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.


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‐HT1A, 5‐HT2A, 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.

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