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Pharmacologically, can tricyclic antidepressants have a side-effect profile similar to neuroleptics?

Pharmacologically, can tricyclic antidepressants have a side-effect profile similar to neuroleptics?


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Torticollis (wryneck, cervical dystonia) is a neurologic movement disorder causing involuntary muscle spasms in the neck. Often, neuroleptics can cause such a side effect. I'm wondering if this condition could also be part of the side-effect profile of tricyclic antidepressants, like amitriptyline.

Some potential indications:

  • Often the basal ganglia are associated with neurological conditions such as movement disorders. -> Do amitriptylines effect the basal ganglia?
  • Dressler and Benecke claim that "Of all patients treated with neuroleptics approximately 2 to 3% develop acute dystonic reactions within days of therapy initiation .When highly potent neuroleptics are used this rate may increase to over 50 %.Young men are at a particularly high risk. Cranial, pharyngeal, cervical and axial muscles are most commonly affected causing oculogyric crisis, grimacing, fixation of the jaw, retrocollis, torticollis or even opisthotonic posturing." -> Do tricyclic antidepressants operate similar to neuroleptics?
  • Geyer and Bressman claim that dystonia can be caused by certain drugs: "In addition to inherited forms of secondary dystonia (dystonia-plus syndromes and neurodegenerative diseases), a variety of acquired insults can cause secondary dystonia in previously unaffected individuals. Many cases are iatrogenic, resulting from drugs that block dopamine receptors; antipsychotic and antiemetic drugs are the most common culprits." -> even though amitriptyline doesn't seem to block dopamine, maybe there is some kind of connection?
  • Tricyclic antidepressants sometimes seem to be used to treat torticollis, so is the reverse effect of causing the condition also thinkable?

Torticollis can occur for several reasons, one of which is a side effect of certain drugs. Rather than highlight one specific drug it is perhaps better to talk about the mechanism of action by which this occurs.

Torticollis in a drug induced form is classed as an extrapyramidial side effect. Classically results from some medications which have anti-dopaminergic effects. The neurotransmitter dopamine is important for the regulation of movement. Different medications have different degrees of anti-dopaminergic effect. To complicate things further there are several different types of dopamine receptors and different drugs have different effects depending on their action on these receptors.

Classically drugs that have been associated with extrapyramidial side effects are some of the antipsychotics but there are case reports of this with trycyclics http://www.ncbi.nlm.nih.gov/pmc/articles/PMC489096/ however this appears to be a very rare, see http://www.sciencedirect.com/science/article/pii/S0924977X97004057.

The paradoxical treatment of torticollis might be dependent on the cause of the condition. Tricyclic anti-depressants have anti-cholinergic effects, i.e. they block the effects of the neurotransmitter acetylcholine. This neurotransmitter works in opposition to dopamine in the basal ganglia (part of the brain responsible for movement control) as such might be used when the dystonia is as a result of doperminergic disregulation.

If you are at all concerned that you may be suffering side effects of any medication, then I highly recommend that you go and discuss this matter with your doctor. The above is a simplified explanation of some of the reasons why these side effects may occur. It is not intended as information for the purposes of self diagnosis and treatment.


Tricyclic Antidepressants

THERESA A. MAYS PHARMD, BCOP , in Cancer Pain , 2006

ADVERSE EFFECTS

The adverse effects of TCAs are directly related to their effect on muscarinic, histaminic, and alpha-1 receptors, with increasing incidence directly linked to the binding affinity to these receptors. Table 22-5 shows the relative frequency of the adverse effects discussed next for each agent.

Anticholinergic Effects

Anticholinergic effects appear to be responsible for the cognitive effects seen with TCAs. For older agents in this class, the cognitive effects are dose-related, with subtle cognitive impairment increasing to not-so-subtle impairment as dosages are increased. The elderly are more susceptible to the cognitive impairment associated with TCAs. 31

Cardiac Side Effects

The TCAs do have cardiac side effects, including orthostatic hypotension, conduction abnormalities, and tachycardia. These agents have not been associated with hypertension or bradycardia. Research has shown that their cardiovascular effects are limited to orthostatic hypotension in patients who have no history of cardiac disease, with an overall incidence of 2% to 3%. 32 Elderly patients have a higher incidence of orthostatic hypotension and are at greater risk from fall injuries.

A recent article reviewed the safety of antidepressant drugs in cardiac patients. 33 TCAs affect cardiac tissue in a similar manner to other class I antiarrhythmics, including prolongation of intraventricular conduction. Other concerning cardiac effects include postural hypotension, which is seen in up to 20% of cardiac patients receiving TCAs. Patients at an increased risk of experiencing postural hypotension have pretreatment orthostatic drops in systolic blood pressure greater than 10 mm Hg.

The authors concluded that imipramine or doxepin are acceptable agents to use in patients without left ventricular dysfunction or significant coronary artery disease. Imipramine and nortriptyline do not seem to alter left ventricular function in patients who have significant left ventricular dysfunction, defined as an ejection fraction of less than 40%. However, there is a high frequency of orthostatic hypotension in patients receiving imipramine therefore, nortriptyline may be the preferred agent for this patient population. Nortriptyline seems to have the least effect on blood pressure of the TCAs studied to date. 33

Due to the TCAs effects on cardiac function in patients with a cardiac history, these agents should not be used as the first line in this patient population for the management of pain.

Seizures

The TCA clomipramine has been linked to seizures, which appear to be dose-related. 31 Other tricyclic antidepressants may increase the risk of seizures, but the risk is usually due to dose and overaggressive use of these agents. One study found a 0.4% incidence of seizures in hospitalized patients who were receiving TCA for affective or panic disorder.

Sexual Dysfunction

The reported incidence of sexual dysfunction associated with TCAs ranges from 25% to 95% of all patients. 34, 35 If a patient develops sexual dysfunction there are several published strategies for managing this adverse effect. The first step is to observe the patient for a period of time to ensure that the sexual dysfunction is not a temporary problem. In addition, the patient's medications should be reviewed for other agents that can also cause sexual dysfunction. If the patient continues to experience sexual dysfunction, the dose of the TCA should be lowered if possible. If this is not an option or it does not correct the problem, the TCA should be stopped and a different agent tried.

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

This adverse effect has been reported infrequently with TCAs. The mechanism behind this adverse effect is unknown however, animal studies have shown that norepinephrine and serotonin increase antidiuretic hormone section by stimulation of alpha-1 adrenergic receptors and serotonin 5-HT1C and 5-HT2 receptors, respectively. 36 One study with clomipramine reported a 16.7% incidence of SIADH versus 1.1% with controls. The risk of developing SIADH with antidepressant medications appears to increase in patients who are greater than 65 years of age, smokers, or receiving concomitant diuretics. 31

Spigset and Hedenmalm 36 published a survey of the World Health Organization Data Base for Spontaneous Reporting of Adverse Drug Reactions for hyponatremia secondary to antidepressants. Reports of hyponatremia existed for amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, and protriptyline. The majority of all cases of hyponatremia with antidepressant agents occurred within 1 month of starting treatment (74.9%) and more than half occurred within 2 weeks of starting treatment. A higher incidence of this adverse effect was reported in women and patients older than 70 years.

Therefore, TCAs may not be appropriate adjunct agents for pain management in patients with underlying malignancies that also cause SIADH, such as lung cancer.

Weight Gain

In patients with nononcologic chronic pain, weight gain does occur with TCAs usually secondary to decreased activity. Amitriptyline has been associated with increasing appetite in some patients.


MAJOR PSYCHIATRIC DISORDERS

Neither the etiology nor the pathogenesis of schizophrenia is known. Current thinking suggests that a genetic predisposition and early injury (in utero or early childhood) may set the stage for neurodevelopmental changes that ultimately manifest as behavioral difficulties later in life (often in early adulthood) and that may be triggered by a stressful lifetime event. 35 For the disease to manifest itself, the effects of several cumulative factors likely combine to result in the clinical disorder. 4 Evidence from brain imaging suggests that broad areas of the brain can lose cell mass in this disorder, suggesting a problem in regulation of brain growth, repair, or cell pruning, rather than dysregulation of a single neurotransmitter. Genetic survey chip studies have also identified differences in neuronal structure and function (e.g., myelination, neuroimmune and mitochondrial genes) suggesting a neurodegenerative cause rather than a specific transmitter disruption. 31

Dopamine hypothesis

RECEPTOR OR PROCESS BLOCKED THERAPEUTIC EFFECT OF BLOCK ADVERSE EFFECTS RESULTING FROM BLOCKADE OF RECEPTOR OR PROTEIN
Histamine (H1) Sedation, anxiolysis, antiallergy effect CNS depression, hypotension, dry mouth, weight gain
Muscarinic Reduction of extrapyramidal side effects Dry mouth, blurred vision, sinus tachycardia, constipation, urinary retention, memory dysfunction
Adrenoceptor
α1-Adrenergic Memory dysfunction, postural (orthostatic) hypotension, reflex tachycardia, epinephrine reversal, dizziness, dry mouth, weight gain, priapism
α2-Adrenergic Blockade of presynaptic autoregulation, increasing CNS 5-HT and NE Priapism
Dopamine (D2) Amelioration of the positive signs and symptoms of psychosis Extrapyramidal movement disorders, sexual dysfunction, dry mouth, weight gain
5-HT reuptake Reversal of depression Gastrointestinal disturbance, sexual dysfunction, activating effects, dry mouth
NE reuptake Reversal of depression Dry mouth, urinary retention, erectile dysfunction, CNS stimulation, tremor, proconvulsant
Dopamine reuptake Antidepressant effect (?) Psychomotor activation, psychosis, proconvulsant action (?), dependence

5-HT, 5-Hydroxytryptamine CNS, central nervous system NE, norepinephrine.


2. Pharmacotherapy for anxiety disorders:current status

2.1. Antidepressant medications

2.1.1. Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs)

The widely studied SSRIs, and to a growing degree, the SNRIs (and for obsessive𠄼ompulsive disorder [OCD] the mixed noradrenergic and serotonergic reuptake inhibitor tricyclic clomipramine), are considered the first-line pharmacological treatments for anxiety disorders (see Ravindran & Stein, 2010, for a review). Specific phobia is the exception. In specific phobia, these medications have rarely been studied or used clinically because exposure therapy is considered the first-line treatment. The few studies comparing SNRIs to SSRIs show similar responses. SSRIs and SNRIs work by blocking the reuptake of serotonin or norepinephrine, respectively, which increases synaptic levels of 5-HT (i.e., serotonin) in the synapse. This starts a cascade of downstream effects on other neurotransmitters, second messengers, and immediate early genes, ultimately producing long-term neurochemical changes in the brain (Krishnan & Nestler, 2008).

SSRIs are efficacious for a wide range of psychiatric disorders (e.g., major depression, Premenstrual Dysphoric Disorder, and eating disorders), have few side effects, and have low potential for abuse they are also equally effective, safer in overdose, and more tolerable than the older tricyclic antidepressants (TCAs Ravindran & Stein, 2010).

Nonetheless, SSRIs have some drawbacks. Approximately 30�% of patients experience more mild and transient side effects, most commonly nausea, diarrhea, headache, insomnia, jitteriness, or restlessness. It is thought that anxious patients are more sensitive to jitteriness with these agents, though this has not been conclusively studied. These effects can be minimized by starting at a low dose and increasing the dose gradually over 2𠄴 weeks. Sexual side effects such as diminished sexual interest, performance, or satisfaction are also common, occurring in one third to half of patients on an SSRI. Erectile dysfunction and anorgasmia can often be improved with various medications, but reduced sexual interest is more difficult to treat and often is more effectively treated with dose reductions or drug holidays. Finally, SSRIs can metabolically interact with and change the blood levels of other drugs, and are associated (especially short half life drugs) with a withdrawal syndrome that can mimic anxiety when suddenly stopped. In addition, SSRIs have been associated with increased suicidal ideation, prompting the US Food and Drug Administration’s (FDA) 𠇋lack box” warning for individuals 24 years old or younger. The evidence behind this warning has been widely criticized (e.g., Kaizar, Greenhouse, Seltman, & Kelleher, 2006), and many experts consider it appropriate to prescribe SSRIs to children with severe functional impairment when followed by careful monitoring (Ravindran & Stein, 2010).

SSRIs and SNRIs usually take between 2 and 6 weeks to produce an initial “partial” response, which is typically defined as at least 25% improvement in symptom severity from baseline (i.e., beyond random noise or natural symptom fluctuations). Full benefit may not be seen for another 4𠄶 weeks, or even longer (e.g., Montgomery, Sheehan, Meoni, Haudiquet, & Hackett, 2002). Across most studies, lower dosages are often as effective as higher dosages (e.g., Marshall, Beebe, Oldham, & Zaninelli, 2001). However, in OCD, higher dosages are associated with better response (Bloch, McGuire, Landeros-Weisenberger, Leckman, & Pittenger, 2009). Venlafaxine, an SNRI, has shown a linear dose–response curve in most studies with depression and some evidence is consistent with this in anxiety disorders (Pollack et al., 2007 Rudolph et al., 1998). In addition to SSRI-like side effects, venlafaxine is associated with elevations in blood pressure, making this a safety issue with older adults and those with cardiovascular issues.

Nevertheless, nonresponse can occur for many reasons, including insufficient dose or duration of treatment, poor adherence, or true treatment resistance. This complicates clinical management because different causes of nonresponse generally indicate different management strategies. Data from patients with depression, and some uncontrolled data with anxiety, suggest that about 20% of patients may need 10� weeks or longer before responding (Tedeschini, Fava, & Papakostas, 2011). Thus, increasing the dose to the highest level tolerated is always recommended for any patient with an incomplete response (i.e., not having achieved remission). Nonadherence to and beliefs about medication may be factors in nonresponse as well. Only half of patients refill their first prescription (Mullins, Shaya, Meng, Wang, & Bron, 2006), and many patients discontinue their medications within the first six months of treatment (Grilo et al., 1998 Warden et al., 2009). Psychological factors, including negative beliefs about perceived harmful effects, stigma, and lack of 𠇋uy in” to the treatment rationale, are negatively related to adherence and outcome (e.g., Aikens, Nease, Nau, Klinkman, & Schwenk, 2005 Warden et al., 2009). These issues can be addressed through careful psychoeducation and monitoring. Clearly, treatment nonresponse is both important and highly idiographic.

There are serious questions about how much, and in whom, the placebo effect contributes to antidepressant response. In a recent meta-analysis, Fournier et al. (2010) found that for patients with mild or moderate depression symptoms, drug response (compared with placebo), may be minimal or nonexistent however, for patients with very severe depression, the benefit of antidepressants over placebo is substantial. However, a recent study with a much larger and more complete database suggests that initial severity of depression is unrelated to antidepressant response (Gibbons, Hur, Brown, Davis, & Mann, 2012). The relationship of response to initial severity should be systematically examined in the anxiety disorders as well.

Most data on the causes of treatment nonresponse, response, and relapse are correlational. Even classic randomized controlled trials (RCTs) do not reveal what causes these classes of effects at the level of individual patients. Meta-analyses can provide some guidance through estimates of individual versus combined treatment effects, but these studies often collapse across trials differing in dose, duration, treatment algorithms, and other methods. Once subsets of studies are identified that more closely match the clinical question, there may be too few studies to make a precise estimate. Accordingly, methodologists have developed a new type of clinical trial, the Sequential Multiple Assignment Randomized Trial (SMART), that allows investigators to compare the efficacy of entire pre-specified treatment sequences (Oetting, Levy, Weiss, & Murphy, 2011). This novel approach should be used to examine the optimal treatment sequence for partial or nonresponders to initial anxiety treatments. Other multi-stage clinical trial designs have been developed that allow investigators to estimate true drug response from placebo response at the individual level (e.g., Marks, Thanaseelan, & Pae, 2009).

2.1.2. Other antidepressants

Extensive studies of TCAs show that they have similar efficacy to SSRIs for panic disorder (PD e.g., Mavissakalian, 2003) and generalized anxiety disorder (GAD e.g., Schmitt et al., 2005). Only one tricyclic, the highly serotonergic clomipramine, works in OCD (e.g., Katz, DeVeaugh-Geiss, & Landau, 1990). TCAs are lethal in overdose, and, compared to SSRIs, have a markedly broader, more problematic, and less tolerable side effect profile, including dry mouth, blurred vision, constipation, urinary retention, cardiac arrhythmia, tachycardia, sedation, postural hypotension, dizziness, and headache. Nonetheless, TCAs may work when first-line agents do not.

Monoamine oxidase inhibitors (MAOIs) are effective for both PD and SAD and are thought by some experts to be excellent options for severe, treatment-resistant anxiety disorders (e.g., Bakish et al., 1995). However, they have the worst side effect profile and greatest safety burden of all antidepressants. Patients on an MAOI can experience dangerous hypertensive reactions if they consume foods that contain tyramine (e.g., cheese, beer, and wine) or use certain drugs (e.g., meperidine, decongestants, or energy drinks containing ephedrine or phenylpropylamine). They may also gain weight, lose sleep, and feel sedated during the day while taking MAOIs. Thus, clinicians do not routinely prescribe MAOIs to their patients with anxiety disorders, although they are probably not considered frequently enough in treatment-resistant patients.

Few double-blind, placebo-controlled RCTs have examined the efficacy of other antidepressants for anxiety disorders. Mirtazapine may be efficacious in SAD (e.g., Muehlbacher et al., 2005 Schutters, Van Megen, Van Veen, Denys, & Westenberg, 2010) and posttraumatic stress disorder (PTSD e.g., Davidson et al., 2003) nefazodone in PTSD but not GAD (Van Ameringen et al., 2007) and trazodone in GAD (Rickels, Downing, Schweizer, & Hassman, 1993). Finally, bupropion has not demonstrated efficacy in PTSD and PD (Becker et al., 2007 Hertzberg, Moore, Feldman, & Beckham, 2001), though it is often used as an adjunctive antidepressant across the anxiety disorders. There are also problematic adverse side effects with mirtazapine (e.g., weight gain, sleepiness, lipid abnormalities, and leukopenia), nefazodone (rare liver toxicity Aranda-Michel et al., 1999), and bupropion (e.g., seizure risk).

2.2. Benzodiazepines

Benzodiazepines bind to a specific receptor site on the gamma-aminobutyric acid𠄺 receptor (GABA𠄺) complex and facilitate GABA inhibitory effects by acting on a chloride ion channel (Davidson, 1989). They were initially considered first-line treatments for anxiety because of their tolerability and equal efficacy to TCAs, but became second-line options when it became clear that SSRIs were both more tolerable and efficacious. Currently, benzodiazepines are primarily used for individuals who have had suboptimal responses to antidepressants (e.g., Simon et al., 2009).

Benzodiazepines are also used for their potent, short-term effects (e.g., flying on an airplane) or to help reduce anxiety during the initial weeks of an antidepressant when anxiolytic effects have yet to occur (Goddard et al., 2001). These uses are appealing to the patient but not always desirable, as they can reinforce pill taking, serve as a safety signal that undermines self-efficacy (Westra, Stewart, & Conrad, 2002), and become incorporated into the conditioned fear response. These concerns are exacerbated when benzodiazepines are taken on an as-needed basis. As-needed use links pill taking to rapid reduction in anxiety, powerfully reinforcing avoidance in anxiety-provoking situations and encouraging longer-term reliance on the drug. This may be one reason why benzodiazepines have been associated with reduced response to cognitive behavioral therapy (e.g., Watanabe, Churchill, & Furukawa, 2007). However, for select individuals with significant residual anxiety after antidepressant treatment, these agents may help achieve total symptom remission.

Chronic benzodiazepine use is associated with physiological dependence, short-term cognitive and psychomotor impairment, and rebound anxiety upon discontinuation. Patients with a history of substance abuse are at increased risk of abusing benzodiazepines. Where clinically indicated, benzodiazepines can be gradually tapered and eventually discontinued over a period of several months while starting another medication or CBT (Otto et al., 2010).

2.3. Alpha�lta calcium channel anticonvulsants

The alpha�lta calcium channel class of anticonvulsants, including both gabapentin and the newer agent pregabalin, widely reduce neuronal excitability and resemble the benzodiazepines in their ability to alter the balance between inhibitory and excitatory neuronal activity. Also similar to benzodiazepines, these drugs have a rapid onset of action and are superior to placebo in GAD (Feltner et al., 2008) and SAD (Feltner, Liu-Dumaw, Schweizer, & Bielski, 2011). Meta-analytic evidence suggests that pregabalin may even reduce depressive symptoms that co-occur with GAD (Stein, Baldwin, Baldinetti, & Mandel, 2008). These drugs have fewer problems with abuse, tolerance, and withdrawal than benzodiazepines and in fact have been used as treatments for both alcohol (Furieri & Nakamura-Palacios, 2007) and stimulant dependence (Urschel, Hanselka, & Baron, 2011).

2.4. Beta blockers and azapirones

Beta blockers and azapirones have even fewer uses. Beta blockers have been prescribed as single-dose agents for performance-related anxiety (e.g., musician at a critical audition James, Burgoyne, & Savage, 1983) because they can reduce the peripheral physical symptoms (e.g., palpitations and hands trembling) of anxiety within 30� min however, they do not affect the cognitive and emotional symptoms of anxiety. Azapirones bind to the 5-HT1A receptor and are thought to alter control of the firing rate of serotonin neurons. They typically take 2𠄴 weeks to take effect, are generally well tolerated, and lack the dependence issues of the benzodiazepines. However, GAD is the only anxiety disorder in which the azapirones have consistently demonstrated efficacy (Davidson, DuPont, Hedges, & Haskins, 1999). Because GAD often includes a depression component, antidepressant medications are the more logical treatment choice (Ravindran & Stein, 2010).

2.5. Approach to initial non-response

Many patients with anxiety disorders do not respond completely to initial treatment. At this point, prescribers often combine an antidepressant with an effective anxiolytic drug that has a different mechanism of action, such as a benzodiazepine or other type of antidepressant (so-called 𠇌ombination” treatment). Typically, they will switch to a new agent if the symptoms do not decrease by 25% within 6 weeks and will add a different agent if symptoms do not fully remit within 12 weeks. Another approach, known as 𠇊ugmentation,” refers to adding a treatment that is not necessarily known to be effective by itself, but which enhances response to the other drug (e.g., addition of an atypical antipsychotic medication such as risperidone, olanzapine, or quetiapine).

Very few studies have empirically evaluated the efficacy of combination or augmentation strategies in the anxiety disorders. These studies require large sample sizes. In depression, the STAR*D trial (Rush, 2007) systematically examined various add-on strategies following citalopram an (SSRI) nonresponse. The addition of cognitive therapy or medication, using either another antidepressant, sustained-release bupropion, or extended-release venlafaxine strategies, was generally effective for initial nonresponse (Thase et al., 2007). Augmentation strategies using thyroid hormone and lithium were effective at later stages in treatment, but these agents have never been used for refractory anxiety disorders. A study of similar scale has not been conducted in the anxiety disorders.

For severe, treatment-resistant cases of anxiety, augmentation of the antidepressant with an atypical antipsychotic (e.g., risperidone and quetiapine) has been shown to be effective. This strategy appears to be effective for OCD (Ipser et al., 2006 Komossa et al., 2010). There are several small studies of augmentation in GAD, but no controlled evidence for PD or SAD. Recently, small studies supporting this use for PTSD have been called into question by a large RCT showing that augmentation with risperidone conferred no additional advantage (Krystal et al., 2011).

Some antipsychotics have been used as a monotherapy for anxiety disorders. A recent Cochrane review supports the unique efficacy of quetiapine as monotherapy in GAD (Depping, Komossa, Kissling, & Leucht, 2010). However, quetiapine was recently denied FDA approval for GAD, presumably because of its risky side effect profile (e.g., lipid abnormalities, weight gain, and glucose intolerance) and concerns that it would be widely used in primary care without careful consideration of alternative anxiolytic strategies. Similar concerns also exist for other antipsychotics, which can produce severe side effects and often require careful monitoring. These risks likely outweigh the modest benefits in efficacy, though antipsychotic monotherapy may be useful and effective for some patients.

2.6. Pharmacotherapy in combination with psychotherapy

Patients with anxiety disorders prefer psychotherapy over psychotropic medications (Barlow, 2004) but are more likely to receive psychotropic medications first (Wang et al., 2005). There has been some interest in adding cognitive behavioral interventions to existing treatment with antidepressants or benzodiazepines but, with the possible exception of PD (Bandelow, Seidler-Brandler, Becker, Wedekind, & Rüther, 2007 Otto, Smits, & Reese, 2005), this approach has not yielded strong additive effects. These results have led some investigators to conclude that combined treatment should not be considered a first-line approach (Otto et al., 2005) and should be reserved for patients with severe anxiety who require medication (Zwanzger, Diemer, & Jabs, 2008). However, limited data have failed to show efficacy for adding medication to CBT (Simon et al., 2008) or CBT to medication (Simon et al., 2009) in patients with refractory anxiety disorders.

2.7. Summary

As reviewed in Table 1 , SSRIs, and possibly SNRIs, are the first-line treatments for most anxiety disorders. However, patients often show partial or nonresponse, prompting a change in the current medication or the addition of a new medication. Unfortunately, the empirical literature for these augmentation strategies is still in its infancy. Clinical care in these cases is guided more by trial and error, using broad empirically derived principles. Innovations in the design of clinical trials should allow future research to examine the efficacy of multiple strategies for the treatment of nonresponse.

Table 1

Non-psychiatrists’ guide to pharmacotherapy interventions for the anxiety disorders.

SPPTSDPDSADGADOCD
Selective serotonin reuptake inhibitor (SSRI) 11111 a
Shift to different SSRI or SNRI 22222
Augmentation with additional SSRI or SNRI 33333
Other antidepressants (MAOIs, other) c 43324
Tricyclic antidepressants 32331 b
Augmentation with atypical antipsychotics 44444
Anticonvulsants 444
Azapirones 3
Beta blockers2 3
Benzodiazepines2 334

Note: 1 = First-line intervention:multiple randomized control trials (RCTs) showing efficacy.

2 = Secondary intervention:often used as an intervention for non- or partial-response of first-line intervention, with some RCTs showing efficacy, though evidence may be mixed.

3 or 4 = Alternative intervention after 1st and 2nd line interventions, often with less RCT support or more significant side effect profile.

SP = specific phobia PTSD = posttraumatic stress disorder PD = panic disorder SAD = social anxiety disorder GAD = generalized anxiety disorder OCD = obsessive𠄼ompulsive disorder SNRI = serotonin norepinephrine reuptake inhibitor MAOI = monoamine oxidase inhibitor.


Discussion

In this large observational study, which included more than 160,000 patients with depressive disorder treated with antidepressants, recent long-term use of antidepressants in moderate to high daily doses was associated with an 84% increase in risk of diabetes. This association was present for both tricyclic antidepressants and SSRIs. Antidepressant treatment for shorter periods or with lower daily doses was not associated with an increased risk. Recent use of other antidepressants was associated with an 80% increase in risk of diabetes however, a dose or duration effect could not be detected, probably because of the rather low number of exposed case and comparison subjects.

Our results are supported by recently published data from the randomized Diabetes Prevention Program trial, which investigated newly developing diabetes in patients at high risk of diabetes receiving the antidiabetic drug metformin, lifestyle intervention, or placebo (14) . Continuous antidepressant use over an average study duration of 3.2 years was associated with an increased risk of diabetes of 2.60 (95% CI=1.37–4.94) in the placebo arm and 3.39 (95% CI=1.61–7.13) in the lifestyle intervention arm. Intermittent use of antidepressants similarly increased the risk of diabetes in both treatment arms. There was no increased risk observed in the metformin arm of the study, possibly because of weight loss instead of weight gain under metformin (20) . Metformin also attenuated the effect of other risk factors for diabetes, such as baseline BMI (21).

Observational studies have produced conflicting data on the risk of diabetes in antidepressant users. Knol et al. (15) , using prescription data from the PHARMO database, did not identify an increased risk of diabetes in antidepressant users. Their study had several limitations. In contrast to our study, they lacked information on BMI, lifestyle factors, and the indication for antidepressant treatment, and hence they could not adjust for these factors in the statistical analysis. Their study included only patients with antidiabetic treatment as cases of diabetes, whereas we also included patients diagnosed with diabetes who had not yet received antidiabetic treatment. In contrast to our study, which included patients with new use of antidepressants, Knol et al. also included patients with prevalent use, thereby possibly overrepresenting patients who tolerate antidepressant treatment well. They also did not consider the duration or dose of antidepressant treatment, which was most important in our analysis.

Some other observational studies suggest an association between antidepressants and diabetes. Brown et al. (16) reported an increased risk of diabetes in concurrent users of tricyclic antidepressants and SSRIs as compared with those taking tricyclics alone. A similar analysis of combined use was not possible in our study, since we excluded users of more than one antidepressant to ensure pure exposure categories. In a Norwegian cross-sectional health survey, SSRIs were found to be associated with abdominal obesity and hypercholesterinemia, and a trend toward an association with diabetes was observed (22) . An analysis of spontaneous reports of adverse drug reactions recorded in the World Health Organization’s Adverse Drug Reaction Database showed increased reporting odds ratios of hyperglycemia and hypoglycemia associated with the use of antidepressants (23) . The association of hyperglycemia was most pronounced after more than 1 year of antidepressant use. We similarly observed an increase in the risk of diabetes only with long-term use of antidepressants.

What are possible mechanisms for the observed association? Weight gain is a common side effect in short- and long-term treatment with tricyclic antidepressants and was already described in the 1970s (24 , 25) . An initial rapid weight gain is followed by a lower but continuous gain at a steady rate (26) . There are conflicting data on the question of whether individual tricyclic antidepressants differ in potential for causing weight gain. While some studies indicated higher weight gain with amitriptyline than with other tricyclic antidepressants (27 , 28) , others did not (29 , 30) . We observed an increased risk of diabetes only with long-term use of amitriptyline. Risk estimates for long-term use of clomipramine, nortriptyline, and trimipramine were also elevated more than twofold but did not reach statistical significance, most likely because of the low number of case and comparison subjects exposed to these drugs.

Weight changes associated with SSRI treatment are complex. There is evidence for an initial stable weight or even weight loss with use of SSRIs followed by weight gain if used for longer periods (31 , 32) . Some studies have suggested differences in the potential of individual SSRIs to cause weight gain. In a randomized, double-blind 6-month trial of SSRI continuation therapy, weight gain was more often reported for patients treated with paroxetine than for those treated with sertraline (33.1% versus 20.2%, p<0.05) (33) . Another randomized trial also reported the greatest increase in weight with paroxetine as compared with sertraline or fluoxetine (34) . This corresponds to our finding of a fourfold increase in risk of diabetes associated with long-term therapy with paroxetine in daily doses above 20 mg/day but not with long-term use of fluoxetine, citalopram, or sertraline. Our finding of an increased risk with fluvoxamine, which has not been reported to cause marked weight gain, was based on four exposed case subjects and two comparison subjects and should thus be interpreted with caution.

From the heterogeneous group of other antidepressants, we observed an increased risk of diabetes associated with recent long-term use of venlafaxine. There are conflicting data on weight changes associated with venlafaxine treatment. While some studies reported no weight gain (35) or even weight loss (36 , 37) , others found weight gain with higher doses of venlafaxine (38) or at least reversal of initial weight loss during long-term treatment (39) . The prescribing information of venlafaxine addresses weight loss as a potential adverse effect but also mentions weight gain as a frequent adverse effect (40) . It should be noted, however, that the observed risk of diabetes associated with long-term use of venlafaxine was based on eight exposed case subjects and 10 exposed comparison subjects.

Other mechanisms beyond weight gain may have a role in the increased diabetes risk associated with antidepressants. It is interesting in this respect that in the Diabetes Prevention Program trial the increased risk of diabetes in users of antidepressants remained significantly elevated even after adjustment for the observed increase in body weight (14) . Thus, other mechanisms, such as hyperglycemic effects of noradrenergic activity of antidepressants, may play a role.

Could our results be explained by the fact that depression itself and not the antidepressant drug treatment increases the risk of diabetes? It has been reported that patients with depression have a 35% increase in risk of developing diabetes as compared with nondepressed individuals (15) . The underlying reasons for this association are unknown. One might argue that patients treated with antidepressants for >24 months are a special subgroup with an increased risk of diabetes only because of their active depressive disorder. There are several reasons why this explanation is rather unlikely. First, one would expect to see increased risks with most individual antidepressants used for >24 months if the increased diabetes were caused by the depression and not by the drug. In contrast, our results indicate that antidepressants differ with respect to their diabetogenic potential. Second, in the Diabetes Prevention Program, elevated Beck Depression Inventory scores at baseline were not associated with an increased risk of diabetes, but the use of antidepressants was (14) . Third, in our study, all cohort members were treated with only one antidepressant during the entire follow-up period. A high proportion of long-term users probably responded to treatment, as otherwise a switch to another antidepressant would have been indicated. Fourth, in an explorative analysis using the number of days with a diagnosis of depression in the year before the index date as a proxy for depression severity, there was no indication of increased severity in long-term users. Inclusion of this proxy variable into the multivariate models did not affect our main findings.

One strength of our study is that all information was recorded prospectively so that recall bias can be ruled out. Selection bias in the choice of comparison subjects is unlikely because the study was designed as a nested case-control study in a defined cohort of antidepressant users, providing both case and comparison subjects. We included only depressed patients to exclude other indications for antidepressant use and to ensure a more homogeneous study population. We excluded prevalent users of antidepressants to avoid overrepresentation of patients who tolerated antidepressant treatment well (“depletion of susceptible” bias). We ensured by study design that all patients were exposed to only one antidepressant during the entire follow-up period.

Some limitations of our study must also be considered. First, because of the new-user criterion in our study design, it was not possible to investigate second-line antidepressants, such as MAO inhibitors. Second, weight gain during follow-up was not systematically recorded, so it was not possible to analyze this factor. Third, antidepressants causing massive initial weight gain might have been withdrawn early before diabetes developed. For these drugs, we might have underestimated the true risks. Fourth, because of the naturalistic character of the GPRD, adjustment for the severity of depression was limited to an analysis considering an indicator for depression severity that might not have removed all residual confounding from this possible source of bias. If drugs were primarily prescribed to patients with atypical depression, we might have overestimated the risk associated with these drugs. This might apply, for instance, to venlafaxine, which has been reported to be associated with initial weight loss in clinical trials. Finally, because we used the GPRD database, we could consider only ambulatory prescriptions and had no information about in-hospital medication.

Presented in part at the 23rd International Conference on Pharmacoepidemiology and Therapeutic Risk Management, Quebec City, Canada, Aug. 19–22, 2007. Received July 21, 2008 revision received Nov. 7, 2008 accepted Dec. 17, 2008 (doi: 10.1176/appi.ajp.2008.08071065). From the Bremen Institute for Prevention Research and Social Medicine, Bremen, Germany the Institute of Clinical Pharmacology and Toxicology, and the Institute for Social Medicine, Epidemiology, and Health Economics, Charité-Universitaetsmedizin, Berlin the Department of Epidemiology, Biostatistics, and Occupational Health, Faculty of Medicine, McGill University, Montreal and the Division of Clinical Epidemiology, Royal Victoria Hospital, Montreal. Address correspondence and reprint requests to Dr. Andersohn, Institute for Social Medicine, Epidemiology, and Health Economics, Charité-Universitaetsmedizin Berlin, 10098 Berlin, Germany [email protected] (e-mail).

Dr. Andersohn reports no competing interests. Dr. Schade has received grant support from Schering AG. Dr. Suissa has received grant support from the Canadian Institute of Health Research, AstraZeneca Pharmaceuticals, Boehringer Ingelheim, Organon, and Wyeth, consulting fees from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Bayer Schering Pharma AG, and lecture fees from Boehringer Ingelheim and Pfizer. Dr. Garbe has received consulting fees from Byk-Gulden and consulting fees and an unrestricted grant from Bayer Schering Pharma AG for acquisition of access to the U.K. General Practice Research Database.

Supported in part by a grant from the Canadian Foundation for Innovation and the Canadian Institutes of Health Research and an unrestricted grant from Bayer Schering Pharma AG for database acquisition. The funding sources were not involved in the design, realization, analysis, or publication of the study.

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Psychopharm Exam 3

First was fluoxetien (Prozac)
-five more eventually marketed
-not necessarily more efficacious but have better profile of toxicity or side effects
-availability has not reduce number of treatment resistant patients

Clinically similar psychostimulants (amphetamines) but with lower pptential for abuse. No effect on SE so none of those side effects

Vary in degree to which they block other neurotransmitters (Prozac is least selective and Celexa is most selsctive)

Don't block postsynaptic receptors.

Increasing 5HT in cleft effects all 5HT receptors, which is basis of side effects
-5HT1 is responsible for therapeutic effects
-5HT2 is responsible for side effects

No AChR or histaminic effects not fatal in overdose

leads to cluster of responses, characterized by cognitive disturbances (disorintation, confusion, etc), behavioral agiitation, autonomic nervous system dysfunction (fever, shivering, etc.) and neuromuscular impairments. Visual hallucinations aslo been reported

Reflect excess serotoin at 5HT2 receptors (site of action of psychidelic drugs like LSD)

Serotoinine side effects may be more intense due to better specificity

Most associated with serotonin syndrome and other side effects new onsent of preciptation of psychosis

Comparable efficacy of TCA imipramine, but fewer serious side effects and better patient compliance

Larger doses associated with ECG irregularities, seizures, and rare fatalities

Lower effect on liver enzymes good for multiple drugs

Adverse effects resemble those of other SSRIs

THerapeutically-active optical isomer of Celexa

Others have looked to this

Strongest action is blockade of 5HT2, but also inhibits 5HT and NE recuptake

Blocks adrenergic heteroreceptors located on terminals of 5HT releasing neurons (normally inhibit 5HT release, so blocking increases)

Increased SE release simultates only 5HT1 receptors because mritazepine blocks 2 and 3

Buproprion (Wellbutrin) is a dopamine-norepinephrine reuptake inhibitor. Also used as an anticraving drug (Zyban) for treatment of nicotine dependnece

Shown remarkable short-term effects protrophic

Stress is associated with depression, some effort must be made to manipulate HPA axis

Phenobarbitol was introduces as sedative drug first in class of barbiturates huge margin of safety

Attempts were made to mitigate side effects. Meprobamate (Equanil) and carisoprodol (Soma) were introduced but their safety was about the same.

Barbiturates: Pentabarbitol, Phenobarbitol
Non-barbiturate sedative-hypnotics developed, non are used (i.e., Quaaludes are illegal)

Benzodiazepines - not lipid solibue

Nonbenzodiazepine benzodiazepine receptor agonist - binds to benzo receptor site, but not chemically benzo (Z-drugs)

Bicuculine is competitive agonist that binds reversibly to the GABA site

Hypofunctional GABA-A receptor activity could sensitize amygdala to anxiogenic response to otherwise nondistressing signals

Inhibiting protein synthesis that would be necessary to create a long-term memory

Short-acting are extremely lipid soluble, cross the BBB rapidly, and induce sleep within seconds intravenously

REM sleep is supressed. COgnitive inhibition.

Barbiturate and alcohol combination is especially bad

Stimulate syntehsis of metabolic enzymes in liver, producing tolerance (need more)

Withdrawal from high doses of barbiturates may result in hallucinations, restlessness, etc

No adbantage much like barbiturates

Meprobamate (Equanil, Miltown) - pharmacologically comparable

Carisoprodol (Soma) precursor to meprobamate, which is active form

Quaalude (Methaqualone) - popular date rape drug

Chloral hydrate (Noctec) - date rape drug derivative of EtOH

Paraldehyde - polymer of acetaldehyde used to treat DTs and alcohol withdrawal (delerium tremens)

True anxiolytic effect as opposed to sedative

All are GABA agonists (increase chloride flux) - allosteric modulators that increase GABA binding to GABA-A receptor binding site

Any drug that activates the benzodiazepine receptor

Usually metabolized pharmacologically inactive products then excreted in urine several metabolized to pharmacologically active intermediates

Dementing: depressive, increased rates of falling, motor incoordination

Complicate cognitive-behavior therapies, dementing

Rebound increasing anxiety and insomnia complicate withdrawal

"Addicting," characterized by physical and psychological dependence - problem in patients with alcohol and substance-abuse problems

Impair real-world driving performance

Single agents not useful for treatign comorbid depression. Can make chornic pain worse.

Intentional anterograde amnesia

Panic attacks and nonspecified treatments that may accompany other psychological disorders

Prescribed as hypnotic drugs intended for treatment of insomnia can great amnestic-like behaviors

Limited use as anticonvusants complicates cognitive-behavioral therapies

Zaleplon (Sonata) - very short half life (<1 hr) nonaddictive

Eszopiclone (Lunesta) - similar to zolpidem and traditional BZs long half life 5-7hrs, increased risk of next-day sedation

Users tend to be older females, abusers tend to be younger male drug users (escalate and become dependent)

Inhaled are subject to abuse (nitrous oxide)

Involved in GABA agonism - short acting barbiturates, nonbarbiturates

Also induces analgesia and psychedelic hallucinations

Does not reduce blood pressure important for critically-ill surgery patients

Melatonin is regulated by pineal gland on 24-hours cycle, with levels increasing towards bedtime

Selective weak 5-HT1A agonist, approved for the use of GAD

Anxiolytic and antidepressant

Bipolar, explosive behavioral disorders, alcohol withdrawal and cravings, certain pain states

Barbiturates were the first antiepeleptic drugs, now rarely used.

Benzodiazepines: Diazepam, Loranzepam
Nonbenzodiazipine BZRAs: Zolepidem, Zalepon

General anesthetics: nitrous oxide, halothane, ketamine

Involves manic and depressive episodes that can be either mild/moderate or severe

High lethality rate (19% succeed at suicide)

Onset occurs more rapidly and earlier, psychomotor retardation

"Reversed vegetative symptoms"

Subtance abuse, ADHD, anxiet (OCD/panic), impulse control

100% concordant to axis 1 disorders
Success with one helsp the other

Increased levels related to increased grey matter volume

Narrow therapeutic range (need careful monitoring)

Some have adverse reactions

Reduced renal clearance
Organic brain disorder
Vomiting, diarrhea
Diuretics
Low sodium intake, high excretion
Variations of NA intake will affect Li retention

Mild: listless, nausea, slurring, diarrhea, coarse tremor

Originally developed as anticonvulsants, important analgesics

Used for BD, relapse, detoxification, behaviorol dyscontrol

Significant overlap with atyical antipsychotics

may have been attempts at self-medication for symptom relief

Less ill: monotherapy with lithium/valproate, or antipsychotic (olanzapine)

Depressive episodes: first use lithium/lamotragine (anticonvulsant mood stabilizer)

Adding to mood stabilizer increases risk of manic flip

Bupropion has least risk with Venlafaxin as the greatest

Acute mania/mixed
-Li, valproate, carbamazepine, haloperidol (FGA), new generation

Mood stabalizations prophylaxis
-Lithium, lamotrigine, valproate

Probably less effective than Li, but supierior in combination

Less udes due to serious side effects and avaiability of other drugs
Induces its own metabolism

Inactivates voltage-sensitive sodium channels (efficacy takes longer due to 2nd messenger system)

Blood disorders: Leukopenia (aka leukocytopenia or leucopenia) decreased number of whit blood cells, increased risk of infection
Agranulocytes - auto induction of P450 enzymes
Hypoatremia (electrolyte distrubance when Na levels too low)

CBZ oxidized to CBZ-epoxide, responsible for many side effects

Analogue of CBZ - inactive "prodrug" that liver converts into active species

Doesn't induce hepatic enzymes, feewr drug-drug interactions than CBZ

Tiredness, headaches, dizziness, etc.

Binds and inhibits GABA transaminase, which breaks down GABA (increases available GABA)

May inhibit GABA reuptake and Na+ action potentials may affect gene transcription

70% response rate in lithium resistant patients

GI distress weight gain, liver signs, termors, sedation, hair loss

Increase risk of bolycystic ovarian syndrome (PCOS) - menstral irregularities, etc.

Teratogenicity - neural defects including spinal bifida in first trimester

Rduced drinking, no differences on manic/depessive symptoms

Effective in bipolar, PTSD, schizoaffective disorder

Half-life 36 hours, well absorbed

INhibits glutamate relase, antiepileptic, antianic and analgesic

"more acitivating" therefore useful in Bipolar Depression and rapid cycling - antidepressant

Effective anticonvulsants and antimanic - 50% of bipolar patients will improve with it

Greater cognitive dysfunction than with gabapentin or lamotrigine

Irritability, tingling, anxiety, depression

Similar efficacy to valproate, more expensive.

Atypical antipsychotic increaslingly being used. Cloapine is more antimanic than antidepressant

Risperidone is more antidepressant than antimanic, may aggravate mania

○ Valproic acid (Depakene)
○ Carbamazepine (Tegretol)
○ Gabapentin (Neurotin) and Lamotrigine (Lamictal)
○ Topiramate (Topamax)
Oxcarbazepine (Trileptal)

Antimanic potency positively correlated with affninty for D3 receptors (support dopaming blockade hypothesis of antimanic action)


Contents

Amitriptyline is indicated for the treatment of major depressive disorder and neuropathic pain and for the prevention of migraine and chronic tension headache. It can be used for the treatment of nocturnal enuresis in children older than 6 after other treatments have failed. [10]

Depression Edit

Amitriptyline is effective for depression, [21] but it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability. [22] It can be tried for depression as a second-line therapy, after the failure of other treatments. [11] For treatment-resistant adolescent depression [23] or for cancer-related depression [24] amitriptyline is no better than placebo. It is sometimes used for the treatment of depression in Parkinson disease, [25] but supporting evidence for that is lacking. [26]

Pain Edit

Amitriptyline alleviates painful diabetic neuropathy. It is recommended by a variety of guidelines as a first or second line treatment. [12] It is as effective for this indication as gabapentin or pregabalin but less well tolerated. [27]

Low doses of amitriptyline moderately improve sleep disturbances and reduce pain and fatigue associated with fibromyalgia. [28] It is recommended for fibromyalgia accompanied by depression by Association of the Scientific Medical Societies in Germany [28] and as a second-line option for fibromyalgia, with exercise being the first line option, by European League Against Rheumatism. [13] Combinations of amitriptyline and fluoxetine or melatonin may reduce fibromyalgia pain better than either medication alone. [29]

There is some (low-quality) evidence that amitriptyline may reduce pain in cancer patients. It is recommended only as a second line therapy for non-chemotherapy-induced neuropathic or mixed neuropathic pain, if opioids did not provide the desired effect. [30]

Moderate evidence exists in favor of amitriptyline use for atypical facial pain. [31] Amitriptyline is ineffective for HIV-associated neuropathy. [27]

Headache Edit

Amitriptyline is probably effective for the prevention of periodic migraine in adults. Amitriptyline is similar in efficacy to venlafaxine and topiramate but carries a higher burden of adverse effects than topiramate. [14] For many patients, even very small doses of amitriptyline are helpful, which may allow to minimize the side effects. [32] Amitriptyline is not significantly different from placebo when used for the prevention of migraine in children. [33]

Amitriptyline may reduce the frequency and duration of chronic tension headache, but it is associated with worse adverse effects than mirtazapine. Overall, amitriptyline is recommended for tension headache prophylaxis, along with lifestyle advice, which should include avoidance of analgesia and caffeine. [34]

Other indications Edit

Amitriptyline is effective for the treatment of irritable bowel syndrome however, because of its side effects, it should be reserved for select patients for whom other agents do not work. [35] There is insufficient evidence to support its use for abdominal pain in children with functional gastrointestinal disorders. [36]

Tricyclic antidepressants decrease the frequency, severity, and duration of cyclic vomiting syndrome episodes. Amitriptyline, as the most commonly used of them, is recommended as a first-line agent for its therapy. [37]

Amitriptyline may improve pain and urgency intensity associated with bladder pain syndrome and can be used in the management of this syndrome. [38] [39] Amitriptyline can be used in the treatment of nocturnal enuresis in children. However, its effect is not sustained after the treatment ends. Alarm therapy gives better short- and long-term results. [40]

In the US, amitriptyline is commonly used in children with ADHD as an adjunct to stimulant medications without any evidence or guideline supporting this practice. [41] Many physicians in the UK commonly prescribe amitriptyline for insomnia [42] however, Cochrane reviewers were not able to find any randomized controlled studies that would support or refute this practice. [43]

The known contraindications of amitriptyline are: [10]

  • History of myocardial infarction
  • History of arrhythmias, particularly any degree of heart block
  • Severe liver disease (e.g., cirrhosis)
  • Being under six years of age
  • Patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days.

Amitriptyline should be used with caution in patients with epilepsy, impaired liver function, pheochromocytoma, urinary retention, prostate enlargement, hyperthyroidism, and pyloric stenosis. [10]

In patients with the rare condition of shallow anterior chamber of eyeball and narrow anterior chamber angle, amitriptyline may provoke attacks of acute glaucoma due to dilation of the pupil. It may aggravate psychosis, if used for depression with schizophrenia, or precipitate the switch to mania in those with bipolar disorder. [10]

CYP2D6 poor metabolizers should avoid amitriptyline due to increased side effects. If it is necessary to use it, half dose is recommended. [44] Amitriptyline can be used during pregnancy and lactation, in the cases when SSRI do not work. [45]

The most frequent side effects, occurring in 20% or more of users, are dry mouth, drowsiness, dizziness, constipation, and weight gain (on average 1.8 kg [46] ). [21] Other common side effects (in 10% or more) are vision problems (amblyopia, blurred vision), tachycardia, increased appetite, tremor, fatigue/asthenia/feeling slowed down, and dyspepsia. [21]

A less common side effect of amitriptyline is urination problems (8.7%). [47]

Amitriptyline-associated sexual dysfunction (occurring at a frequency of 6.9%) seems to be mostly confined to males with depression and is expressed predominantly as erectile dysfunction and low libido disorder, with lesser frequency of ejaculatory and orgasmic problems. The rate of sexual dysfunction in males treated for indications other that depression and in females is not significantly different from placebo. [48]

Liver tests abnormalities occur in 10-12% of patients on amitriptyline, but are usually mild, asymptomatic and transient, [49] with consistently elevated alanine transaminase in 3% of all patients. [50] [51] The increases of the enzymes above the 3-fold threshold of liver toxicity are uncommon, and cases of clinically apparent liver toxicity are rare [49] nevertheless, amitriptyline is placed in the group of antidepressants with greater risks of hepatic toxicity. [50]

Amitriptyline prolongs the QT interval. [52] This prolongation is relatively small at therapeutic doses [53] but becomes severe in overdose. [54]

The symptoms and the treatment of an overdose are largely the same as for the other TCAs, including the presentation of serotonin syndrome and adverse cardiac effects. The British National Formulary notes that amitriptyline can be particularly dangerous in overdose, [55] thus it and other TCAs are no longer recommended as first-line therapy for depression. The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available. Activated charcoal may reduce absorption if given within 1–2 hours of ingestion. If the affected person is unconscious or has an impaired gag reflex, a nasogastric tube may be used to deliver the activated charcoal into the stomach. ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised. Body temperature should be regulated with measures such as heating blankets if necessary. Cardiac monitoring is advised for at least five days after the overdose. Benzodiazepines are recommended to control seizures. Dialysis is of no use due to the high degree of protein binding with amitriptyline. [5]

Since amitriptyline and its active metabolite nortriptyline are primarily metabolized by cytochromes CYP2D6 and CYP2C19 (see Amitriptyline#Pharmacology), the inhibitors of these enzymes are expected to exhibit pharmacokinetic interactions with amitriptyline. According to the prescribing information, the interaction with CYP2D6 inhibitors may increase the plasma level of amitriptyline. [10] However, the results in the other literature are inconsistent: [7] the co-administration of amitriptyline with a potent CYP2D6 inhibitor paroxetine does increase the plasma levels of amitriptyline two-fold and of the main active metabolite nortriptyline 1.5-fold, [56] but combination with less potent CYP2D6 inhibitors thioridazine or levomepromazine does not affect the levels of amitriptyline and increases nortriptyline by about 1.5-fold [57] a moderate CYP2D6 inhibitor fluoxetine does not seem to have a significant effect on the levels of amitriptyline or nortriptyline. [58] [59] A case of clinically significant interaction with potent CYP2D6 inhibitor terbinafine has been reported. [60]

A potent inhibitor of CYP2C19 and other cytochromes fluvoxamine increases the level of amitriptyline two-fold while slightly decreasing the level of nortriptyline. [58] Similar changes occur with a moderate inhibitor of CYP2C19 and other cytochromes cimetidine: amitriptyline level increases by about 70%, while nortriptyline decreases by 50%. [61] CYP3A4 inhibitor ketoconazole elevates amitriptyline level by about a quarter. [8] On the other hand, cytochrome P450 inducers such as carbamazepine and St. John's Wort decrease the levels of both amitriptyline and nortriptyline [57] [62]

Oral contraceptives may increase the blood level of amitriptyline by as high as 90%. [63] Valproate moderately increases the levels of amitriptyline and nortriptyline through an unclear mechanism. [64]

The prescribing information warns that the combination of amitriptyline with monoamine oxidase inhibitors may cause potentially lethal serotonin syndrome [10] however, this has been disputed. [65] The prescribing information cautions that some patients may experience a large increase in amitriptyline concentration in the presence of topiramate. [66] However, other literature states that there is little or no interaction: in a pharmacokinetic study topiramate only increased the level of amitriptyline by 20% and nortriptyline by 33%. [67]

Amitriptiline counteracts the antihypertensive action of guanethidine. [5] [68] When given with amitriptyline, other anticholinergic agents may result in hyperpyrexia or paralytic ileus. [66] Co-administration of amitriptyline and disulfiram is not recommended due to the potential for the development of toxic delirium. [5] [69] Amitriptyline causes an unusual type of interaction with the anticoagulant phenprocoumon during which great fluctuations of the prothrombin time have been observed. [70]

Pharmacodynamics Edit

Molecular targets of amitriptyline (AMI) and main active metabolite nortriptyline (NTI) [71]
Site AMI NTI Species Ref
SERT 2.8–36 15–279 Human [72] [73]
NET 19–102 1.8–21 Human [72] [73]
DAT 3,250 1,140 Human [72]
5-HT1A 450–1,800 294 Human [74] [75]
5-HT1B 840 ND Rat [76]
5-HT2A 18–23 41 Human [74] [75]
5-HT2B 174 ND Human [77]
5-HT2C 4-8 8.5 Rat [78] [79]
5-HT3 430 1,400 Rat [80]
5-HT6 65–141 148 Human/rat [81] [82] [83]
5-HT7 92.8–123 ND Rat [84]
α1A 6.5–25 18-37 Human [85] [86]
α1B 600-1700 850-1300 Human [85] [86]
α1D 560 1500 Human [86]
α2 114–690 2,030 Human [73] [74]
α2A 88 ND Human [87]
α2B >1000 ND Human [87]
α2C 120 ND Human [87]
β >10,000 >10,000 Rat [88] [79]
D1 89 210 (rat) Human/rat [89] [79]
D2 196–1,460 2,570 Human [74] [89]
D3 206 ND Human [89]
D4 ND ND ND ND
D5 170 ND Human [89]
H1 0.5–1.1 3.0–15 Human [89] [90] [91]
H2 66 646 Human [90]
H3 75,900>1000 45,700 Human [89] [90]
H4 34-26,300 6,920 Human [90] [92]
M1 11.0–14.7 40 Human [93] [94]
M2 11.8 110 Human [93]
M3 12.8–39 50 Human [93] [94]
M4 7.2 84 Human [93]
M5 15.7–24 97 Human [93] [94]
σ1 287-300 2,000 Guinea pig/rat [95] [96]
hERG 3,260 31,600 Human [97] [98]
PARP1 1650 ND Human [99]
TrkA 3,000
(agonist)
ND Human [100]
TrkB 14,000
(agonist)
ND Human [100]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Amitriptyline inhibits serotonin transporter (SERT) and norepinephrine transporter (NET). It is metabolized to nortriptyline, a stronger norepinephrine reuptake inhibitor, further augmenting amitriptyline's effects on norepinephrine reuptake (see the Table on the right).

Mechanism of action Edit

Inhibition of serotonin and norepinephrine transporters by amitriptyline results in interference with neuronal reuptake of serotonin and norepinephrine. Since the reuptake process is important physiologically in terminating transmitting activity, this action may potentiate or prolong activity of serotonergic and adrenergic neurons and is believed to underlie the antidepressant activity of amitriptyline. [66]

Inhibition of norepinephrine reuptake leading to increased concentration of norepinephrine in the posterior grey column of the spinal cord appears to be mostly responsible for the analgesic action of amitriptyline. Increased level of norepinephrine increases the basal activity of alpha-2 adrenergic receptors, which mediate an analgesic effect by increasing gamma-aminobutyric acid transmission among spinal interneurons. The blocking effect of amitriptyline on sodium channels may also contribute to its efficacy in pain conditions. [4]

Pharmacokinetics Edit

Amitriptyline is readily absorbed from the gastrointestinal tract (90-95%). [4] Absorption is gradual with the peak concentration in blood plasma reached after about 4 hours. [3] Extensive metabolism on the first pass through the liver leads to average bioavailability of about 50% (45% [3] -53% [4] ). Amitriptyline is metabolized mostly by CYP2C19 into nortriptyline and by CYP2D6 leading to a variety of hydroxylated metabolites, with the principal one among them being (E)-10-hydroxynortriptyline [7] (see metabolism scheme), [4] and to a lesser degree, by CYP3A4. [8]

Nortriptyline, the main active metabolite of amitriptyline, is an antidepressant on its own right. Nortriptyline reaches 10% higher level in the blood plasma than the parent drug amitriptyline and 40% greater area under the curve, and its action is an important part of the overall action of amitriptyline. [3] [7]

Another active metabolite is (E)-10-hydroxynortiptyline, which is a norepinephrine uptake inhibitor four times weaker than nortriptyline. (E)-10-hydroxynortiptyline blood level is comparable to that of nortriptyline, but its cerebrospinal fluid level, which is a close proxy of the brain concentration of a drug, is twice higher than notriptyline's. Based on this, (E)-10-hydroxynortiptyline was suggested to significantly contribute to antidepressant effects of amitriptyline. [106]

Blood levels of amitriptyline and nortriptyline and pharmacokinetics of amitriptyline in general, with clearance difference of up to 10-fold, vary widely between individuals. [107] Variability of the area under the curve in steady state is also high, which makes a slow upward titration of the dose necessary. [15]

In the blood, amitriptyline is 96% bound to plasma proteins nortriptyline is 93–95% bound, and (E)-10-hydroxynortiptyline is about 60% bound. [5] [108] [106] Amitriptyline has an elimination half life of 21 hours, [3] nortriptyline - 23-31 hours, [109] and (E)-10-hydroxynortiptyline - 8-10 hours. [106] Within 48 hours, 12-80% of amitriptyline is eliminated in the urine, mostly as metabolites. [6] 2% of the unchanged drug is excreted in the urine. [110] Elimination in the feces, apparently, have not been studied.

Therapeutic levels of amitriptyline range from 75 to 175 ng/mL (270–631 nM), [111] or 80–250 ng/mL of both amitriptyline and its metabolite nortriptyline. [112]

Pharmacogenetics Edit

Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. [113] Increased concentrations of amitriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. [114] [115] [116] [117]

Individuals can be categorized into different types of CYP2D6 or CYP2C19 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers, [44] and have "normal" metabolism of amitriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use amitriptyline much faster than extensive metabolizers patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. [114] [115] [44] [117]

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for a lack of efficacy and side effects, respectively. The consortium also recommends considering an alternative drug not metabolized by CYP2C19 in patients who are CYP2C19 ultrarapid metabolizers. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. If use of amitriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. [44] The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are CYP2D6 poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are CYP2D6 intermediate metabolizers. [118]

Amitriptyline is a highly lipophilic molecule having an octanol-water partition coefficient (pH 7.4) of 3.0, [119] while the log P of the free base was reported as 4.92. [120] Solubility of the free base amitriptyline in water is 14 mg/L. [121] Amitriptyline is prepared by reacting benzosuberone with 3-(dimethylamino)propylmagnesium chloride and then heating the resulting intermediate product with hydrochloric acid to eliminate water. [4]

Amitriptyline was first developed by the American pharmaceutical company Merck in the late 1950s. In 1958, Merck approached a number of clinical investigators proposing to conduct clinical trials of amitriptyline for schizophrenia. One of these researchers, Frank Ayd, instead, suggested using amitriptyline for depression. Ayd treated 130 patients and, in 1960, reported that amitriptyline had antidepressant properties similar to another, and the only known at the time, tricyclic antidepressant imipramine. [122] Following this, the US Food and Drug Administration approved amitriptyline for depression in 1961. [123]

In Europe, due to a quirk of the patent law at the time allowing patents only on the chemical synthesis but not on the drug itself, Roche and Lundbeck were able to independently develop and market amitriptyline in the early 1960s. [124]

According to research by the historian of psychopharmacology David Healy, amitriptyline became a much bigger selling drug than its precursor imipramine because of two factors. First, amitriptyline has much stronger anxiolytic effect. Second, Merck conducted a marketing campaign raising clinicians' awareness of depression as a clinical entity. [124] [122]

English folk singer Nick Drake died from an overdose of Tryptizol in 1974. [125]

Generic names Edit

Amitriptyline is the English and French generic name of the drug and its INN , BAN , and DCF , while amitriptyline hydrochloride is its USAN , USP , BANM , and JAN . [126] [127] [128] [129] Its generic name in Spanish and Italian and its DCIT are amitriptilina, in German is Amitriptylin, and in Latin is amitriptylinum. [127] [129] The embonate salt is known as amitriptyline embonate, which is its BANM , or as amitriptyline pamoate unofficially. [127]

The few randomized controlled trials investigating amitriptyline efficacy in eating disorder have been discouraging. [130]


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PREVALENCE, CHARACTERISTICS AND IMPACT OF TINNITUS

Prevalence

Most individuals at one time or another experience transient tinnitus lasting seconds or minutes however, others experience long-lasting tinnitus that can persist for a lifetime. The prevalence of tinnitus among those over 65 years of age ranges from 12% to 15% (1𠄶). Approximately < 1% of the population suffers from severe, debilitating tinnitus that negatively impacts sleep, concentration, work and quality of life, and which requires medical treatment or counseling. Tinnitus occurs roughly equally in females and males (7, 8). As with most disorders, the prevalence of tinnitus increases with age and peaks at around 60� years (7).

In 2005, it was estimated that the potential market in the U.S. for tinnitus treatment was approximately $10 billion (9). The Veterans Administration Benefits Report ranked tinnitus as the second most prevalent service-related disability. Among those who began receiving benefits in 2006, tinnitus was ranked first among service-related disabilities at 9.7% of the total (http://www.vba.va.gov/bln/21/). In 2005, the annual compensation for tinnitus-related disability was $418 million. The economic impact of this disabling disorder, combined with the growing number of noise-exposed combat personnel and the swelling ranks of elderly individuals with tinnitus (10, 11), has generated renewed interest in finding therapeutic compounds that can suppress or manage tinnitus.

Perceptual characteristics of tinnitus

A little over half of tinnitus patients perceive the phantom sound as coming from inside the ear (tinnitus aurium), suggesting that tinnitus might originate in the inner ear. Others report that the phantom sound is located inside the head (tinnitus cerebri), raising the possibility of a central origin (12, 13), while a few patients perceive the phantom sound as coming from outside the head. Approximately 60% of patients experience bilateral tinnitus, while the remainder hear the sound in just one ear (14).

Patients often undergo detailed audiometric and psychoacoustic evaluation to assess the status of the auditory pathway. The pure- tone audiogram, which identifies the frequencies where hearing is impaired, is an important procedure, as tinnitus is generally associated with hearing loss. In younger individuals hearing loss is most often associated with noise exposure, while in older individuals it is often associated with age-related hearing loss or presbycusis. The prevalence of tinnitus steadily increases with the degree of age-related hearing loss (7). Despite the frequent association between hearing loss and tinnitus, many individuals with hearing loss do not experience tinnitus. Conversely, some individuals with normal hearing experience tinnitus. The definition of “normal” hearing, however, can be misleading, because most hearing tests are only performed at octave intervals from 125 to 8000 Hz. It is conceivable that these “normal” listeners may actually have undetected hearing loss at interoctave intervals, or hearing loss between 8000 and 20,000 Hz, where hearing is seldom evaluated, or other auditory disorders that are not detected by an audiogram. Clinical trials that assess the efficacy of drugs used to treat tinnitus often use psychoacoustic tests to determine if the loudness, pitch or other qualities of the tinnitus change as a result of treatment. In some individuals, the perceptual qualities of tinnitus may fluctuate from morning to evening or from day to day, while in others the tinnitus remains stable over time (15). If the patient’s tinnitus fluctuates, it is important to have several baseline measurements prior to the start of treatment.

The pitch and spectral qualities of tinnitus vary from one individual to the next, but the most common descriptors used are those of ringing, buzzing, hissing or whistling (16). Because the auditory system is organized tonotopically such that different frequencies activate different anatomical locations in the auditory pathway (similar to a piano keyboard), the pitch and spectral qualities of the tinnitus may provide clues regarding the neurons that trigger the phantom sensation. The pitch or spectral qualities of tinnitus are often located in the region of maximum hearing loss or at the boundary between normal and abnormal hearing (17, 18). These results suggest that the neurons responsible for the perception of tinnitus may be located at the edge or boundary of maximum hearing loss (19).

Loudness, a perceptual phenomenon, is most closely related to sound intensity, a physical measure assessed in units of decibels (dB). Loudness measurements of tinnitus are often obtained with a 10-point visual analog scale, with a score of 10 being very loud and a score of 1 being soft. When patients are asked to rate the subjective loudness of their tinnitus, the average loudness rating is

6.3, suggesting that the phantom sound is moderately loud (20). Other approaches estimate tinnitus loudness by having the subject adjust the level of an external sound so that it matches the perceived loudness of their tinnitus. In most cases, the tinnitus is matched to an external tone less than 10 dB above the threshold of hearing (< 10 dB sensation level, or 10 dB SL). These low dB SL values may suggest that the tinnitus is not very loud however, such results may be misleading because dB SL is a measure referenced to the individual’s threshold of hearing at that frequency. If a patient has a 40-dB hearing loss and matches the loudness of the tinnitus to 10 dB SL, the sound level would be 50 dB HL, i.e., 50 dB above the normal threshold for hearing at that frequency. Additionally, when a patient suffers from hearing loss, they often experience loudness recruitment, i.e., the loudness of a sound increases rapidly once the sound level exceeds the patient’s threshold.

Masking, the ability of one loud sound to cover up a less intense sound, has been used as a treatment for tinnitus, allowing the patient to voluntarily escape from the tinnitus (21, 22). The minimum masking intensity provides an objective method of assessing the loudness of tinnitus. Masking can be expressed in dB SPL (sound pressure level), an acoustic measure, or in terms of dB SL, the sound level relative to the subject’s threshold. The minimum masking level can be used to assess the severity of tinnitus (23) and to evaluate the ability of a drug or devices to ameliorate tinnitus severity (24�). In many cases, tinnitus can be masked at relatively low intensities in others, high intensities are required, and in a few cases, the tinnitus is unmaskable or made worse by external sounds (16, 28, 29). Masking also provides insights into the neural origins of tinnitus. When a real tone is presented to one ear, it is easily masked by sounds presented to the same ear, but difficult to mask by sounds presented to the opposite ear (30). In contrast, when the phantom sound of tinnitus is perceived in one ear, it can usually be masked by a sound presented to the same ear or the opposite ear (31, 32). One interpretation of these finding is that the neural generator for tinnitus resides in the central auditory system where neural responses from the two ears can interact with one another, rather than in the inner ear where the neural responses are largely independent. Another striking difference between a real sound and tinnitus is that the masker sometimes becomes less effective in covering up the tinnitus the longer it is presented, whereas masking of external sounds remains relatively constant over time (33, 34).

Emotional and psychological responses to tinnitus

A patient’s emotional or psychological response to tinnitus can vary from one individual to the next, even among patients whose tinnitus is similar. Consequently, it is important to determine how a drug affects a person’s social or emotional response to tinnitus, as well as its perceptual qualities. Frequently used questionnaires for assessing a patient’s reaction to tinnitus are the Tinnitus Handicap Inventory, Tinnitus Handicap Questionnaire and Tinnitus Reaction Questionnaire (35�). These questionnaires focus on issues related to the degree of handicap, sleep, social interactions, emotion, concentration, depression and annoyance of tinnitus. Drugs used to treat tinnitus should either reduce the tinnitus perception or the emotional response, and ideally both.

Tinnitus classification

Subjective tinnitus is associated with many different diseases and disorders, and it sometimes emerges as a side effect of medications used to treat other diseases (39). Attempts have been made to classify different forms of tinnitus based on the site of lesion, the patient’s description, the clinician’s observations, the perceptual characteristics, causation, neurophysiological characteristics, response to treatment and various combinations of these factors (12, 40�). While none of the classification schemes is widely accepted, there is evidence that certain types of tinnitus may respond well to a particular type of drug therapy (44�).


Anxiolytic and antidepressant-like activities of the novel and potent non-imidazole histamine H3 receptor antagonist ST-1283

1 Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates 2 Institut für Pharmazeutische Chemie, Biozentrum, Johann Wolfgang Goethe University, Frankfurt, 3 Heinrich Heine University Duesseldorf, Institut fuer Pharmazeutische and Medizinische Chemie, Düsseldorf, Germany 4 Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University,
Al Ain, United Arab Emirates

*These authors contributed equally to this work

Abstract: Previous studies have suggested a potential link between histamine H3 receptors (H3R) signaling and anxiolytic-like and antidepressant-like effects. The aim of this study was to investigate the acute effects of ST-1283, a novel H3R antagonist, on anxiety-related and depression-related behaviors in comparison with those of diazepam and fluoxetine. The effects of ST-1283 were evaluated using the elevated plus maze test, open field test, marbles burying test, tail suspension test, novelty suppressed feeding test, and forced swim test in male C57BL/6 mice. The results showed that, like diazepam, ST-1283 (7.5 mg/kg) significantly modified all the parameters observed in the elevated plus maze test. In addition, ST-1283 significantly increased the amount of time spent in the center of the arena without altering general motor activity in the open field test. In the same vein, ST-1283 reduced the number of buried marbles as well as time spent digging in the marbles burying test. The tail suspension test and forced swim test showed that ST-1283 was able to reduce immobility time, like the recognized antidepressant drug fluoxetine. In the novelty suppressed feeding test, treatment with ST-1283 decreased latency to feed with no effect on food intake in the home cage. Importantly, pretreatment with the H3R agonist R-&alpha-methylhistamine abrogated the anxiolytic and antidepressant effects of ST-1283. Taken together, the present series of studies demonstrates the novel effects of this newly synthesized H3R antagonist in a number of preclinical models of psychiatric disorders and highlights the histaminergic system as a potential therapeutic target for the treatment of anxiety-related and depression-related disorders.

Keywords: anxiety, depression, histamine, H3 receptor, R-&alpha-methylhistamine, ST-1283

Anxiety and depression belong to neurobehavioral disorders which are considered by their diagnostic measures into obsessive-compulsive, panic, social phobia, and post-traumatic stress disorders. Benzodiazepines are the most commonly prescribed anxiolytic drugs, being efficacious against a spectrum of anxiety disorders, whereas the major classes of antidepressants are selective serotonin reuptake inhibitors, tricyclic antidepressants, and serotonin noradrenaline reuptake inhibitors, and are known as antidepressants in patients with a wider spectrum of anxiety and depressive disorders. 1,2 However, accumulating evidence shows that there are issues with addiction, tolerance, and dependence/withdrawal, as well as adverse effects, including sedation, cognitive and psychomotor impairment, and anterograde amnesia associated with clinical use of benzodiazepines. As a result, the clinical efficacy of benzodiazepines is restricted to generalized anxiety disorders, social phobia, and panic disorders, 3 while the antidepressant classes of drugs, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and serotonin noradrenaline reuptake inhibitors, have a slow onset of action (4𔃄 weeks) and their own side-effect profiles. 3 Moreover, several clinical studies have shown that patients with generalized anxiety disorder who do not achieve remission are resistant to first-line medications, such as selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors. Therefore, there is a pressing need to use hydroxyzine, a first-generation antihistamine, as an adjunctive treatment. 4 Consequently, there is an ongoing need to discover new therapeutic targets for the development of novel, more effective, and safer drugs with anxiolytic-like and antidepressant-like activities.

Since their discovery, there has been increasing evidence supporting a role for central histamine H3 receptors (H3Rs) in various brain functions, including cognition, emotion, stress, and feeding. 5 Moreover, the most recent advances in preclinical and clinical trials using H3R antagonists have shown distinct pharmacologic actions, indicating their importance for diverse central nervous system-related therapeutic applications, such as depression, schizophrenia, sleep-wake disorders, dementia, and epilepsy. 6,7

Central histamine plays an important role in anxiety and depression. There have been numerous studies indicating a functional relationship between anxiety and histaminergic neurotransmission in classical animal models. The H1R antagonist chlorpheniramine improved anxiety in the rat elevated plus maze test (EPM) and the open field test (OFT). 8 It has also been reported that anxiety-like behavior is decreased in the EPM test for mice lacking H1Rs. 9

The possible involvement of H3R function in depression has been described previously. 10,11 Lamberti et al found that the highly selective H1R agonist 2-(3-trifluoromethylphenyl)histamine, the better known H1R agonist 2-thiazolylethylamine, and the standard H3R antagonist/inverse agonist thioperamide had antidepressant-like activity in the mouse forced swim test (FST). 12 Moreover, it has been reported very recently that the newly developed non-imidazole H3R antagonist, 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)phenyl] amide, was active in the FST, suggesting the potential therapeutic utility of H3R antagonists/inverse agonists as antidepressive agents. 13

Taken together, these findings support the concept that the histaminergic system enhances an anxiogenic-like response mainly via activation of H1Rs and inhibition of H3Rs. However, there is still quite limited information available regarding the psychopharmacologic profiles of H3R antagonists/inverse agonists, in particular their therapeutic value for anxiety and depression disorders. 14 The H3R subtype, as a presynaptic autoreceptor, was found to suppress the synthesis and release of histamine in the central nervous system. 15,16 It was also shown to behave as a presynaptic heteroreceptor, modulating the release of many other important neurotransmitters, such as dopamine, noradrenaline, acetylcholine, gamma aminobutyric acid, and serotonin. 16󈝿

Therefore, in this study the effects of the novel highly potent and selective non-imidazole H3R antagonist, ST-1283 [3-(5-methyl-4-(4-(3-(piperidin-1-yl)propoxy)phenyl)-4H-1,2,4-triazol-3-yl)pyridine], with high in vitro human H3R affinity in the subnanomolar concentration range and a pKi value of 9.62 20 was investigated for its effect on anxiety-related and depression-related behaviors in adult male C57BL/6 mice.

Adult male C57BL/6 mice (aged 14 weeks and weighing 24󈞊 g) bred in the local central animal facility of the College of Medicine and Health Sciences (United Arab emirates University) were used in all the experiments. The animals were group-housed (five per cage) in a temperature-controlled vivarium (approximately 22°C), on a 12󈝸-hour light–dark cycle, with lights on at 6 am. The mice were acclimated to our testing facility for 7 days before any experimental procedure. Bedding was produced locally and autoclaved before use, and the mice had free access to tap water and a standard rodent chow diet (except as specified later) obtained from the National Feed and Flour Production and Marketing Company LLC (Abu Dhabi, United Arab Emirates). All procedures were approved by the College of Medicine and Health Sciences Animal Research Care and Use Ethics Committee (approvals A15-11 and A28-12). All efforts were made to minimize suffering and the number of animals used.

The H3R antagonist 3-(5-methyl-4-(4-(3-(piperidin-1-yl) propoxy)phenyl)-4H-1,2,4-triazol-3-yl) pyridine (ST-1283, 5 mg/kg and 7.5 mg/kg) and the H3R agonist R-α-methylhistamine (RAMH, 10 mg/kg) were synthesized by the Institut für Pharmazeutische Chemie, Goethe University Frankfurt am Main, Germany, and were validated in a previous study. 20 Diazepam 1 mg/kg manufactured by Gulf Pharmaceutical Industries (Ras Al Khaimah, United Arab Emirates) was obtained from Dr Essam Emam (Department of Medicine, Tawam Hospital, Al Ain, United Arab Emirates) and fluoxetine (Prozac ® , 10 mg/kg) was obtained from Eli Lilly (Indianapolis, IN, USA). Both diazepam and fluoxetine were used as reference compounds. All drugs were diluted in isotonic saline and injected intraperitoneally at a volume of 10 mL/kg adjusted to body weight 30 minutes before each behavioral experiment. The experimental groups were as follows: vehicle (nɫ), ST-1283 5 mg/kg (n៞), ST-1283 7.5 mg/kg (nɩ), diazepam (nɪ), and fluoxetine (nɪ).

These experiments provide the first behavioral assessment of the ST-1283-injected mice in anxiety-like and depression-like behaviors in mice.

The EPM test was performed as previously described. 21󈞄 Briefly, a four wooden-armed apparatus was elevated 40 cm above the ground and consisted of two opposite open arms (40 cm × 6 cm) and two opposite closed arms of the same size with high black-painted walls. The arms were connected by a central square (6 cm × 6 cm). An animal was placed in the center of the maze facing an open arm. Testing took place between 9 am and 1 pm in an order randomized for drug treatment. The maze was kept light with a 60 W bulb placed at a height of approximately one meter above the maze. The amount of time spent with head and forepaws on the open arms and closed arms of the maze as well as the number of entries into each arm was manually scored for 5 minutes. The maze was thoroughly cleaned with a tissue dampened with 70% (volume/volume v/v) alcohol to remove the odor after each mouse was tested. The total number of entries into the closed arms is usually used as an index of locomotor activity in the test. 21󈞄

The OFT was performed as previously described for C57BL/6 mice. 21󈞄 Briefly, the open field was a 32 cm × 32 cm white plexiglass square arena surrounded by a 20 cm high wall and divided into 64 equal squares by black lines. The 16 central squares are regarded as the “center” of the field. A 60 W light bulb was positioned approximately one meter above the arena. Mice were transferred one hour beforehand to the testing room and placed in the center of the field. The following parameters were manually scored: the number of lines crossed (defined as at least three paws in a square) and time spent in the center of the arena during a 10-minute test. Less time spent in the central area is usually taken as a measure of a higher level of anxiety and vice versa. After each test, the arena was sprayed with 70% ethanol and wiped thoroughly to remove the residual odor.

We followed the test as previously described 21,23 for analysis of the effects of ST-1283 on the marble burying test (MBT). Briefly, this test was performed using a white plexiglass cage with approximately 5 cm deep sawdust bedding lightly pressed to give a flat surface. Twenty glass marbles were evenly spaced over the bedding. The mice were placed in the center of the marble-containing cage and the total duration of digging bouts was manually recorded for each animal in a 10-minute test. The mouse was then returned to its home cage, and the number of buried marbles was scored. A marble was considered partially buried if at least 70% of its surface was covered by bedding. 21,23 Marbles that were no longer visible were considered completely buried.

This method, reported originally by Steru et al, 25 was followed with slight modifications. 23 In brief, each mouse was suspended on the edge of a rod 50 cm above a table top using adhesive Scotch tape placed approximately 1 cm from the tip of the tail. Tail climbing was prevented by passing the mouse’s tail through a small plastic cylinder prior to suspension, as described by Can et al. 26 The duration of immobility was manually scored for a 6-minute observation period. Mice were considered immobile only when they hung down passively and were completely motionless. The parameter recorded was the number of seconds spent immobile.

Novelty suppressed feeding test

The novelty suppressed feeding (NSF) test was performed as described previously. 23 Briefly, 24 hours before testing, the mice were food-deprived, and only water was available. At the time of testing, each mouse was placed in one corner of a clear plastic box and allowed to explore for a maximum of 15 minutes. The test box (32 cm × 32 cm × 15 cm) was filled with 2 cm of fresh autoclaved bedding and three preweighed food pellets were placed on a circular white filter paper in the center of the arena. The time taken to bite a food pellet was manually scored. Immediately after an eating event, the mouse was placed back to its home cage and allowed to feed freely for 5 minutes. The amount of food consumption in the home cage was measured. For this test, latency until eating food was measured as well as amount of food consumed.

The FST test was performed according to the method originally described by Porsolt et al. 27 Mice were individually placed into glass cylinders containing 15 cm of water at ㅑ°C. The mice were left in the cylinders for 6 minutes and immobility was analyzed. The mice were then removed from the container and left to dry in a heated enclosure before being returned to their home cages. The mice were judged to be immobile when they ceased struggling and remained floating motionless in the water (without any vertical or horizontal movements), making only the movements necessary to keep their heads above the water level as described previously. 23

IBM ® SPSS Statistics ® version 20 software (IBM Middle East, Dubai, United Arab Emirates) was used for all statistical comparisons. Mean values and standard errors were calculated for each group. Dependent variables for each behavioral model were analyzed using one-way analysis of variance, with “dose” as a between-subject factor. When relevant, post hoc analyses were performed by Student’s t-tests with Bonferroni corrections for multiple comparisons. Pɘ.05 denotes a statistically significant difference.

C57BL/6 mice exhibited anxiolytic activity following ST-1283 administration

Figure 1 shows a dose-response curve for the effects of acute administration of ST-1283 (0, 5, or 7.5 mg/kg) on the anxiety indices (percentage of time spent in open arms, number of entries into open arms, and percentage entries into open arms) and locomotor activity (number of entries into closed arm) of mice exposed to the EPM. One-way analysis of variance showed that ST-1283 dose-dependently increased the percentage of time spent exploring the open arms of the maze during a 5-minute session (F(2,23) ɥ.959, Pɢ.033, Figure 1A). Relative to the vehicle condition, only the 7.5 mg/kg dose of ST-1283 produced a significant increase in the percentage of time spent on the open arms (Pɢ.038 and Pɢ.180 for each dose, respectively). As a positive control, and compared with vehicle, diazepam 1 mg/kg induced a significant increase in the percentage of time spent exploring the open arms (F(1,15) ៮.220, Pɘ.001). Analyses of data characterizing the number of entries into the open arms of the maze (F(2,23) ɧ.270, Pɢ.013) yielded essentially the same results. As shown in Figure 1B, only the highest dose of ST-1283 (7.5 mg/kg) was significantly different from that obtained with vehicle pretreatment (Pɢ.011). Diazepam 1 mg/kg also increased the number of entries into the open arms (F(1,15) ៳.424, Pɘ.001). Similarly, pretreatment with ST-1283 altered the percentage of entries into the open arms (F(2,23) ɦ.894, Pɢ.017). Post hoc evaluation revealed that, compared with vehicle, the mice injected with the higher dose of ST-1283 (7.5 mg/kg) displayed a higher percentage of entries into the open arms (Pɢ.015). In contrast, no significant difference was found between vehicle- and ST-1283 (5 mg/kg)-treated mice (Pɢ.221, Figure 1C). As a positive control, diazepam 1 mg/kg induced a significant increase in the percentage of entries into the open arms (F(1,15) ៬.436, Pɘ.001). Interestingly, no significant changes were found in the number of closed arm entries following ST-1283 injection (F(2,23) ɢ.044, Pɢ.957, Figure 1D), nor following diazepam injection (F(1,15) ɢ.302, Pɢ.590), indicating that locomotor activity per se was not affected following ST-1283 injection relative to that obtained with saline pretreatment. Thus, the observed behavioral changes were not accompanied by any significant alterations in the distance traveled during this period.

Figure 1 Effects of acute ST-1283 pretreatment on exploratory behavior on the elevated plus maze test. ST-1283 dose-dependently increased the percentage of time spent on the open arms of the elevated plus maze ( A ), increased the number of entries into the open arms ( B ) and the percentage of entries into the open arms ( C ). Pretreatment with the H3R antagonist did not affect the number of closed arm entries ( D ).
Notes: *Denotes significant differences between drug doses and saline controls (Pɘ.05) # denotes significant differences between diazepam and saline controls (Pɘ.001). Vehicle nɫ ST-1283 5 mg/kg n៞ ST-1283 7.5 mg/kg nɩ, diazepam nɪ. Data are shown as the mean ± standard error of the mean.
Abbreviations: DZP, diazepam OA, open arms.

We used the OFT to further corroborate anxiety-like behavior and simultaneously rule out possible intrinsic impairment of spontaneous locomotor activity. Locomotor activity was measured by the number of line crossings in the arena. One-way analysis of variance showed that, compared with vehicle, both ST-1283 and diazepam had no effect on total line crossings (F(2,23) ɢ.247, Pɢ.783) and (F(1,15) ɢ.055, Pɢ.818), respectively (Figure 2A). However, significant treatment differences were found with regard to time spent in the central area (F(2,23) ɦ.309, Pɢ.026). In fact, mice injected with the ST-1283 (7.5 mg/kg) spent more time in the central area (Pɢ.026 compared to vehicle). However, at the lower dose, ST-1283 had no effect on time spent in the central area (Pɢ.198 compared to vehicle) (Figure 2B). As a positive control, diazepam 1 mg/kg also increased the amount of time spent in the center of the arena (F(1,15) ᠇.575, Pɘ.001).

Figure 2 Effects of acute ST-1283 pretreatment on anxiety-like behavior in the open field test and marbles burying test. In the open field test, ST-1283 had no effect on total line crossing ( A ) but dose-dependently increased the time spent in the center of the arena ( B ). In the marbles burying test, acute ST-1283 decreased the number of buried marbles ( C ) and the time spent digging ( D ).
Notes: *Denotes significant differences between drug doses and saline controls (Pɘ.05) # denotes significant differences between diazepam and saline controls (Pɘ.001). Vehicle nɫ ST-1283 5 mg/kg n៞ ST-1283 7.5 mg/kg nɩ, DZP nɪ. Data are shown as the mean ± standard error of the mean.
Abbreviation: DZP, diazepam.

We then explored differences in anxiety-like and obsessive–compulsive-like behavior in vehicle-treated and ST-1283-treated mice using the digging test and the MBT. In parallel with our findings in the OFT and EPM tests, ST-1283-treated mice showed a significant decrease in the number of buried marbles compared with vehicle-injected mice (F(2,23) ɦ.114, Pɢ.030). Post hoc evaluations revealed that mice injected with the higher (7.5 mg/kg) dose showed an approximately 1.8-fold decrease in the number of buried marbles (Pɢ.039 and Pɢ.127 for vehicle versus ST-1283 5 mg/kg, Figure 2C). Diazepam 1 mg/kg also decreased the number of buried marbles (F(1,15) ៫.166, Pɘ.001). In addition, analysis of digging duration showed a main effect of treatment (F(2,23) ɦ.517, Pɢ.022). In fact, mice injected with the ST-1283 (7.5 mg/kg) spent more time digging (Pɢ.025 compared to vehicle). However, at the lower dose, ST-1283 had no effect on time spent digging (Pɢ.141 compared to vehicle) (Figure 2D). Further, compared with vehicle, the positive diazepam control showed a decrease in time spent digging (F(1,15) ០.912, Pɢ.003).

ST-1283 injection reduced depression-like behavior in C57BL/6 mice

Because anxiety and depression are often comorbid, we next analyzed the effects of H3R blockade with ST-1283 using three measures of depression, ie, the tail suspension test (TST), NSF, and FST.

In the TST, acute treatment with either ST-1283 (F(2,23) ɥ.846, Pɢ.036) or fluoxetine 10 mg/kg intraperitoneally (F(1,15) ៥.020, Pɢ.001) elicited a significant change in immobility time compared with vehicle. As shown in Figure 3A, there was a significant effect of ST-1283 on immobility time at the high dose of 7.5 mg/kg (Pɢ.042 versus vehicle). In contrast, low-dose peripheral administration of ST-1283 5 mg/kg did not significantly alter immobility time in the mouse TST model (Pɢ.182 versus vehicle).

Figure 3 Effects of acute ST-1283 pretreatment on depression-like behavior in the TST, the novelty suppressed feeding test, and the forced swim test. Acute ST-1283 decreased immobility time in the TST ( A ) and decreased the feeding latency in the novelty suppressed feeding test ( B ). However, ST-1283 did not affect eating in the home cage ( C ). Similarly, ST-1283 dose-dependently decreased the immobility time in the forced swim test ( D ).
Notes: *Denotes significant differences between drug doses and saline controls (Pɘ.05) # denotes significant differences between fluoxetine and saline controls (Pɘ.001). Vehicle nɫ ST-1283 5 mg/kg n៞ ST-1283 7.5 mg/kg nɩ, fluoxetine nɪ. Data are shown as the mean ± standard error of the mean.
Abbreviations: TST, tail suspension test FXT, fluoxetine FST, forced swim test.

Novelty suppressed feeding

We next tested the groups of mice using the NSF test. Acute treatment with ST-1283 significantly improved the NSF test results by reducing feeding latency (F(2,23) ɧ.530, Pɢ.011). As shown in Figure 3B, at the higher dose, ST-1283-treated mice showed significantly shorter feeding latencies than control mice (Pɢ.011). However, at the 5 mg/kg dose, ST-1283- injected animals did not show significantly reduced feeding latency compared with controls (Pɢ.115). This was not due to increased appetite because food consumption in home cage was not significantly changed following acute administration of ST-1283 (F(2,23) ɢ.217, Pɢ.807, Figure 3C). As the positive control, treatment with fluoxetine led to an overall decrease in time to first eating event (F(1,15) ᠎.013, Pɘ.001, Figure 3B) in the NDF test, but did not affect food intake in the home cage (F(1,15) ɢ.208, Pɢ.655, Figure 3C).

Similar to the antidepressant-like activity reported in the TST and the NSF, acute treatment with ST-1283 significantly affected immobility time in the mouse FST (F(2,23) ɦ.750, Pɢ.019). As shown in Figure 3D, only high-dose administration of ST-1283 decreased immobility times in the FST (Pɢ.019). However, no change in immobility time was observed when mice were injected with ST-1283 5 mg/kg (Pɢ.153 versus vehicle). As the positive control, fluoxetine 10 mg/kg induced a significant decrease in immobility (F(1,15) ៣.808, Pɢ.001).

RAMH blocked ST-1283-attenuated anxiety-like behavior in mice

In this set of experiments we tested whether the anxiolytic and antidepressant effects induced by ST-128 can be abrogated by pretreatment with the H3R-selective agonist RAMH injected at a dose of 10 mg/kg 15 minutes before administration of ST-1283 7.5 mg/kg.

One-way analysis of variance indicated that there were significant differences between the groups with regard to the percentage of time spent by the mice in the open arm compartments of the maze (F(2,18) ɧ.507, Pɢ.014). Figure 4A shows that, compared with vehicle, treatment with ST-1283, as expected, increased the percentage of time spent by mice in the open arms of the EPM apparatus (anxiolytic-like effect Pɢ.023). However, acute administration of RAMH at the 10 mg/kg dose counteracted the anxiolytic-like effect of ST-1283 (Pɢ.032 versus ST-1283 and Pɣ.000 versus vehicle). When the number of entries in the open arms was measured, there were significant differences between the groups (F(2,18) ɩ.355, Pɢ.005). As shown in Figure 4B, post hoc evaluations revealed that ST-1283 increased the number of entries into the open arms (Pɢ.007 versus vehicle). However, preinjection with RAMH reversed the anxiolytic-like effect of ST-1283 (Pɢ.014) and lowered the number of open arm entries. Similarly, one-way analysis of variance showed a significant effect of drug treatment on the percentage of entries into the open arms in the EPM test (F(2,18) ɧ.540, Pɢ.013). Post hoc comparisons revealed that ST-1283 7.5 mg/kg significantly increased the percentage of entries into the open arms compared with the vehicle-treated group (Pɢ.023), and treatment with RAMH abrogated the ST-1283-induced anxiolytic effect (Pɢ.031, Figure 4C). As shown in Figure 4D, measures of general activity (closed arm entries) did not differ significantly between any of the groups (F(2,18) ɣ.142, Pɢ.341).

Figure 4 Effects of acute RAMH pretreatment on ST-1283-induced anxiolytic effects in the elevated plus maze test. RAMH pretreatment abrogated the effects of ST-1283 on the percentage of time spent in the open arms ( A ), the number of entries into the open arms ( B ), and the percentage of entries into the open arms ( C ). Pretreatment with the H3R agonist RAMH did not affect the number of closed arm entries ( D ).
Notes: *Denotes significant differences between ST-1283 and saline controls (Pɘ.05) # denotes significant differences between RAMH and ST-1283 (Pɘ.05). Vehicle nɩ ST-1283 7.5 mg/kg nɨ, RAMH nɪ. Data are shown as the mean ± standard error of the mean.
Abbreviations: CA, closed arm OA, open arm RAMH, R-α-methylhistamine.

In addition to EPM, the OFT was used to examine anxiety-like behavior and locomotion. As seen in Figure 5A, there were no significant effects of acute exposure to ST-1283 and RAMH on overall locomotor activity (F(2,18) ɢ.015, Pɢ.985). In contrast, one-way analysis of variance revealed that there was a main effect of treatment on time spent in the center of the arena (F(2,18) ɧ.095, Pɢ.018). Post hoc evaluations demonstrated that, as expected, mice treated with ST-1283 spent significantly more time in the center of the arena than those treated with vehicle (Pɢ.032). Interestingly, this effect was inhibited when RAMH was injected before ST-1283 (Pɢ.038, Figure 5B).

Figure 5 Effects of acute RAMH pretreatment on ST-1283-induced anxiolytic effects in the open field test and marbles burying test. In the open field test, RAMH pretreatment had no effect on total line crossing ( A ) but abrogated the effects of ST-1283 on the time spent in the center of the arena ( B ). In the marbles burying test, acute RAMH pretreatment blocked the effects of ST-1283 on the number of buried marbles ( C ) and time spent digging ( D ).
Notes: *Denotes significant differences between ST-1283 and saline controls (Pɘ.05) # denotes significant differences between RAMH and ST-1283 (Pɘ.05). Vehicle nɩ ST-1283 7.5 mg/kg nɨ, RAMH nɪ. Data are shown as the mean ± standard error of the mean.
Abbreviation: RAMH, R-α-methylhistamine.

The results of the MBT are shown in Figure 5C and D. One-way analysis of variance revealed that there was a significant treatment effect with regard to the number of marbles buried (F(2,18) ɦ.758, Pɢ.022, Figure 5C). Bonferroni post hoc comparison testing showed that the response of the control mice was significantly different from the mice that received ST-1283 (Pɢ.039). However, RAMH-injected mice buried significantly more marbles than the ST-1283- treated animals (Pɢ.046). To assess whether impaired marble burying is associated with digging behavior, we measured the time spent digging. As seen in Figure 5D, one-way analysis of variance showed that time spent digging was affected by drug treatment (F(2,18) ɦ.592, Pɢ.024). Post hoc comparison showed that mice injected with ST-1283 spent significantly less time digging than controls (Pɢ.048). However, acute injection of RAMH reversed the effect of ST-1283 (Pɢ.045).

RAMH blocked ST-1283-attenuated depression-like behavior in mice

To examine further the role of H3R in the behavioral effects of ST-1283, we investigated whether RAMH could block the effects of ST-1283. The immobility time in the TST for animals treated with ST-1283 with or without RAMH is shown in Figure 6A. One-way analysis of variance showed that there was a main effect of treatment (F(2,18) ɧ.502, Pɢ.014). Post hoc analysis indicated a significant decrease in immobility time elicited by administration of ST-1283 7.5 mg/kg (Pɢ.021). In contrast, pretreatment with RAMH significantly increased the amount of immobility time in the TST as compared with the group treated with ST-1283 alone (Pɢ.036).

Figure 6 Effects of acute RAMH pretreatment on ST-1283-induced antidepressant effects in the TST, feeding latency and food intake in the NSF, and FST.
Notes: *Denotes significant differences between ST-1283 and saline controls (Pɘ.05) # denotes significant differences between RAMH and ST-1283 (Pɘ.05). Vehicle nɩ ST-1283 7.5 mg/kg nɨ, RAMH nɪ. Data are shown as the mean ± standard error of the mean.
Abbreviations: RAMH, R-α-methylhistamine FST, forced swim test NSF, novelty suppressed feeding TST, tail suspension test.

Novelty suppressed feeding

The effects of acute ST-1283 with and without RAMH treatment were tested in C57BL/6 mice using the NSF test. One-way analysis of variance revealed a significant effect of drug treatment (F(2,18) ɧ.841, Pɢ.011) on feeding latency (Figure 6B). Bonferroni post hoc evaluation indicated that, compared with vehicle, acute intraperitoneal administration of ST-1283 7.5 mg/kg reduced the latency to feed in the NSF test (Pɢ.014). These effects of ST-1283 were completely blocked by RAMH (Pɢ.041), with a similar magnitude of effect to that seen in the vehicle group (Pɣ.000). Home cage feeding was assessed for each mouse by returning it to its familiar environment immediately after the NSF test and measuring the amount of food consumed over a period of 5 minutes. As depicted in Figure 6C, acute administration of ST-1283 alone or with RAMH had no effect on home food consumption (F(2,18) ɢ.985, Pɢ.393).

The findings of the FST are shown in Figure 6D. One-way analysis of variance revealed that the drug treatments had a significant effect on time spent immobile (F(2,18) ɨ.261, Pɢ.009). Post hoc comparison showed that, as expected, ST-1283 7.5 mg/kg significantly decreased immobility time (Pɢ.009 versus vehicle). These effects of ST-1283 were completely blocked by RAMH (Pɢ.049), with no significant difference in behavior found between the RAMH and vehicle groups (Pɣ.000).

An extensive in vivo pharmacologic and behavioral evaluation was performed and clearly indicated the efficacy profile of the H3R antagonist ST-1283 in animal models of anxiety and depression. To the authors’ knowledge, these studies provide the first evidence that an H3 antagonist belonging to the non-imidazole class has anxiolytic-like and antidepressant-like effects. In consideration of anxiolytic-like effects, our major finding was that acute blockade of H3Rs altered anxiety-like behavior in the EPM mouse model. At a dose of 7.5 mg/kg, ST-1283 significantly increased the percentage of time spent in the open arms of the maze. The number and percentage of open arm entries were also significantly increased in response to treatment with ST-1283. Typically, in studies based on EPM, either the number of open arm entries or the percentage of time spent or both have been taken into consideration. 28󈞊 When both parameters were included, the anxiolytic-like action of ST-1283 was only evident at a dose of 7.5 mg/kg and was significantly higher when compared with the 5 mg/kg dose. Interestingly, our results showed that both ST-1283 7.5 mg/kg and diazepam 1 mg/kg did not change the number of entries into the closed arms, thereby excluding the possibility of artifactual changes in general behavior or activity following pretreatment with ST-1283 as compared with saline pretreatment. The suggestion that the changes are associated with anxiolytic-like effects is consistent with previous experimental results indicating that H3 −/− knockout mice show fewer anxiety-like effects in the EPM model. 31 However, our results are in conflict with those of a recent study by Mohsen et al who reported that the specific H3R antagonist JNJ-10181457 (10 mg/kg) was anxiogenic when C57BL/6 mice were tested in the elevated zero maze. 32 The discrepancy between these studies regarding the effect of H3R antagonists could be explained by differences in procedure (EPM versus elevated zero maze) and mouse age (14 weeks versus 7 weeks). It should be also emphasized that Mohsen et al used a repeated exposure approach whereby mice were first habituated to the maze on day 1 and tested in the presence of the H3R antagonist JNJ-10181457 24 hours later. 32 However, in our study, the mice were naïve to the EPM and were only tested once in the presence of the drug. Consequently, care should be taken with regard to such factors in future studies. It is clear that more research is required to determine further the reasons for the different observations with H3R antagonists regarding anxiety-like behaviors. Therefore, local stereotaxic injection of viral vectors to modulate H3R function in discrete brain regions is currently under consideration to test the impact of the H3R on emotion-related behavior.

Moreover, by testing in the EPM it is important to ensure that there are no differences in overall activity levels in the experimental groups, since reduced activity could otherwise wrongfully be interpreted as increased measures of anxiety. 29 Therefore, we investigated ST-1283 further in the mouse OFT model, and our results show that neither ST-1283 (5 mg/kg and 7.5 mg/kg) nor the reference anxiolytic drug diazepam (1 mg/kg) altered the total amount of line crossings when compared with vehicle. However, significant treatment differences were found for time spent in the center of the arena, with mice injected with the higher dose (7.5 mg/kg) but not the lower dose (5 mg/kg) showing higher scores than those injected with vehicle. Therefore, the results obtained clearly validate the anxiolytic-like behavior and at the same time exclude possible intrinsic impairment in spontaneous locomotor activity following treatment with ST-1283.

To examine further the possible effect of acute H3R blockade on anxiety-like behavior in the mouse, ST-1283 was tested in the MBT. Interestingly, the results for the MBT were consistent with those for the EPM and OFT, since only pretreatment with ST-1283 7.5 mg/kg significantly decreased the number of buried marbles and significantly shortened the digging duration, demonstrating the anxiolytic-like effects of ST-1283.

It is well known that both anxiety disorders and depressive disorders are highly prevalent and frequently comorbid conditions. Therefore, the antidepressant-like effect of pretreatment with ST-1283 (5 mg/kg and 7.5 mg/kg, intraperitoneally) was tested in the mouse TST, NSF, and FST models. Our results showed that acute H3R blockade significantly reduced immobility time and feeding latency when compared with vehicle. These results further support the role of H3Rs in neurobehavioral disorders and also corroborate the main conclusion of the current study, ie, that H3R blockade is associated with an antidepressant-like effect in mice. Importantly, the NSF test results showed that food intake was not altered following acute treatment with ST-1283 (5 mg/kg and 7.5 mg/kg) or with the reference drug fluoxetine (10 mg/kg, intraperitoneally). Further, the antidepressant-like activity observed for ST-1283 in the TST and NSF were confirmed by the mouse FST, and immobility time was significantly decreased when the mice were injected with 7.5 mg/kg. Interestingly, our results are in agreement with a previous study in which the H3R antagonist thioperamide (10 mg/kg, intraperitoneally) showed antidepressant-like effects in the mouse FST model. 33 Moreover, consistent with the antidepressant-like effect of ST-1283 observed in our study, the histamine-N-methyltransferase inhibitor, metoprine (2, 7, and 20 mg/kg, subcutaneously) and the histamine precursor L-histidine (500 and 1,000 mg/kg subcutaneously) also showed an antidepressant-like effect in an earlier study by Lamberti at al using the FST. 12

The mouse FST is normally used to assess potential antidepressant compounds based on the abilities of clinically effective antidepressants to reduce the immobility that animals typically display after active and unsuccessful attempts when exposed to inevitable stressors. 27 The FST is sufficiently specific, given that it discriminates antidepressants from neuroleptics and anxiolytics. 3,7 However, ligands enhancing locomotor activity may give rise to a false-positive effect in this test. 34,35 Therefore, the number of entries into the closed arms in the EPM test and the number of line crossings in the OFT were used as indicators of locomotor activity. Our results showed that ST-1283 at a dose of 7.5 mg/kg did not alter locomotor activity in mice. Thus, the anxiolytic and antidepressant actions observed for ST-1283 seem unlikely to be due to an increase in locomotor activity of the mice.

Interestingly, ST-1283 at a dose of 7.5 mg/kg exhibited both anxiolytic-like and antidepressant-like actions. However, the question remains as to the mechanism by which ST-1283 exerts these effects. At least part of the mechanism behind the ST-1283-induced anxiolytic and antidepressant effects appears to be associated with the inhibitory effect of ST-1283 on H3Rs and subsequently enhanced synthesis and release of histamine. Pretreatment with 10 mg/kg of the H3R agonist RAMH abrogated the anxiolytic-like effects observed for ST-1283 in the EPM, OFT, and MBT, without affecting the general activity of the treated mice. Moreover, the antidepressant-like behaviors observed for ST-1283 in the mouse TST, NSF, and FST were also blocked following administration of RAMH 10 mg/kg. Importantly, previous studies have shown that RAMH and immepip dihydrobromide, both H3R agonists, do not affect spontaneous locomotor activity, even at doses much higher than those in the pharmacologically effective range, suggesting that these H3 agonists do not induce hypolocomotion, which may result from suppression of histaminergic neurotransmission. 36,37 Moreover, previous studies have shown that anxiolytic drugs such as diazepam and buspirone (a serotonin 5-HT1A agonist) significantly inhibit brain histamine turnover in rodents. 38,39 Zolantidine, a central nervous system-penetrating H2R antagonist, was also found to amplify the anxiogenic-like effect induced by thioperamide, an imidazole-substituted standard H3R antagonist/inverse agonist, in the mouse light/dark box test. 40 These findings further corroborate the association of histaminergic neurotransmission with antianxiety-like and antidepressant-like behaviors. Further, the H3R subtype acts as a presynaptic autoreceptor and heteroreceptor primarily in the central nervous system, controlling the synthesis and release of histamine and modifying the release of several other neurotransmitters, eg, dopamine, serotonin, gamma aminobutyric acid, noradrenaline, and acetylcholine. 6,7 Therefore, further investigations are needed to clarify whether other monaminergic neurotransmitters are involved in the effects observed with ST-1283. Further, species differences in affinity for H3R between humans and mice have to be considered when evaluating the preliminary results obtained for ST-1283. 41 Moreover, anxiety-related behaviors were recently found to be mainly mediated via H2Rs, highlighting the potential importance of investigating the affinity of ST-1283 for H2Rs in humans and mice to further corroborate the results obtained in the current study.

The H3R antagonist ST-1283 appears to be an antidepressant compound with anxiolytic properties at the same dose level. The results of this study could lead to a search for a new group of antidepressant and anxiolytic compounds. However, the exact mechanisms by which H3R antagonists exert their action in animal models of anxiety and depression await full elucidation. Nonetheless, considerable experimental effort is still required to fully understand the mechanisms of the histaminergic interaction in anxiety and depression and to assess the potential utility of H3R antagonists/inverse agonists as therapeutic possibilities in the treatment of anxiety-like and depression-like disorders.

AB and BS were responsible for the study concept and design. AB contributed to the acquisition and analysis of the animal data. HS, BS, JSS, and MW were responsible for the generation, synthesis, and in vitro pharmacologic characterization of ST-1283. AB and BS drafted the manuscript. HS critically revised the manuscript. All authors critically reviewed the content of the manuscript and approved the final version for publication.

This work was supported by grants from the United Arab Emirates University (to AB and BS) and by the EU COST Actions (BM0806, BM1007, CM1103, and CM1207), Hesse LOEWE Schwerpunkte Fh-TMP, OSF and NEFF, the Else KrönerStiftung, TRIP, and the Deutsches Konsortium für Translationale Krebsforschung DKTK (to HS). The funders played no part in the study design, or in the collection, analysis, or interpretation of the data, writing of the report, or the decision to submit the paper for publication. The authors would like to thank Dr Essam Emam (Department of Medicine, Tawam Hospital, Al Ain, United Arab Emirates) for providing the diazepam used in this study, Mohamed Elwasila and Mohamed Shafiullah for their technical assistance, and Dr Mahmoud Hag Ali from the Central Animal Facility for his advice regarding veterinary care. The authors would also like to acknowledge Professor Keith Bagnall for his critical and careful proofreading.

The authors have no financial interests that might be perceived to influence the results or the discussion reported in this article.

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