19 Leticia Mattos de Souza Dantas1, Sharon L. Crowell‐Davis1, and Niwako Ogata2 1 University of Georgia, Athens, GA, USA 2 Purdue University, West Lafayette, IN, USA In the first edition of this book, the focus of this chapter was drug augmentation (adding a second agent when a patient’s response to the current medication was subpar). In the second edition of Veterinary Psychopharmacology, this chapter has been expanded to address common questions and concerns when it comes to using psychoactive drugs. When a patient fails to respond to a given drug at a given dose, the clinician has three main options. They can: (i) increase the dose of the drug currently being given if the maximum dose has not been reached and the patient is not exhibiting any undesirable side‐effects; (ii) change drugs; or (iii) augment or complement the first drug with a second (or more) drug(s). There are not set protocols or controlled clinical studies in veterinary clinical behavioral medicine, which leaves the clinician with a process of trial and error to endure. However, some combinations are supported by studies in human medicine (and others might have contraindications and should be avoided). Caution is always warranted when data are lacking in a given species. A common example of a synergistic effect (in which two drugs will, together, be more effective than either alone) is the augmentation of a serotonin reuptake inhibitor with a serotonin agonist. These drugs work together to facilitate serotonin activity. Other drug combinations have a complementary effect. A common example is treatment of a patient with chronic anxiety that peaks under certain conditions or have specific phobias. In these cases, daily administration of a maintenance anti‐anxiety medication (such as selective serotonin reuptake inhibitor or other antidepressant) can be supplemented with context specific administration of a fast‐acting drug such as a benzodiazepine or an alpha‐2 agonist. A complementary effect can also be achieved by combining drugs with different speeds of onset and duration of action. For example, patients are sometimes presented with severe separation anxiety disorder or other problems that lead to destruction and excessive vocalization, to the point of clients facing eviction or the animal being under the risk of euthanasia. In this situation, waiting for a slow onset of action medication to take effect (which is the case with most antidepressants used in veterinary medicine) is not the best option. Short‐acting drugs that target panic signs may be chosen in the early stages of treatment until antidepressants and behavior therapy have time to take effect. In cases of serotonin dysregulation leading to anxiety and behavioral changes, augmentation of a serotonin reuptake inhibitor with an azapirone (such as buspirone) or serotonin antagonist and reuptake inhibitor (SARI) (such as trazodone) may be beneficial (Bakish 1991; Gruen and Sherman 2008). For example, human patients with major depression who have been unresponsive to fluoxetine (at least 30 mg daily) or citalopram (at least 40 mg daily) have shown better improvement when they received buspirone augmentation of 20–60 mg day−1 vs. placebo. No serious events were observed (Appelberg et al. 2001). Likewise, patients with obsessive‐compulsive disorders may respond positively when fluoxetine treatment is supplemented with buspirone (e.g. Jenike et al. 1991). The combination of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), and desipramine, a tricyclic antidepressant (TCA), results in more rapid improvement in patients with major depression than treatment with desipramine alone, presumably because of more rapid down‐regulation of ß‐adrenergic receptors (Baron et al. 1988; Nelson et al. 1991). Even though there are numerous clinical examples published to support a working knowledge to prescribers, the level of scientific evidence is still weak. The examples are primarily combining slow onset of action medications (such as SSRIs or TCAs) with fast onset of action medications (such as benzodiazepines, a SARI, or an alpha‐2 agonist). The combination of clomipramine and alprazolam has been shown to be beneficial in the treatment of storm phobia in dogs (Crowell‐Davis et al. 2003). Fluoxetine and alprazolam have been combined in the treatment of urine spraying in a cat (Seibert 2004a, 2004b). This logic is also used in human anxiety disorders (e.g. Goddard et al. 2001; Stahl 2002). Ogata and Dodman (2011) reported a clinical case series of combination administration with either SSRI, TCA, or azapirone with oral administration of an alpha‐2 agonist (clonidine) to manage fear‐based behavior problems in dogs such as noise phobias, separation anxiety disorder, or fear/territorial aggression. The owners’ feedback to adding clonidine was positive in 18 out of 22 cases in this study. Combinations of SSRIs, TCAs, benzodiazepines, azapirones, or antipsychotics and trazodone to treat canine anxiety disorders (n = 56) were also reported by Gruen and Sherman (2008) where 34 out of 56 clients reported that the combination treatment helped to improve their dog’s anxiety. Another example of drug combination introduced in veterinary clinical behavioral medicine is treatment of canine compulsive disorders where fluoxetine and the NMDA receptor antagonist, memantine, were used together (Maurer and Dodman 2007; Schneider et al. 2009). Although the case number of these reports was small (total of five cases), the author concluded that combination of the two medications caused higher improvement when it was compared with monotherapy of fluoxetine. Gabapentin and pregabalin have been shown to be effective in neuropathic pain conditions, and are widely used off‐label to treat other conditions such as anxiety and insomnia in humans (Smith et al. 2016). Accordingly, they have been increasingly used in clinical behavioral medicine as well. In a (human) randomized double‐blind, placebo‐controlled study, the adjunctive effect of pregabalin in refractory generalized anxiety patients was shown. In this study, patients were randomized into two groups, receiving either pregabalin adjunctive (n = 180) or placebo (n = 176) adjunctive for eight weeks in addition to their original monotherapy with an SSRI (escitalopram or paroxetine) or a serotonin norepinephrine reuptake inhibitor (SNRI) (venlafaxine‐XR). The result was that 50% of the patients who failed to respond adequately to SSRI or SNRI monotherapy responded better with the addition of pregabalin. The response rate was significantly different from those with placebo but adverse effects were the same between the groups, and none of the serious adverse events were considered to be related to the study drug (Rickels et al. 2012). Since there is so far no literature available about combination treatments in veterinary clinical behavioral medicine with either gabapentin or pregabalin, a prudent approach is recommended. In addition to potential issues of producing overdoses by giving two drugs that either act the same, or are metabolized by the same mechanisms (and thus compete with each other), combining drugs can present the risk of producing adverse consequences specific to the way particular drugs interact with each other. Serotonin syndrome has been reported in monkeys, rats, rabbits, dogs, and humans (e.g. Oates and Sjoerdsma 1960; Hess and Doepfner 1961; Curzon et al. 1963; Grahame‐Smith 1971; Sinclair 1973; Brown et al. 1996; Martin 1996). This is a consequence of taking excessive quantities of medications that increase serotonin levels and/or taking certain medications that interact incompatibly in regards to serotonin metabolism. There is no diagnostic test for serotonin syndrome, and diagnosis is based on a history of medication with drugs that may interact incompatibly or a history of medication with excessive quantities of drugs that facilitate serotonin activity, combined with presenting symptoms and the exclusion of other medical conditions. The potential for serotonin syndrome is one reason that it is important to get a complete listing of all herbal medications being given to a patient, as some, such as St. John’s Wort, act on serotonin. The mechanism for serotonin syndrome is not fully understood, but most investigators believe the primary mechanism is excess 5‐HT1A‐receptor stimulation (Brown et al. 1996; Martin 1996). Signs and symptoms can be grossly grouped into mental changes, neuromuscular changes, and autonomic changes. In humans, the problem is usually mild and resolves in 24–72 hours, but it can cause death (Beaumont 1973; Mendis et al. 1981; Tackley and Tregaskis 1987; Brennan et al. 1988; Kline et al. 1989; Neuvonen et al. 1993; Kuisma 1995). The most serious cases result when an SSRI has been taken with (i) an MAO inhibitor, which decreases serotonin metabolism, (ii) a serotonin receptor agonist, such as buspirone, (iii) a tricyclic antidepressant, which is a non‐selective serotonin reuptake inhibitor, or (iv) meperidine, tryptophan, or dextromethorphan. Specific changes in mental status symptoms reported in humans include confusion, agitation, coma, hypomania, and anxiety. Motor abnormalities include myoclonus, hyperreflexia, muscle rigidity, restlessness, tremor, ataxia, shivering, nystagmus, and seizures. Cardiovascular changes include hypertension, hypotension, and sinus tachycardia. Gastrointestinal signs and symptoms include nausea, diarrhea, abdominal pain, and excessive salivation. Other signs include diaphoresis, hyperpyrexia, tachypnea, and unreactive pupils (Brown et al. 1996). Some of these signs can be similar to the most common reported side effects of antidepressants. Due to this, the authors warrant caution when side effects are reported in patients. Serotonin syndrome should be considered and increasing the dose (to “see if the patient will get over side effects”) is risky and not recommended. Treatment and management include discontinuation of all serotonergic medications and supportive treatment. Benzodiazepines such as diazepam or lorazepam may be given for myoclonus and the hyperthermia resulting from myoclonus. However, clonazepam is not effective with serotonin syndrome (Nierenberg and Semprebon 1993; Skop et al. 1994; Brown and Skop 1996). In severe cases, 5‐HT antagonists such as cyproheptadine, methysergide, or propranolol can be given (Goldberg and Huk 1992; Brown et al. 1996; Martin 1996). Gwaltney‐Brant et al. (2000) reported on 21 cases of dogs that had been exposed through accidental poisoning to the nutritional supplement 5‐Hydroxytryptophan, which is the immediate precursor to serotonin. The dose consumed ranged from 2.5 to 573 mg kg−1. The dog that had been exposed to 2.5 mg kg−1 received no treatment and exhibited no symptoms. One dog, which had consumed a dose of 222 mg kg−1, had emesis induced within 30 minutes. This dog exhibited no symptoms. The lowest dose at which signs developed was 23.6 mg kg−1. The lowest dose at which death occurred was 128 mg kg−1. The time of onset of clinical signs varied from 10 minutes to 4 hours after ingestion. Nineteen of the dogs developed clinical toxicosis. Of these, three died. Mental status changes included depression, coma, and disorientation. Sensorimotor changes included tremors, hyperesthesia, ataxia, paresis, hyperreflexia, and weakness. Respiratory and cardiovascular signs included tachycardia, cyanosis, and dyspnea. Gastrointestinal signs included vomiting, diarrhea, abdominal pain, flatulence, and bloat. Other signs included mydriasis, transient blindness, hypersalivation, hyperthermia, hypothermia, and vocalization. Treatment included decontamination by inducing emesis, anticonvulsants, thermoregulation, and fluid therapy. The 16 dogs that exhibited clinical toxicosis and recovered all did so within 36 hours of beginning treatment. Clinical blindness, if present, was the last sign to resolve. Because of their long half‐lives, serotonin syndrome has occurred five to six weeks or later after discontinuation of fluoxetine, paroxetine, sertraline or irreversible MAOIs (Pato et al. 1991; Coplan and Gorman 1993; Martin 1996). According to a meta‐analysis in humans regarding safety and tolerability of antidepressant co‐treatment in acute major depressive disorder with 23 studies of 2435 samples, noradrenergic and specific serotonergic antidepressants (NsSSA) or TCA or SSRIs were associated with more adverse events such as tremor, sweating, or weight gain. Although it was sparse data, the authors suggested this augmentation should be chosen with caution (Galling et al. 2015). P‐glycoprotein (P‐gp) plays one of the important roles in the pharmacokinetics and clinical effects (Akamine et al. 2012
Combinations
Introduction
Overview of Drug Augmentation
Potentially Beneficial Combinations
Adverse Interactions and Contraindications
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