramine, and propranolol (Albers et al. 2002).

Fluvoxamine causes the greatest degree of inhibition of CYP1A2, which metabolizes amitriptyline, caffeine, clomipramine, clozapine, haloperidol, imipramine, and olanzapine, in addition to warfarin (Brøsen et al. 1993; Albers et al. 2002).

In addition, SSRIs should not be given with monoamine oxidase inhibitors (MAOIs), because fatal drug interactions can occur.

Overdose

In case of overdose, conduct gastric lavage, give activated charcoal, give anticonvulsants as needed, and provide supportive therapy.

Clinical Guidelines

SSRIs should generally be given once a day. If large doses are required for efficacy, the total daily dose can be divided to minimize side effects. SSRIs should not be given on a sporadic, as‐needed basis. Efficacy of a given SSRI on a given patient should not be evaluated until the patient has been on medication daily for at least a month. If, at one month, some degree of improvement is observed, the medication should be continued at the same dose, or at a higher dose if improvement has been only slight.

SSRIs may alter blood glucose levels. Therefore, while they can be used with diabetic patients, they should be used with caution, and blood glucose levels should be monitored closely. Decreased doses should be used in patients with mild dysfunction of the liver or kidneys. SSRIs should not be used at all in patients with severe dysfunction of the liver or kidneys. There is no relationship between plasma levels of SSRIs and clinical response. Therefore, measuring plasma levels is not useful (Albers et al. 2002). Animal doses are given in Table 8.1.

Table 8.1 Doses of various SSRIs for dogs, cats, horses, and parrots.

SSRI	Dog	Cat	Parrot	Horse
Citalopram	0.5–1.0 mg kg⁻¹
Fluoxetine	1.0–2.0 mg kg⁻¹	0.5–1.5 mg kg⁻¹	2.0–5.0 mg kg⁻¹	0.25–0.5 mg kg⁻¹
Fluvoxamine	1–2 mg kg⁻¹	0.25–0.5 mg kg⁻¹
Paroxetine	1.0–1.5 mg kg⁻¹	0.5–1.5 mg kg⁻¹	2.0 mg kg⁻¹ q12h	0.5 mg kg⁻¹
Sertraline	0.5–4.0 mg kg⁻¹	0.5–1.5 mg kg⁻¹

Note: All doses given are orally, once daily, unless otherwise specified. Do not evaluate efficacy until the patient has received the medication daily for at least one full month.

Specific Medications

I. Citalopram Hydrobromide

Chemical Compound: (±)‐1‐(3‐Dimethylaminopropyl)‐1‐(4‐fluorophenyl)‐1,3 dihydroisobenzofuran‐5‐carbonitrile
DEA Classification: Not a controlled substance
Preparations: Generally available as 10‐, 20‐, and 40‐mg tablets and as a 2‐mg ml⁻¹ peppermint‐flavored oral solution.

Clinical Pharmacology

Citalopram is a strong inhibitor of serotonin reuptake and has little effect on reuptake of dopamine or norepinephrine. Of the currently available SSRIs, it appears to be the most selective inhibitor of 5‐hydroxytryptamine (5‐HT) uptake (Pollock 2001). It has very little to no effect on the 5‐HT_1A, 5‐HT_2A, dopamine D₁ and D₂, α ₁, α ₂ and β‐adrenergic, histamine H₁, γ‐aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors.

Citalopram is metabolized to desmethylcitalopram (DCT), di‐desmethylcitalopram (DDCT), citalopram‐N‐oxide, and a deaminated propionic acid. At steady state, while the parent compound, citalopram, is the predominant component, DCT and DDCT occur in significant amounts. Citalopram is more effective than its metabolites in preventing serotonin reuptake. Dogs appear to convert more citalopram to metabolites than do humans. Specifically, in dogs, peak DDCT concentrations are approximately equal to peak citalopram concentrations, whereas in humans, steady‐state peak DDCT plasma concentrations are less than 10% of citalopram concentrations (Forest Laboratories, Inc. 2002).

In humans, when a single oral dose is given, peak blood levels are reached in two to four hours (Pollock 2001). When it is given daily, steady‐state plasma concentrations are reached in about seven days (Forest Laboratories, Inc. 2002). The half‐life in humans is about 1.5 days, while the half‐life of demethylcitalopram is 2 days and of DDCT, 4 days (Pollock 2001).

Citalopram is metabolized by CYP2C19, CYP3A4, and CYP2D6 (Pollock 2001; Forest Laboratories, Inc. 2002). Since citalopram is metabolized by multiple enzyme systems, it is not expected that concurrent medication with drugs that affect only one of these systems would cause clinically significant effects.

In geriatric populations and individuals with reduced hepatic or renal function citalopram clearance time is slower than for younger populations without reduced hepatic or renal function. Citalopram doses should be reduced in these populations (Forest Laboratories, Inc. 2002).

Uses in Humans

Citalopram is used to treat depression. It has also been shown to be significantly more effective than placebo in treating impulsive aggressive behavior in humans (Reist et al. 2003).

Contraindications

Citalopram is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). MAOIs should be discontinued for at least two weeks before beginning treatment with citalopram. Likewise, citalopram should be discontinued for at least two weeks before beginning an MAOI.

Side Effects

In a small number of patients, treatment with citalopram can result in anxiety, changes in appetite, vomiting, diarrhea, changes in urinary frequency, insomnia, sedation, excitement, seizures, hyponatremia, abnormal bleeding, mydriasis, and various other side effects unique to individuals, including anaphylaxis.

In studies of carcinogenesis, mice were given up to 240 mg kg⁻¹ day⁻¹ of citalopram for 18 months, and rats were given up to 24 mg kg⁻¹ day⁻¹ for 24 months. No increased carcinogenesis occurred in the mice. Rats exhibited an increased incidence of small intestine carcinoma. Albino rats given 80 mg kg⁻¹ day⁻¹ for two years exhibited degeneration and atrophy of the retinas. Retinal degeneration did not occur in rats given 24 mg kg⁻¹ day⁻¹, mice treated at doses of up to 240 mg kg⁻¹ day⁻¹ for 18 months, or dogs treated for a year with doses of up to 20 mg kg⁻¹ day⁻¹. These doses are greater than what would be used therapeutically in mice and rats. The implication of these findings for other domestic species is not known.

Citalopram has been mutagenic in some bacterial assays. It has not been found to be mutagenic in mammalian assays, however (Forest Laboratories, Inc. 2002).

Citalopram at doses of 16–72 mg kg⁻¹ day⁻¹ decreased mating behavior in both male and female rats and decreased fertility at doses ≤32 mg kg⁻¹ day⁻¹. In rat embryo/fetal development studies, pregnant rats were given citalopram at doses of 32, 56, or 112 mg kg⁻¹ day⁻¹. This resulted in decreased embryo/fetal growth and survival and an increased rate of abnormalities at the high dose of 112 mg kg⁻¹ day⁻¹. Toxicity, with clinical signs, occurred in the pregnant females at this dose. There were no harmful effects on the fetuses at 56 mg kg⁻¹ day⁻¹ or lower. In rabbit embryo/fetal development studies, pregnant females were given 15 mg kg⁻¹ day⁻¹ with no adverse consequences (Forest Laboratories, Inc. 2002).

Citalopram is excreted in milk. In humans, sedation, decreased feeding, and weight loss have been recorded in the infants of mothers being treated with citalopram. When considering giving citalopram to a pregnant or nursing female, the potential benefits must be weighed against the potential risks to the embryo, fetus, or young animal (Forest Laboratories, Inc. 2002).

Citalopram has a longer half‐life in geriatric patients than in younger patients. It is recommended that the lower range of the dose be given in geriatric patients (Forest Laboratories, Inc. 2002).

Five of 10 beagles given citalopram at a dose of 8 mg kg⁻¹ day⁻¹ died between days 17 and 31 after initiation of treatment. Some data suggest that dogs convert citalopram to its metabolites more than do humans. The phenomenon of sudden death was not observed in rats given up to 120 mg kg⁻¹ day⁻¹, which produced plasma levels of citalopram and its metabolites similar to those observed in dogs on 8 mg kg⁻¹ day⁻¹. Subsequent intravenous studies showed that DDCT produced prolonged QT intervals. Combined with the fact that dogs metabolize more citalopram to DDCT than do other species studied, this medication should not be considered a first‐choice SSRI to use in this species (Forest Laboratories, Inc. 2002).

Overdose

Gastric lavage may be useful if conducted soon after ingestion. Induction of emesis is not recommended. Give activated charcoal and provide supportive therapy. There is no specific antidote.

Other Information

While the peppermint‐flavored solution may seem an obvious choice for use in very small animals, taste aversion could be a problem with various species and individuals. Other SSRIs may be better choices for animals under 10 kg.

In humans, citalopram has not been shown to significantly affect the metabolism of digoxin, warfarin, theophylline, or triazolam (Forest Laboratories, Inc. 2002).

Effects Documented in Nonhuman Animals

Dogs

Citalopram has been effectively used to treat canine acral lick dermatitis (ALD) in dogs when given at a dose of 0.5–1.0 mg kg⁻¹ daily. Specifically, six of nine dogs responded, with the average time to achieving a status of “much improved” or better being 2.6 weeks. Side effects that were observed in this population included sedation, anorexia, and constipation. Long‐term follow‐up of more than one year was available on three dogs. One was continued on a dose of 0.5 mg kg⁻¹ and remained lesion‐free. One relapsed on two occasions when medication was discontinued, but recovered when medication was resumed at a maintenance dose of 0.33 mg kg⁻¹; a third relapsed when medication was discontinued. This dog was changed to fluoxetine for economic reasons and responded to that agent, on which it was likewise maintained for more than one year (Stein et al. 1998).

II. Fluoxetine Hydrochloride

Chemical Compound: (+)‐N‐methyl‐3‐phenyl‐3‐(ααα‐trifluoro‐ρ‐tolyl) oxypropylamine hydrochloride
DEA Classification: Not a controlled substance
Preparations: Generally available as 10‐ and 20‐mg tablets, 10‐, 20‐, and 40‐mg capsules, a slow release 90‐mg tablet, and a mint‐flavored solution of 20 mg/5 ml. Reconcile is available in 8‐, 16‐, 32‐ and 64 mg chewable tablets.

Clinical Pharmacology

Fluoxetine is a strong inhibitor of serotonin reuptake and a very weak inhibitor of norepinephrine reuptake. Fluoxetine also has very little binding to muscarinic, histaminergic, and α 1‐adrenergic receptors compared with other antidepressants such as the tricyclic antidepressants.

Fluoxetine is well absorbed after oral administration, although food may delay its absorption by one to two hours. Metabolism is not proportional to dose; that is, when fluoxetine is given repeatedly, it is metabolized more slowly than if it is given as a single dose. In humans, peak plasma concentrations of a single oral dose occur in six to eight hours, while the elimination half‐life is one to six days (Altamura et al. 1994; Eli Lilly 2004). It is extensively metabolized in the liver to norfluoxetine, its principal metabolite, which is a less‐potent SSRI, but has an elimination half‐life of 4–16 days. In animal models, S‐norfluoxetine has been found to be comparable to the parent compound in inhibition of serotonin reuptake (Altamura et al. 1994; Eli Lilly 2004). In the dog fluoxetine is well absorbed (up to 72%) after oral administration and it is largely metabolized in the liver. After a single dose with approximately 2 mg/kg body weight, peak plasma concentrations occur around 1.8 hours (fluoxetine) and around 12.8 hours (norfluoxetine) while elimination half‐life ranged from 3 to 12.9 hours (fluoxetine) and from 33 to 64 hours (norfluoxetine) (Elanco Animal Health 2007).

The elimination half‐life of fluoxetine is substantially delayed in patients with liver disease as compared to patients without liver disease. In contrast, human patients on dialysis had steady‐state fluoxetine and norfluoxetine concentrations similar to those of patients with normal kidneys. Thus, while the presence of liver disease should always be considered cause for reducing the dose, patients with renal disease may be able to tolerate a normal dose. Elderly patients have not been observed to have a higher incidence of adverse events than young adult patients (Eli Lilly 2004).

The median lethal dose in rats is 452 mg kg⁻¹ PO. The median lethal dose in mice is 248 mg kg⁻¹. Phospholipids have been shown to increase in the tissues of dogs, mice, and rats chronically medicated with fluoxetine (Eli Lilly 2004).

Uses in Humans

Fluoxetine hydrochloride is used to treat depression, premenstrual dysphoric disorder, obsessive‐compulsive disorder (OCD), and bulimia in humans.

Contraindications

The combination of fluoxetine and MAOIs can result in serious and sometimes fatal drug interactions. The two medications should never be given together. Because of the long half‐life of fluoxetine, treatment with a MAOI should not be initiated until five weeks have passed since the discontinuation of fluoxetine. Conversely, fluoxetine treatment should not be initiated until two weeks have passed since the discontinuation of an MAOI. Thioridazine should also not be given with fluoxetine or until at least five weeks have passed since discontinuation of fluoxetine, because fluoxetine may result in elevated levels of thioridazine. Rarely, various allergic events may occur in response to fluoxetine, including anaphylactoid reactions.

Fluoxetine inhibits the liver enzymes cytochrome CYP2C9, CYP2D6, CYP2C19, and CYP3A4. Therefore, elevated levels of medications that are metabolized by any of these enzymes may occur when given concurrently, for example, tricyclic antidepressants, benzodiazepines, carbamazepine, and haloperidol. Low doses should be used when these are combined with fluoxetine.

Co‐administration of fluoxetine and tryptophan may lead to adverse events. Because tryptophan is available over the counter, clients should be cautioned to not supplement their pet with tryptophan when it is being medicated with fluoxetine or any other serotonin reuptake inhibitor.

Co‐administration with warfarin can result in increased bleeding.

Side Effects

In a small number of patients, treatment with fluoxetine can result in anxiety, changes in appetite, vomiting, diarrhea, changes in urinary frequency, insomnia, sedation, excitement, seizures, hyponatremia, abnormal bleeding, and decreased sexual motivation. Decreased sexual motivation has been documented to occur in nonhuman animals, as well as humans (Matuszcyk et al. 1998). While this side effect makes fluoxetine undesirable for use in breeding animals, it makes it potentially useful for treatment of problems of undesirable sexual behavior in neutered animals and is irrelevant for animals with behavior problems that are not intended for breeding. Veterinary patients that exhibit increased anxiety with administration of fluoxetine may improve and be subsequently maintained on this medication if the dose is decreased.

Fluoxetine may alter the metabolism of blood glucose. In particular, hyperglycemia may develop during treatment with fluoxetine, while hypoglycemia may develop upon withdrawal from fluoxetine. However, in humans, fluoxetine is effectively used to treat depression in diabetic patients (Lustman et al. 2000). In diabetic patients, insulin doses may need to be modified when initiating and discontinuing treatment with fluoxetine.

Fluoxetine is tightly bound to plasma protein. Therefore, concomitant administration with drugs that are also tightly bound to plasma protein (e.g. digitoxin) can produce plasma levels of either (or both) drugs that are high compared with what they are if given alone, resulting in adverse side effects.

Fluoxetine can alter anticoagulant effects and cause increased bleeding in patients concurrently given warfarin.

Fluoxetine has not been found to be carcinogenic, mutagenic, or impair fertility. However, in rats given 7.5 mg kg⁻¹ daily or 12 mg kg⁻¹ daily of fluoxetine during pregnancy, there was increased postpartum pup death. Rats given 5 mg kg⁻¹ daily did not have increased pup mortality. Also, when ewes in late gestation are given a 70 mg IV bolus of fluoxetine over a two‐minute period, transient decreases in uterine artery blood flow, fetal PO₂, and oxygen saturation occur within the first 15 minutes. These values do not return to normal after the passage of 24 hours. In addition, fetal pH decreases and fetal PCO₂ increases during the first 4 hours and then they return to normal within 24 hours. There are no differences in uterine artery blood flow, blood gas status, or cardiovascular measures between fluoxetine‐treated ewes and control ewes (Morrison et al. 2002).

Because of potential risks to the fetus, fluoxetine should not be given to pregnant females unless the potential benefits clearly outweigh the potential risks to the fetus. Likewise, because fluoxetine is excreted in milk, it is recommended that it not be given to nursing females unless either a clear need outweighs the fact that the offspring are also being medicated or the offspring are fed a milk substitute. While caution is indicated, children of women who took fluoxetine throughout pregnancy did not show any decrement in birth weight, preschool IQ, language development, or behavior (Nulman et al. 2001).

During toxicity testing, rats were given up to 12 mg kg⁻¹ daily of fluoxetine for two years without any evidence of carcinogenicity.

Overdose

There are no specific antidotes for overdose with fluoxetine. In 87 cases in which humans ingested an acute overdose of fluoxetine without concurrent ingestion of other drugs, the most common symptoms were tachycardia, drowsiness, tremor, vomiting, or nausea. Thirty of the patients (47%) did not develop any symptoms. Asymptomatic patients ingested a mean dose of 341 mg and a maximum dose of 1200 mg (Borys et al. 1992). Gastric lavage may be helpful if done soon after the overdose. Induction of emesis is not recommended. Give activated charcoal and supportive therapy. Give diazepam for seizures.

Doses in Nonhuman Animals

Doses reported for dogs generally range from 1.0–2.0 mg kg⁻¹day⁻¹, while doses reported for cats run a bit lower, generally ranging from 0.5–1.5 mg kg⁻¹ day⁻¹. Smaller animals and/or species with faster metabolism, such as birds, will need higher doses to obtain clinical efficacy. Doses reported for birds range from 2.0 to 5 mg kg⁻¹ day⁻¹. Conversely, larger animals are likely to need smaller doses on a per kilogram basis. While there are no clinical reports of the treatment of rats, mice, or rabbits with fluoxetine, these species have tolerated very high doses in laboratory studies of toxicity. Horses may be effectively treated with 100–200 mg daily, or approximately 0.25–0.50 mg kg⁻¹.

Discontinuation of Fluoxetine

For patients that have been on fluoxetine for several weeks or months, it is recommended that discontinuation be done gradually rather than abruptly. In practice, if fluoxetine is effective in the treatment of the target behavior or anxiety‐related problem, continue medication for another one to three months, depending on the severity of the primary problem. Once it is confirmed that the problem has achieved long‐term remediation with medication, fluoxetine is decreased at a rate not to exceed 25% of the maintenance dose per week. Some patients experience relapses at given decreases. If this happens, go back up to the lowest effective dose and continue for another one to three months, and then attempt to decrease the dose again.

Other Information

Fluoxetine has been more extensively used in the treatment of behavior problems in domestic animals than any other SSRI. Cats exhibit a strong distaste for the mint‐flavored solution designed for humans. Rather than attempt to give this orally, it is recommended that a compounding pharmacist prepare a solution in a tuna‐ or chicken‐flavored liquid or that tablets are dispensed.

While fluoxetine is not approved for use in the treatment of aggression in humans, several small studies have supported the hypothesis that it is effective in treating aggression (e.g. impulsive aggression, self‐injurious behavior) in some patients (see, e.g. Charney et al. 1990; Coccaro et al. 1990; Cornelius et al. 1991; Markowitz 1992; Kavoussi et al. 1994). In addition, a meta‐analysis of 3992 patients treated with fluoxetine or placebo during clinical trials revealed that aggressive events were four times less likely to occur in fluoxetine‐treated patients than in placebo‐treated patients (Heiligenstein et al. 1993). Fluoxetine has been shown to suppress aggression in various laboratory animal species, for example, golden hamsters (Mesocricetus auratus) and lizards (Anolis carolinensis) (Deckel 1996; Deckel and Jevitts 1997; Ferris et al. 1997).

Effects Documented in Nonhuman Animals

Administration of fluoxetine to dogs and cats is quite common in small animal practice in North America. One survey study using 127 veterinary professional participants in North America showed 83% of clinician prescribed it to their feline and canine patients for an array of behavior problems. These were anxiety disorders, aggressive behavior, compulsive disorders, phobias/fear and other problem behaviors, with anxieties being more common in dogs. While in cats, elimination behaviors, anxiety disorders, aggression, dermatologic/grooming, compulsive disorders and others, elimination behaviors being most common (Kaur et al. 2016).

Cats

Fluoxetine in a 15% pluronic lecithin organogel (PLO gel) formulation can be absorbed through the skin of cats into the systemic circulation. However, bioavailability of transdermally administered fluoxetine is only 10% that of the oral route although it was administered in a single dose. When concentrations are increased to achieve clinically effective levels, dermatitis results. Thus, transdermal administration of fluoxetine is not recommended (Ciribassi et al. 2003). Eichstadt et al. (2017) made a comparison of serum concentration between daily administration of transdermal (5 mg kg⁻¹) with the proprietary transdermal base (PCCA Lipoderm) and oral (1 mg kg⁻¹) fluoxetine in cats. The drug administration for both routes was daily for 60 days. The blood concentrations or fluoxetine and norfluoxetine were seemingly accumulated by time and the concentrations between the two routes were significantly different at the 30‐day point. Oral administration was much higher for both concentrations. Since this study did not evaluate the clinical effects, the author did not conclude if the given transdermal dose was clinically sufficient.

Hartmann (1995), in a letter to the American Journal of Psychiatry, reported on a cat with ALD that had not responded to more conventional treatments, including hypoallergenic diets, diphenhydramine, and diazepam, but the condition resolved when given fluoxetine at 0.25–0.38 mg kg⁻¹ daily. The only side effect observed was mild sedation.

Romatowski (1998) described two clinical cases of cats that responded to fluoxetine. One was a 16‐month‐old, 3‐kg, spayed female Siamese cat that was presented with symmetrical, self‐induced alopecia on the forelimbs. The cat was also a nervous and hyperactive pet. There were no cutaneous lesions other than the hair loss, and the cat had no fleas or flea manure. Treatment with methylprednisolone, phenobarbital, a commercial lamb and rice diet, and finally, megestrol acetate, all failed to resolve the problem. In fact, during these treatments, the hair loss became more extensive and eventually involved the abdomen, flanks, and thighs in a symmetrical pattern. Finally, treatment with fluoxetine, 0.66 mg kg⁻¹ (2 mg daily) was attempted. The cat discontinued the excessive licking and after five months had grown a full hair coat. The owner also reported that the cat was more relaxed and a more pleasant pet.

The second case described by Romatowski involved two five‐year‐old, spayed female, domestic shorthair littermates. The two cats had gotten along well until they were moved to a new home approximately one year prior to presentation. Before the move, the cats had been entirely indoors. After the move, they were allowed access to the backyard. One cat began rejecting the other, hissing whenever she approached. The rejected cat began intermittently urinating in various places in the house on a variety of substrates, for example, countertops, plastic or paper bags, the sleeping place of the cat that was rejecting her, and the owner’s clothes. Urinalysis of the cat with the elimination behavior problem was unremarkable. Treatment with buspirone, 5 mg two times a day (b.i.d) for 30 days, was ineffective, as was treatment with diazepam, 1 mg b.i.d. Both cats were then placed on 2 mg fluoxetine daily. This treatment resulted in a discontinuation of the hissing behavior. The cats resumed sleeping together and grooming each other, behavior that had not occurred since the move. Inappropriate elimination was decreased by 50%.

Pryor et al. (2001) treated 17 neutered urine‐spraying cats, all over one year of age, with fluoxetine or a fish‐flavored liquid placebo in a randomized, double‐blind, placebo‐controlled trial. The initial dose was 1 mg kg⁻¹ PO given once daily. If the patient did not achieve a 70% reduction in urine spraying by the fifth week, the dose was increased to 1.5 mg kg⁻¹. To maintain blinding, any cat that did not show improvements, including those on placebo, were given a 50% increased dose of their compounded medication. Treatment was carried out for eight weeks, followed by an additional four weeks of monitoring the cats after they had discontinued medication.

Standardized environmental management was as follows: (i) the owners were provided with an enzymatic cleaner that they were to use on all soiled areas; (ii) the owners were instructed to provide as many litter boxes as cats in the household, plus one more; (iii) the owners were instructed to clean all feces and urine from the litter boxes once a day and to completely change the litter material and wash the litter boxes once per week; and (iv) the owners were instructed to refrain from physically or verbally punishing the cats.

Cats on the treatment showed a significant decrease in spraying behavior, compared with baseline premedication measures after two weeks of treatment. Their spraying rate continued to decrease throughout treatment. In contrast, the mean weekly spraying rate of cats on placebo decreased slightly during the first week and did not decrease further thereafter. This slight decrease was probably a response to the environmental management and increased regular supervision that was necessarily occurring because of the research. By the end of the trial, all cats on treatment had demonstrated a 90% reduction in the number of urine marks each week. Total cessation of spraying occurred in 66% of the cats on treatment by the eighth week. For weeks two through eight, there was a significant difference in response for the cats on placebo versus the cats on treatment. The most common side effect reported was decreased food intake; however, this was reported in four of the nine cats on treatment and three of the seven cats on placebo. The decreased food intake was never to such a degree that it was cause for concern or considered clinically significant. Vomiting occurred in one cat on treatment and two cats on placebo. Lethargy occurred in three cats on treatment and two cats on placebo.

After medication was discontinued, two of the nine cats that had been treated did not resume spraying. However, the other seven cats resumed some degree of marking. There was a linear correlation between the rate of marking during baseline and the rate of marking four weeks after treatment. Because of this finding, it is recommended that most cats, particularly those with higher rates of urine marking prior to treatment, that is, four or more marks per week, should be treated for a period longer than eight weeks.

Dogs

Six laboratory dogs overdosed with fluoxetine given orally developed grand mal seizures that were controlled with intravenous boluses of diazepam. In another study, the electrocardiogram (ECGs) of dogs given high doses of fluoxetine were evaluated. Tachycardia and increased blood pressure occurred. However, no changes occurred in the PR, QRS, or QT intervals (Eli Lilly 2004).

Overall (1995) described a case of a dog with “dominance‐related” interdog aggression, “dominance aggression” to the dog’s owner, fear of strangers, and stereotypic circling. Initial treatment with behavior modification alone resulted in resolution of the aggression toward the owner, but did not resolve the interdog aggression or fear of strangers. Therefore, medication treatment was initiated. After an initial period of treatment with fluoxetine alone, then buspirone, then buspirone with fluoxetine, and finally fluoxetine alone, the dog was maintained on fluoxetine at a dose of 0.54 mg kg⁻¹ daily for a period of 28 months. During this time, there was only one incident of interdog aggression, and there was no owner‐directed aggression. Side effects included constant mydriasis after the initiation of treatment with fluoxetine. Renal and hepatic function were not compromised while on the long‐term fluoxetine treatment.

In a later study, Dodman et al. (1996) conducted a single‐blind crossover trial of the treatment of owner‐directed “dominance” aggression in nine dogs. Diagnosis was based entirely on context and frequency of aggression and did not include signaling behavior. Therefore, patients with what the author considers to be other forms of affective aggression may have been included in this study’s population. Patients were treated with fluoxetine at a dose of 1 mg kg⁻¹ PO q24h, and one week of a placebo. The fluoxetine and placebo were placed into gelatin capsules so that they were visually indistinguishable. While owners were not told which week their dog would be getting the placebo, all dogs received the placebo during the first week of the trial to avoid a carryover effect from the fluoxetine, since it has a long half‐life. No behavior modification or training was carried out during the five‐week study.

A significant reduction in owner‐directed incidents of aggression was observed by the end of treatment. While on medication, some dogs exhibited changes in level of activity, changes in food or water intake, increased alertness, shaking, barking, and reclusion. While it is not recommended that medication be used alone in the treatment of canine affective aggression, it is clear from this report that SSRI medications such as fluoxetine can be useful adjuncts to treatment with behavior modification. Fluoxetine has also been used to treat additional cases of inter‐dog aggression (at 1.1 mg kg⁻¹ PO daily, in combination with behavior modification) (Dodman 2000).

Rapoport et al. (1992) compared fluoxetine to fenfluramine in 14 dogs with ALD in an 11‐weeks crossover treatment trial. Dogs were treated for five weeks with up to 0.96 ± 0.29 mg kg⁻¹ daily of fluoxetine and for another five weeks with up to 0.92 ± 0.24 mg kg⁻¹ daily of fenfluramine. Owners used a 10‐point scale to rate their dogs’ licking with 0 being no licking at all and 10 being the worst licking ever observed. There was no order effect, so ratings were combined across both orders. Dogs on fluoxetine exhibited, on average, a 39% decrease from baseline scores. By five weeks, improvement on fluoxetine was significantly greater than improvement on fenfluramine, which was slight. Concurrent studies were carried out on an additional 13 dogs that were treated with clomipramine or desipramine and another 10 dogs that were treated with sertraline or placebo in a similar crossover trial. Comparisons in response across trials showed that fluoxetine was more effective than desipramine, fenfluramine, and sertraline in reducing licking. Four of the 14 dogs treated with fluoxetine showed lethargy, 1 showed loss of appetite, and 1 showed hyperactivity. Two of the dogs treated with fluoxetine showed complete remission of excessive licking, while four showed a 50% reduction in licking.

Stein et al. (1992) likewise used fluoxetine, 1–2 mg kg⁻¹ daily for an eight‐week open trial on five dogs with ALD. One dog almost entirely discontinued self‐injurious behavior, but developed polyuria and polydipsia. Two others showed substantial improvement with no side effects. One dog was removed from the study at two weeks when there was no response, while another was removed from the study because it exhibited sedation. Subsequent use of fluoxetine in cases of OCD manifested as canine acral lick have been reported as having about a 50% success rate (Karel 1994). In the author’s experience, improvement may not be exhibited for four weeks or more. Sedation, when it occurs, is often transient, and dogs usually return to normal levels of activity after a couple of weeks.

Wynchank and Berk (1998) subsequently conducted a double‐blind, randomized, placebo‐controlled trial of the use of fluoxetine in the treatment of ALD in dogs. All dogs on treatment were dosed at 20 mg day⁻¹, regardless of size, for six weeks. The smallest dog was 5 kg. Thus, this dog was dosed at 4 mg kg⁻¹. For a dog to qualify for the study, a veterinarian must have diagnosed the dog with ALD at least six months before the beginning of the trial. Other causes of licking behavior must have been ruled out, as well.

Fifty‐eight dogs, ranging in age from 1 to 13 years, completed the trial. For dogs that were on the treatment, owner rating of the licking behavior and appearance of the lesion decreased significantly over the course of treatment. The placebo group did not exhibit a significant decline. There was a significant difference between treatment and placebo groups in both change in appearance of the lesion and general condition of the dog by the end of the study. Veterinarians who were blinded as to whether or not the photographs were before or after treatment evaluated photographs of the lesions. Changes in the scores for lesion severity were significantly better for the treatment group than for the placebo group. No adverse events were reported.

Irimajiri et al. (2009) reported the efficacy of fluoxetine for compulsive disorders in dogs by randomized, controlled clinical trial. Sixty‐three dogs with compulsive disorders were randomly assigned to treatment with fluoxetine (1–2 mg kg⁻¹ daily) or a placebo without any behavior or environmental modification during 42 day study. The owners kept daily diary of the severity of episodes and the researchers collected the information through telephone interviews every 2 weeks. It was found that the severity of the condition was more likely to decrease (odds ratio, 8.7) in the fluoxetine group compared to the placebo group. However, mean number and duration of compulsive episodes, as determined from daily diary entries, did not differ significantly between groups. They also reported that the most common adverse effects were decreased appetite and mild lethargy. When fluoxetine was used to treat anxiety, Reisner (2003) reported forty dogs treated for generalized anxiety disorder with fluoxetine at 0.37–1.2 mg kg⁻¹, 27 (67%) improved, 9 showed no significant behavior change, and 4 got worse while on this treatment (Reisner 2003).

Reconcile, a chewable tablet form of fluoxetine, is the another FDA approved veterinary medication for the treatment of separation anxiety in dogs, but only in conjunction with behavior modification. Sherman‐Simpson et al. (2007) conducted a multiple‐center, placebo‐controlled, double‐blind, parallel‐arm study to investigate the clinical efficacy and safety of Reconcile (1–2 mg kg⁻¹ daily), in conjunction with behavior management for the treatment of separation anxiety in dogs. A total of 242 client‐owned dogs were randomized into the study for 8‐week treatment. They found about 42% of dogs treated with Reconcile improved within 1 week of treatment, which was significantly greater than the 17% of dogs with placebo. Although dogs in both groups continued to improve over the course of the 8‐week treatment period, dogs in reconcile group demonstrated a significant improvement compared to the placebo group (72% improvement vs. 50% respectively). Later, another multi‐center, placebo‐controlled, double‐blind randomized parallel‐arm study on 208 client‐owned dogs diagnosed with separation anxiety conducted without behavior modification training (Landsberg et al., 2008). In this study Reconcile (1–2 mg kg⁻¹ daily ) or placebo was given for 6 weeks. Without behavior modification the dogs showed 58% improvement in overall separation anxiety severity scores comparing to its pre‐treatment score, however, the there was no significant difference when it was compared to the placebo group. Based on the outcome between two studies, the authors of the study recommended that pharmacotherapy should have the conjunction with behavior modification to get the optimal outcome.

Parrots

Mertens (1997) reported that 12 of 14 birds treated with fluoxetine for feather‐picking (2.3 mg kg⁻¹ daily for at least four weeks) exhibited initial improvement but subsequently relapsed. An increased dose up to as high as 3 mg kg⁻¹ b.i.d. again resulted in improvement with a subsequent relapse. Side effects observed included frequent sneezing (two birds) one week after initiation of treatment, temporary ataxia, and lethargy about one hour after medication (two birds). Additionally, one bird that had an extensive vocabulary, including songs and poems, forgot word sequences and exhibited a reduced vocabulary. All problems disappeared after treatment was discontinued. All birds were kept in good housing conditions, with provision of intra‐ and interspecific social contact, good dietary management, and exercise.

Seibert (2004) treated a 3.5‐year‐old white female cockatiel (Nymphicus hollandicus) (1 mg kg⁻¹ of fluoxetine PO, q24h) with a compulsive disorder that was specifically manifested as chewing the third digit of the right foot. The bird responded two weeks after initiation of treatment. After three months of treatment, the dosage was decreased. By five months treatment was successfully discontinued.

Primates

Vervet monkeys with various stereotypic behaviors, for example, saluting, somersaulting, weaving, and head tossing, were treated with fluoxetine (1 mg kg⁻¹ daily for six weeks) or placebo. Results of assessment by a rater blind to treatment status identified a significant difference between fluoxetine‐treated and placebo‐treated monkeys by the end of the trial (Hugo et al. 2003).

III. Fluvoxamine

Chemical Compound: 5‐Methoxy‐4′‐(trifluoromethyl)valerophenone‐(E)‐O‐(2‐aminoethyl)oxime maleate
DEA Classification: Not a controlled substance
Preparations: Generally available as 25‐, 50‐, and 100‐mg tablets.

Clinical Pharmacology

Fluvoxamine specifically inhibits reuptake of serotonin in both blood platelets and brain synaptosomes (Claassen et al. 1977). It has a weak affinity for histaminergic, α‐ or β‐adrenergic, muscarinic, or dopaminergic receptors. Absorption is not affected by food intake. In humans, steady‐state plasma concentrations are achieved in about 10 days. Once people have achieved steady state, peak plasma concentrations occur in three to eight hours. The pharmacokinetics of fluvoxamine are nonlinear. Specifically, higher doses of fluvoxamine produce proportionally higher concentrations in the plasma than do lower doses.

Fluvoxamine is metabolized by the liver, primarily via oxidative demethylation and deamination. Nine metabolites have been identified. The major human metabolites are fluvoxamine acid, the N‐acetyl analog of fluvoxamine acid, and fluvoxethanol, all of which have little to no serotonin reuptake prevention activity. Humans excrete only about 2% of fluvoxamine as the parent compound. The remaining 98% is excreted as various metabolites (Solvay Pharmaceuticals 2002).

Excretion occurs primarily via the kidneys. In healthy humans, an average of 94% of the medication is excreted in the urine within 71 hours of dosing. Geriatric patients clear fluvoxamine more slowly than young adults. Patients with liver disease clear fluvoxamine more slowly than do healthy patients. However, patients with renal disease have not been found to clear fluvoxamine any more slowly than do persons without renal disease (Solvay Pharmaceuticals 2002).

Uses in Humans

Fluvoxamine is used to treat OCD in humans.

Contraindications

Fluvoxamine should not be administered with terfenadine or cisapride. These are metabolized by the P450 isozyme 3A4. While there is no definitive proof that fluvoxamine is a 3A4 inhibitor, there is strong evidence that it is. Thus, co‐administration could result in elevated terfenadine or cisapride levels, which could result in QT prolongation, ventricular tachycardia, and other cardiac symptoms (Solvay Pharmaceuticals 2002).

Fluvoxamine should not be administered at the same time as MAOIs. It should not be used in patients that have previously received an MAOI until the patient has been off the MAOI for at least two weeks. Conversely, MAOIs should not be given until a patient has stopped fluvoxamine for at least two weeks.

The metabolism of benzodiazepines by hepatic oxidation, including alprazolam, midazolam, and triazolam (see Chapter 3) can be reduced by combined use with fluvoxamine. Benzodiazepines metabolized by glucuronidation, including lorazepam, oxazepam, and temazepam, are not likely to be affected by co‐administration with fluvoxamine (Solvay Pharmaceuticals 2002).

Fluvoxamine can alter the efficacy and activity of warfarin, propanaolol, tricyclic antidepressants, and theophylline, as well as other drugs metabolized by the P450 enzyme system. Tryptophan may increase the serotonergic activity of fluvoxamine and should be used in combination with caution (Solvay Pharmaceuticals 2002).

Side Effects

In a small number of patients, treatment with fluvoxamine can result in anxiety, changes in appetite, vomiting, diarrhea, changes in urinary frequency, insomnia, sedation, excitement, seizures, hyponatremia, abnormal bleeding, mydriasis, decreased libido, and various other side effects unique to individuals, including anaphylaxis.

Studies of the potential for carcinogenicity, mutagenicity, and impairment of fertility by fluvoxamine have not revealed any such effects. Rats were treated with doses of up to 240 mg kg⁻¹ day⁻¹ for 30 months, and hamsters were treated with doses of up to 240 mg kg⁻¹ day⁻¹ for up to 20 months, with no carcinogenic effect. In fertility studies, male and female rats were given up to 80 mg kg⁻¹ day⁻¹ PO of fluvoxamine, with no deleterious effects on mating, duration of gestation, or pregnancy (Solvay Pharmaceuticals 2002).

In teratology studies in which pregnant rats were given up to 80 mg kg⁻¹ day⁻¹ PO and pregnant rabbits were given up to 40 mg kg⁻¹ day⁻¹ PO, there were no fetal malformations. In other studies, in which pregnant rats were dosed through weaning with 5, 20, 80, and 160 mg kg⁻¹ day⁻¹ PO there was an increase in pup mortality at birth in rats that were dosed at 80 mg kg⁻¹ and higher, decreased neonatal pup weights at 160 mg kg⁻¹, and decreased long‐term survival of the pups at all doses. Results of a cross‐fostering study suggested that some of the postnatal deficits in survival were due to maternal toxicity; that is, the mothers being chronically medicated at such high doses were not as competent mothers as were unmedicated rats. However, there may have been some direct drug effect on the offspring.

Fluvoxamine is excreted in the milk. In deciding whether to medicate pregnant or lactating females, potential risks to the offspring must be weighed against the potential benefits to the mother (Solvay Pharmaceuticals 2002).

In human studies, the side‐effect profile for pediatric patients has been found to be similar to the side‐effect profile for adult patients (Solvay Pharmaceuticals 2002).

Overdose

Gastric lavage may be useful if it is conducted soon after ingestion of an overdose. Give activated charcoal and provide supportive therapy. There is no specific antidote.

Other Information

Comparisons of humans treated with either placebo or fluvoxamine showed no significant effect of fluvoxamine on various vital sign indicators, serum chemistries, hematology, urinalysis, or ECG changes. Fluvoxamine has not been found to significantly affect the pharmacokinetics of digoxin (Solvay Pharmaceuticals 2002).

Effects Documented in Nonhuman Animals

Fluvoxamine has a specific antiaggressive effect on maternal aggression, because it results in decreased aggression at doses that do not cause concurrent nonspecific decreases in activity (Olivier and Mos 1992).

IV. Paroxetine Hydrochloride

Chemical Compound: (−)‐Trans‐4R‐(4′‐fluorophenyl)‐3S‐[(3′, 4′‐methylene‐dioxyphenoxyl)methyl]piperidine hydrochloride hemihydrate
DEA Classification: Not a controlled substance
Preparations: Generally available as 10‐, 20‐, 30‐, and 40‐mg tablets and a 2‐mg ml⁻¹ orange‐flavored suspension. Controlled‐release tablets are available in 12.5‐, 25‐, and 37.5‐mg sizes.

Clinical Pharmacology

Paroxetine has weak effects on neuronal reuptake of norepinephrine and dopamine, but is primarily a highly selective inhibitor of serotonin reuptake. It has little affinity for muscarinic, α₁‐, α₂‐, β‐adrenergic, dopamine (D₂)‐, 5‐HT₁‐, 5‐HT₂‐, or histamine (H₁) receptors. Thus, there are fewer anticholinergic, sedative, and cardiovascular side effects than some other serotonin reuptake inhibitors, such as amitriptyline, that also have substantial effects on muscarinic, histaminergic and α₁‐adrenergic receptors. Paroxetine has multiple metabolites, each about 1/50th as potent as the parent compound. Thus, clinical efficacy of paroxetine is essentially from the parent compound, and there are no significant contributions from metabolites (SmithKline Beecham Pharmaceuticals 2004).

Paroxetine is completely absorbed when given orally and can be given with or without food. In humans, the half‐life is about 10 days, with 64% being excreted in the urine, 2% as paroxetine, and the remainder as metabolites of paroxetine. The remaining 36% is excreted in the feces, < 1% as paroxetine, and the remainder as metabolites. With chronic daily dosing, steady‐state plasma concentrations are achieved in about 10 days. Paroxetine is distributed throughout the body, including the central nervous system, with about 95% being bound to plasma protein (SmithKline Beecham Pharmaceuticals 2004).

The presence of renal or hepatic disease produces increased concentrations of paroxetine in the plasma. Therefore, patients with mild renal or hepatic impairment should be started on a very low dose and the dose titrated upward over time. Plasma levels in older patients are also elevated. Therefore, the starting dose should be low in all geriatric patients and subsequently titrated upward as necessary (SmithKline Beecham Pharmaceuticals 2004).

Paxil CR tablets are formulated so that dissolution occurs gradually over a period of several hours. There is also an enteric coat that prevents release of the active ingredient until after the tablet has left the stomach. The consumption of food does not significantly affect release or absorption. For the slower release to occur, the tablet cannot be cut, broken, or chewed (SmithKline Beecham Pharmaceuticals 2004). This limits its potential usefulness in animals weighing less than approximately 10 kg. Even in animals large enough to theoretically be given the controlled release tablets, it is important to remember that these tablets are designed for the human digestive system and dissolve and are absorbed at substantially slower or faster rates in various other species.

Uses in Humans

Paroxetine is used to treat depression, OCD, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder (PTSD).

Contraindications

Do not use paroxetine in combination with any MAOI or with thioridazine, because serious and sometimes fatal drug interactions can result. Patients should not be given paroxetine for at least two weeks before initiating medication with either of these drugs. Patients should not have been given MAOIs for at least two weeks before initiation of paroxetine (SmithKline Beecham Pharmaceuticals 2004).

Paroxetine inhibits the liver enzyme CYP2D6 but otherwise causes less inhibition of liver enzymes than do other SSRIs such as fluoxetine and fluvoxamine. Nevertheless, there are a large number of medications that are metabolized by this enzyme, including amitriptyline, clomipramine, dextromethorphan, imipramine, propranolol, and thioridazine. Thus, lower doses should be used in patients concurrently receiving any drug that is metabolized by this enzyme (SmithKline Beecham Pharmaceuticals 2004).

Do not use in patients with narrow angle glaucoma.

Concurrent use of paroxetine and tryptophan can result in adverse events. Because tryptophan is available over the counter, clients should be advised of this (SmithKline Beecham Pharmaceuticals 2004).

Paroxetine may interact with warfarin, altering its effect on bleeding. Paroxetine is strongly bound to plasma protein, resulting in a greater plasma concentration of any drug administered concurrently that is likewise strongly bound to plasma protein (SmithKline Beecham Pharmaceuticals 2004).

Side Effects

In a small number of patients, treatment with paroxetine can result in anxiety, changes in appetite, vomiting, diarrhea, changes in urinary frequency, insomnia, sedation, excitement, seizures, hyponatremia, abnormal bleeding, mydriasis, decreased libido, and various other side effects unique to individuals, including anaphylaxis (SmithKline Beecham Pharmaceuticals 2004). Studies conducted in humans have shown that the incidence of many side effects is dose‐dependent, that is, the higher the dose, the more likely it is that side effects will occur. Withdrawal reactions occur at a higher rate for paroxetine than for fluoxetine, fluvoxamine, or sertraline in the human population (Price et al. 1996). In case of decreased libido, while this side effect makes paroxetine undesirable for use in breeding animals, it makes it potentially useful for treatment of animals with undesirable sexual behavior. In cats, constipation is a potential side effect of paroxetine (Frank and Dehasse 2003).

Carcinogenicity studies were conducted in mice and rats on paroxetine for two years. Mice were given 1, 5, or 25 mg kg⁻¹ daily, and rats were given 1, 5, or 20 mg kg⁻¹ daily. The male rats in the high‐dose group had significantly more sarcomas than did the male rats in the low‐ or medium‐dose group or on placebo. There was no carcinogenic effect identified in mice or female rats. The implications of these findings for other domestic animals are unknown (SmithKline Beecham Pharmaceuticals 2004). Since the dose that induced cancer in male rats was greater than what would be used as a therapeutic dose for the treatment of behavior problems in pet rats, the findings are probably not of concern in treating this group. Nevertheless, owners should be cautioned.

Studies of potential mutagenicity of paroxetine have not identified any mutagenic effects of this medication.

Female rats experienced a reduced pregnancy rate when given 15 mg kg⁻¹ daily of paroxetine. Male rats given 25 mg kg⁻¹ daily had atrophic changes in the seminiferous tubules and aspermatogenesis. Male rats given 50 mg kg⁻¹ day⁻¹ had vacuolation of the epididymal tubular epithelium (SmithKline Beecham Pharmaceuticals 2004).

In studies of teratogenic effects, pregnant rabbits were given 6 mg kg⁻¹ daily, and pregnant rats were given 50 mg kg⁻¹ daily during organogenesis. There were no teratogenic effects in either species and no increased postnatal pup deaths in rabbits. However, in rats there was increased pup mortality when paroxetine was continued during the last trimester and lactation. The cause of this mortality has not been identified. The implications of these findings for other domestic animals are not known. However, because of these findings and the fact that paroxetine is secreted in milk, it should be used in pregnant and lactating females only when the potential benefits clearly outweigh the risks (SmithKline Beecham Pharmaceuticals 2004).

Geriatric patients have decreased clearance time as compared with younger patients. Therefore, lower dosing is recommended in geriatric patients (SmithKline Beecham Pharmaceuticals 2004).

Overdose

Gastric lavage may be useful if conducted soon after ingestion. Induction of emesis is not recommended. Give activated charcoal, and provide supportive therapy. There is no specific antidote.

Discontinuation of Paroxetine

For patients that have been on paroxetine for several weeks, it is recommended that discontinuation be done gradually rather than abruptly. While abrupt discontinuation of a variety of SSRI treatments can cause withdrawal symptoms, this phenomenon has been most frequently reported with paroxetine in the human literature (Price et al. 1996; Michelson et al. 1998). In practice, if paroxetine is effective in the treatment of the target behavior problem, continue medication for another one to three months, depending on the severity of the primary problem. Once it is confirmed that the problem has achieved long‐term remediation with medication, paroxetine is decreased at a rate not exceeding 25% of the maintenance dose per week. Some patients experience relapses at given decreases. If this happens, go back up to the lowest effective dose and continue for another one to three months, then attempt to decrease the dose again.

Other Information

In double‐blind placebo‐controlled trials conducted on humans, paroxetine was not found to produce any significant changes in ECGs, heart rate, blood pressure, or liver enzymes.

Paroxetine has an insignificant effect on the liver enzyme CYP2C19. Therefore, there is no need for lower doses of benzodiazepines, which are metabolized by this enzyme, as is the case with fluoxetine and fluvoxamine (SmithKline Beecham Pharmaceuticals 2004).

Effects Documented in Nonhuman Animals

Cats

Paroxetine has been used to treat cats for urine marking and aggression toward humans and cats (Frank and Dehasse 2003; Pryor 2003; Pachel 2014).

Dogs

Of 12 dogs treated with paroxetine (0.96–1.75 mg kg⁻¹ PO q24h), for generalized anxiety disorder, 6 (50%) showed improvement, 4 showed no change, and 1 dog got worse (Reisner 2003). The response of the twelfth dog is not reported.

Horses

A mare with a five‐year history of weaving exhibited a 95% decrease in this behavior when given 0.5 mg kg⁻¹ daily PO. Even when stressed, the mare exhibited a 57% improvement over baseline. Specifically, the frequency of weaving changed from 43.5 per minute with kicking to less than 1 per minute. When the mare was stressed, weaving increased to 18.75 per minute (Nurnberg et al. 1997).

V. Sertraline Hydrochloride

Chemical Compound: (1S‐cis)‐4‐(3, 4‐dichlorophenyl)‐(1, 2, 3, 4‐tetrahydro‐N‐methyl‐1‐naphthalenamine hydrochloride
DEA Classification: Not a controlled substance
Preparations: Generally available as 25‐, 50‐, and 100‐mg tablets and a 20‐mg ml⁻¹ liquid.

Clinical Pharmacology

Sertraline is a selective inhibitor of neuronal serotonin reuptake. It has very weak effects on reuptake of norepinephrine and dopamine. Sertraline has no substantial affinity for adrenergic (α₁, α ₂, and β), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5‐HT_1A, 5‐HT_1B, 5‐HT₂), or benzodiazepine receptors. Therefore, the anticholinergic, sedative and cardiovascular effects seen with some other psychoactive drugs, such as the tricyclic antidepressants, are minimal. Chronic administration of sertraline also down‐regulates brain norepinephrine receptors. The half‐life in humans is about 26 hours. Blood levels reach a steady state after approximately one week of daily dosing in a healthy adult. More time is required to achieve steady state in older patients. Sertraline can be given with or without food (Pfizer Inc. 2004).

Sertraline is metabolized extensively during its first pass through the liver, primarily to N‐desmethylsertraline, which has a plasma elimination half‐life of 62–104 hours. N‐desmethylsertraline is a less potent serotonin reuptake inhibitor than is the parent compound. In human subjects given a single radiolabeled dose of sertraline, 40–45% of the radioactivity was recovered via the urine within nine days. Another 40–45% was recovered in the feces. The urine contained only metabolites of sertraline, while the feces contained 12–14% of the original sertraline in an unchanged form, the remainder being metabolites produced by oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation (Pfizer Inc. 2004).

In human pediatric studies, it was found that children and teenagers (6–17 years of age) metabolized sertraline more efficiently than did adults. There was no difference between males and females. In contrast, geriatric patients clear sertraline more slowly than adults (Pfizer Inc. 2004).

Patients with chronic mild liver impairment clear sertraline more slowly than do age‐matched patients with normal liver function. This is not a surprising finding given the significant metabolism of the drug in the liver in normal patients. As discussed above, clearance of unchanged sertraline in the urine is a minor mode of elimination of the parent compound, and almost half of the metabolites are eliminated in the feces. In patients with mild to severe renal impairment the pharmacokinetics of sertraline metabolism and excretion are not significantly different from healthy controls (Pfizer Inc. 2004).

The minimum lethal doses are 350 mg kg⁻¹ PO in male mice, 300 mg kg⁻¹ PO in female mice, 1000 mg kg⁻¹ in male rats, and 750 mg kg⁻¹ in female rats. Death occurs after one to two days (Pfizer Inc. 2004).

Uses in Humans

Sertraline is used to treat depression, OCD, PTSD, panic disorder, and premenstrual dysphoric disorder in humans.

Contraindications

Do not use sertraline in combination with any MAOI, because serious and sometimes fatal drug interactions can result. Patients should not be given sertraline for at least two weeks before initiating medication with an MAOI. Patients should not have been given monoamine oxidase inhibitors for at least two weeks prior to initiation of paroxetine (Pfizer Inc. 2004).

Side Effects

In a small number of patients, treatment with sertraline can result in anxiety, changes in appetite, vomiting, diarrhea, changes in urinary frequency, insomnia, sedation, excitement, seizures, hyponatremia, abnormal bleeding, mydriasis, decreased libido, and various other side effects unique to individuals, including anaphylaxis. Rarely, patients on sertraline may have altered platelet function and abnormal bleeding (Pfizer Inc. 2004).

Sertraline has some effect of inhibiting the biochemical activity of the liver enzyme CYP2D6. While its effect is not as substantial as paroxetine or fluoxetine (Albers et al. 2002), it should be used with caution with drugs that are metabolized by this enzyme, such as the tricyclic antidepressants dextromethorphan and propranolol.

Lifetime carcinogenicity studies have been conducted on mice and rats given up to 40 mg kg⁻¹ day⁻¹ of sertraline. Male mice experienced a dose‐related increase in liver adenomas. Female mice did not experience this increase. Female rats experienced an increase in the rate of follicular adenomas of the thyroid gland at 40 mg kg⁻¹ day⁻¹. This change was not accompanied by thyroid hyperplasia. There was an increase in uterine adenocarcinomas in female rats given 10–40 mg kg⁻¹ day⁻¹ compared with placebo (Davies and Kluwe 1998; Pfizer Inc. 2004).

In tests of mutagenicity, no mutagenic activity has been identified. Doses of 80 mg kg⁻¹ day⁻¹ result in decreased fertility in rats (Davies and Kluwe 1998; Pfizer Inc. 2004).

Pregnant rats have been given sertraline up to 80 mg kg⁻¹ day⁻¹, while pregnant rabbits have been given sertraline up to 40 mg kg⁻¹ day⁻¹. Sertraline was not teratogenic at these doses. When the pregnant rats and rabbits were medicated during the period of organogenesis, delayed ossification occurred in the fetuses when their mothers were on doses of 10 mg kg⁻¹ day⁻¹ in rats and 40 mg kg⁻¹ day⁻¹ in rabbits. At a dose of 20 mg kg⁻¹ day⁻¹ given to rats during the last third of gestation and lactation, there was decreased body weight gain in the pups and increased early postnatal mortality. There was no effect at 10 mg kg⁻¹ day⁻¹. The increased pup mortality was due to the in utero exposure to sertraline at the higher doses (Davies and Kluwe 1998; Pfizer Inc. 2004).

Dogs given ≥40 mg kg⁻¹ PO of sertraline daily orally for two weeks exhibit mydriasis, hindlimb weakness, hyperactivity, and anorexia. Alkaline phosphatase (Alk Ph) activity is increased in dogs given 80 mg kg⁻¹ day⁻¹ for two weeks, while serum transaminase activity (ALT) is increased in dogs receiving 160 mg kg⁻¹ for this period of time. Dogs given ≥10 mg kg⁻¹ daily PO for three months or longer exhibit mydriasis. In addition, dogs given ≥ 30 mg kg⁻¹ daily PO for up to 12 months exhibit transient hyperactivity and restlessness with anorexia and body weight loss or decreased body weight loss. Convulsions may occur at 90 mg kg⁻¹. Dogs treated with sertraline for one year exhibit increased Alk Ph activity when dosed at ≥10 mg kg⁻¹ daily PO, increased relative liver weight when dosed at ≥ 30 mg kg⁻¹ daily PO, and increased ALT when dosed at 90 mg kg⁻¹ daily PO. Lymphoid depletion may occur in dogs given 15–160 mg kg⁻¹ for a short period of time, but has not been observed in dogs treated chronically (Davies and Kluwe 1998).

It is unknown whether sertraline is excreted in milk. As with the other SSRIs, medicating pregnant or lactating females with sertraline should be done cautiously, with the potential benefits to the female being weighed against the risks to the fetus and neonate (Pfizer Inc. 2004).

Other Information

While sertraline is not labeled for use in the treatment of aggression in humans, beneficial effects for patients with borderline personality disorder with impulsive aggression have been observed (e.g. Kavoussi et al. 1994).

Effects Documented in Nonhuman Animals

Dogs

Rapoport et al. (1992) studied the effects of sertraline versus placebo on dogs with ALD in an 11‐week crossover treatment trial, with five weeks each on placebo and on sertraline. Sertraline was dosed at up to 3.42 ± 0.52 mg kg⁻¹ daily. Sertraline was significantly better than placebo, producing a 21% decrease in licking behavior at five weeks as compared with baseline. However, sertraline was less effective than fluoxetine, which was being studied in a similar crossover trial with fenfluramine. Fluoxetine produced a 39% decrease by five weeks when compared to baseline. No side effects were reported for dogs on sertraline. However, only one dog showed clinically significant (50%) improvement in licking behavior.

Reptiles

Male A. carolinensis given sertraline at a dose of 10 mg kg⁻¹ exhibit decreased aggressiveness. In addition, if sertraline is given only to the “dominant” male of a pair that has established their hierarchical relationship prior to treatment, the rank order often reverses. In addition, non‐aggressive associative behavior increases (Larson and Summers 2001).

VI. Escitalopram Oxalate

Chemical Compound: 5‐[5‐(3,4‐dimethoxyphenyl)‐3‐(2‐fluorophenyl)‐3,4‐dihydropyrazol‐2‐yl]‐5‐oxopentanoic acid
DEA Classification: Not a controlled substance
Preparations: Generally available as 5‐, 10‐, and 20‐mg tablets. The 10‐ and 20‐mg tablets are scored. Although escitalopram oxalate equivalent to 1 mg ml⁻¹ escitalopram base oral solution is also available, it contains the following inactive ingredients: sorbitol, purified water, citric acid, sodium citrate, malic acid, glycerin, propylene glycol, methylparaben, propylparaben, and natural peppermint flavor.

Clinical Pharmacology

Escitalopram is S‐enantiomer of the racemic citalopram with antidepressant activity and is the newest marketed SSRI. Escitalopram has no significant affinity for adrenergic (alpha‐1, alpha‐2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT_1A, 5HT_1B, 5HT₂), or benzodiazepine receptors. Although it shares the same mechanistic target, the serotonin transporter (SERT) with other SSRIs, it is further classified as an allosteric SSRI. The additional interaction of escitalopram with an allosteric binding site on the SERT modulates the affinity of escitalopram at the primary (orthosteric) site. This unique pharmacological characteristic of excitalopram leads it to be more efficacious than other SSRIs (Sanchez et al. 2013). Additionally, in the human medicine literature, when efficacy and tolerability are compared, the overall evidence supports that escitalopram could be the first choice before paroxetine, sertraline and citalopram (Sanchez et al. 2013).

In humans when taken orally, escitalopram reaches Tmax in five hours, is 56% protein bound, and reaches steady‐state concentration in the blood within one to two weeks (Spina et al. 2012). The half‐life in humans is about 27–33 hours (Sanchez et al. 2013). Absorption of escitalopram is not affected by food. At steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2–2.5 times the plasma concentrations observed after a single dose. The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent.

Escitalopram pharmacokinetics in subjects 65 years of age were compared to younger subjects in a single dose and a multiple‐dose study. Escitalopram AUC and half‐life were increased by approximately 50% in elderly subjects, and Cmax was unchanged. Therefore, 10 mg day⁻¹ is the recommended dose for elderly patients (Forest Pharmaceuticals, Inc. 2004).

Clinically significant interaction has been observed between low dosages of escitalopram (5 mg day⁻¹) and clonidine, with an increase of central effects of clonidine such as hypothermia and sedation in humans. The molecular mechanisms underlying this interaction are presently unknown (Nikolic et al. 2009).

Uses in Humans

Escitalopram is used to treat major depression and generalized anxiety disorder.

Contraindications

Although the same caution, as being suggested in other SSRIs, to avoid serotonin syndrome is advised, escitalopram is metabolized by at least CYP3A4 and CYP2C19 and to a lesser extent by CYP2D6. In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., co‐administration of escitalopram (20 mg day⁻¹ for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the co‐administration of escitalopram and drugs metabolized by CYP2D6 (Forest Pharmaceuticals, Inc. 2004).

Overall, comparing to other SSRIs such as paroxetine and sertraline, escitalopram has little inhibitory action against other CYP enzymes or P‐glycoprotein and it has a low potential for drug–drug interactions (Sanchez et al. 2013).

Side Effects

According to a meta‐analysis reviewing 117 randomized controlled trials involving 25 928 participants with all 6 SSRIs as well as 6 new‐generation antidepressants, escitalopram and sertraline were the SSRIs that showed a highest tolerability (Cipriani et al. 2009). When side effects are observed in the treatment of major depression with either 10 mg day⁻¹, or 20 mg per day of escitalopram, they usually include insomnia, diarrhea, dry mouth, somnolence, dizziness, sweating increased, constipation, fatigue, and indigestion. The incidence rate was dose‐dependent (Forest Pharmaceuticals Inc. 2004).

In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg kg⁻¹ day⁻¹) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately 56 times the maximum recommended human dose [MRHD] of 20 mg⁻¹ day⁻¹ on a body surface area [mg/m2] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg⁻¹ kg⁻¹ day⁻¹, was present at all dose levels. The developmental no‐effect dose of 56 mg kg⁻¹ day⁻¹ is approximately 28 times the MRHD on a mg/m2 basis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/m2 basis). When female rats were treated with escitalopram (6, 12, 24, or 48 mg kg⁻¹ day⁻¹) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg kg⁻¹ day⁻¹ which is approximately 24 times the MRHD on a mg/m² basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was seen at 24 mg kg⁻¹ day⁻¹. The no‐effect dose was 12 mg kg⁻¹ day⁻¹ which is approximately 6 times the MRHD on a mg/m² basis.

There are no adequate and well‐controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (Forest Pharmaceuticals Inc. 2004).

Overdose

Gastric lavage may be useful if it is conducted soon after ingestion of an overdose. Give activated charcoal, and provide supportive therapy. There is no specific antidote.

Other Information

Paroxetine, sertraline and escitalopram have high affinity at the SERT while paroxetine has the highest affinity at the SERT, whereas escitalopram has the highest degree of selectivity (i.e. >1000‐fold relative to a large number of receptors and neurotransmitter transporters) as compared with paroxetine (>200‐fold) and sertraline (>60‐fold) (Sanchez et al. 2013).

Effects Documented in Nonhuman Animals

Dogs

One study using five clinically healthy beagles (4 male, 1 female, age 5 ± 2 years, weight 12 ± 4 kg) to determine the optimal dosing regimen and the relationship between the dose and the SERT‐occupancy has been published (Taylor et al. 2017). It reported that the elimination half‐life of escitalopram in these beagle dogs was 6.7 hours, therefore, three times a day (t.i.d.) is recommended.

According to the PET scan study, to occupy 80% of the SERT‐sites in the basal ganglia and to elicit a therapeutic effect, the minimal dose requirement in the dogs was of 1.85 mg kg⁻¹ day⁻¹ divided over three administrations. It was also observed that this dose regimen resulted in an occupancy at 81% in the hippocampus, 78% in both the colliculi and thalamus, and 77% in the brainstem region containing the raphe nuclei (Taylor et al. 2017). The main plasma metabolite of escitalopram in dogs is didesmethylmetabolite of escitalopram (S‐DDCT). As mentioned under citalopram, the QT interval on an EEG can be affected by DDCT when the concentrations were more than 300 ng ml⁻¹ in beagle dogs that is a known risk factor of sudden deaths (Le Bloc’h et al. 2003). Taylor et al. (2017) mentioned that the S‐DDCT concentrations from their suggested dose of 1.85 mg kg⁻¹ day⁻¹ divided over three administrations was equal to 290 ng ml⁻¹, however, for long‐term therapy with escitalopram with this dose in dogs, regular cardiac screening is recommended. Due to its highest selectivity on the receptors and transporters as well as little CYP 450 inhibition, these data provided potential options of using escitalopram in dogs.

Important Information for Owners of Pets Being Placed on Any SSRI

The following should be considered when placing an animal on an SSRI.

It is essential that owners inform their veterinarian of all other medication, herbal supplements, and nutritional supplements they are giving their pet, because some of these may interact with the medication.
While their pet may respond within a few days, it may be a month before their pet begins responding. They must be patient.
If their pet exhibits mild sedation in the beginning, it will probably return to normal levels of activity in two or three weeks as its body adjusts to the medication.
If their pet should experience any adverse events such as vomiting, diarrhea, or seizures, they should contact their veterinarian immediately.
All use of the medication being given is extra‐label use. This does not mean that the drug is not indicated for the problem. In fact, there may be an extensive body of scientific and clinical evidence supporting the use of this drug for their pet’s problem. It means that the extensive testing required by the FDA for on‐label usage of the drug for their particular species of pet and their particular pet’s problem has not been conducted or, if in progress, has not been completed. Exceptions to this may occur after the publication of this book if the FDA subsequently approves any of the SSRIs for treatment of various behavior problems in domestic animals.

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8
Selective Serotonin Reuptake Inhibitors

Niwako Ogata¹, Leticia Mattos de Souza Dantas², and Sharon L. Crowell‐Davis²

¹ Purdue University, West Lafayette, IN, USA

² University of Georgia, Athens, GA, USA

Action

Overview of Indications

Contraindications, Side Effects, and Adverse Events

Adverse Drug Interactions

Fluvoxamine causes the greatest degree of inhibition of CYP3A4, which metabolizes alprazolam, buspirone, clomipramine, clonazepam, and imipramine (Albers et al. 2002).

Fluoxetine and fluvoxamine cause the greatest degree of inhibition of CYP2C19, which metabolizes amitriptyline, clomipramine, diazepam, imipramine, and propranolol (Albers et al. 2002).

In addition, SSRIs should not be given with monoamine oxidase inhibitors (MAOIs), because fatal drug interactions can occur.

Overdose

In case of overdose, conduct gastric lavage, give activated charcoal, give anticonvulsants as needed, and provide supportive therapy.

Clinical Guidelines

Table 8.1 Doses of various SSRIs for dogs, cats, horses, and parrots.

SSRI	Dog	Cat	Parrot	Horse
Citalopram	0.5–1.0 mg kg⁻¹
Fluoxetine	1.0–2.0 mg kg⁻¹	0.5–1.5 mg kg⁻¹	2.0–5.0 mg kg⁻¹	0.25–0.5 mg kg⁻¹
Fluvoxamine	1–2 mg kg⁻¹	0.25–0.5 mg kg⁻¹
Paroxetine	1.0–1.5 mg kg⁻¹	0.5–1.5 mg kg⁻¹	2.0 mg kg⁻¹ q12h	0.5 mg kg⁻¹
Sertraline	0.5–4.0 mg kg⁻¹	0.5–1.5 mg kg⁻¹

Note: All doses given are orally, once daily, unless otherwise specified. Do not evaluate efficacy until the patient has received the medication daily for at least one full month.

Specific Medications

I. Citalopram Hydrobromide

Chemical Compound: (±)‐1‐(3‐Dimethylaminopropyl)‐1‐(4‐fluorophenyl)‐1,3 dihydroisobenzofuran‐5‐carbonitrile
DEA Classification: Not a controlled substance
Preparations: Generally available as 10‐, 20‐, and 40‐mg tablets and as a 2‐mg ml⁻¹ peppermint‐flavored oral solution.

Clinical Pharmacology

Uses in Humans

Citalopram is used to treat depression. It has also been shown to be significantly more effective than placebo in treating impulsive aggressive behavior in humans (Reist et al. 2003).

Contraindications

Side Effects

Citalopram has been mutagenic in some bacterial assays. It has not been found to be mutagenic in mammalian assays, however (Forest Laboratories, Inc. 2002).

Citalopram has a longer half‐life in geriatric patients than in younger patients. It is recommended that the lower range of the dose be given in geriatric patients (Forest Laboratories, Inc. 2002).

Overdose

Gastric lavage may be useful if conducted soon after ingestion. Induction of emesis is not recommended. Give activated charcoal and provide supportive therapy. There is no specific antidote.

Other Information

In humans, citalopram has not been shown to significantly affect the metabolism of digoxin, warfarin, theophylline, or triazolam (Forest Laboratories, Inc. 2002).

Effects Documented in Nonhuman Animals

Dogs

II. Fluoxetine Hydrochloride

Chemical Compound: (+)‐N‐methyl‐3‐phenyl‐3‐(ααα‐trifluoro‐ρ‐tolyl) oxypropylamine hydrochloride
DEA Classification: Not a controlled substance
Preparations: Generally available as 10‐ and 20‐mg tablets, 10‐, 20‐, and 40‐mg capsules, a slow release 90‐mg tablet, and a mint‐flavored solution of 20 mg/5 ml. Reconcile is available in 8‐, 16‐, 32‐ and 64 mg chewable tablets.

Clinical Pharmacology

Uses in Humans

Fluoxetine hydrochloride is used to treat depression, premenstrual dysphoric disorder, obsessive‐compulsive disorder (OCD), and bulimia in humans.

Contraindications

Co‐administration with warfarin can result in increased bleeding.

Side Effects

Fluoxetine can alter anticoagulant effects and cause increased bleeding in patients concurrently given warfarin.

During toxicity testing, rats were given up to 12 mg kg⁻¹ daily of fluoxetine for two years without any evidence of carcinogenicity.

Overdose

Doses in Nonhuman Animals

Discontinuation of Fluoxetine

Other Information

Effects Documented in Nonhuman Animals

Cats

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Tags: Veterinary Psychopharmacology

Aug 13, 2020 | Posted by admin in GENERAL | Comments Off

Veterian Key

Fastest Veterinary Medicine Insight Engine

Selective Serotonin Reuptake Inhibitors

Action

Overview of Indications

Contraindications, Side Effects, and Adverse Events

Adverse Drug Interactions

Overdose

Clinical Guidelines

Specific Medications

I. Citalopram Hydrobromide

Clinical Pharmacology

Uses in Humans

Contraindications

Side Effects

Overdose

Other Information

Effects Documented in Nonhuman Animals

Dogs

II. Fluoxetine Hydrochloride

Clinical Pharmacology

Uses in Humans

Contraindications

Side Effects

Overdose

Doses in Nonhuman Animals

Discontinuation of Fluoxetine

Other Information

Effects Documented in Nonhuman Animals

Cats

Dogs

Parrots

Primates

III. Fluvoxamine

Clinical Pharmacology

Uses in Humans

Contraindications

Side Effects

Overdose

Other Information

Effects Documented in Nonhuman Animals

IV. Paroxetine Hydrochloride

Clinical Pharmacology

Uses in Humans

Contraindications

Side Effects

Overdose

Discontinuation of Paroxetine

Other Information

Effects Documented in Nonhuman Animals

Cats

Dogs

Horses

V. Sertraline Hydrochloride

Clinical Pharmacology

Uses in Humans

Contraindications

Side Effects

Other Information

Effects Documented in Nonhuman Animals

Dogs

Reptiles

VI. Escitalopram Oxalate

Clinical Pharmacology

Uses in Humans

Contraindications

Side Effects

Overdose

Other Information

Effects Documented in Nonhuman Animals

Dogs

Important Information for Owners of Pets Being Placed on Any SSRI

References

Action

Overview of Indications

Contraindications, Side Effects, and Adverse Events

Adverse Drug Interactions

Overdose

Clinical Guidelines

Specific Medications