Exploring psychotherapeutic issues and agents in clinical practice
Because of its pharmacology, the benzodiazepine drug oxazepam (Serax®) has a relatively favorable safety and abuse liability profile compared to other drugs in its class (Howland, 2016). The pharmacological effects of oxazepam also suggest a role for it in the treatment of substance abuse and depression, which I will review in this month's column.
Potential Therapeutic Use of Oxazepam for Substance Abuse
Although not all studies are in agreement (Lile, Stoops, Wagner, Glaser, & Rush, 2005), animal and human laboratory investigations have found that certain benzodiazepine drugs, including oxazepam, can inhibit the behavioral effects of psychomotor stimulant drugs (e.g., cocaine, amphetamine) and reduce drug-seeking or drug self-administration behaviors (Goeders, Clampitt, Keller, Sharma, & Guerin, 2009; Goeders & Goeders, 2004; Spence, Guerin, & Goeders, 2016). Spence et al. (2016) compared the discriminative stimulus effects of methamphetamine and cocaine by alprazolam (Xanax®) and oxazepam in rats, and found that oxazepam significantly attenuated the effect of both drugs, whereas alprazolam augmented the effect of methamphetamine and had no apparent effect on cocaine. Drug discrimination is a research procedure that evaluates the subjective effects of drugs in humans or animals. The differential discriminative effect between oxazepam and alprazolam in the study is consistent with their low and high abuse liabilities, respectively.
The relationship between stress, drug craving, and drug use relapse is well recognized, and this relationship has led to efforts to develop pharmacological interventions for treating drug use that work by modulating stress-response systems, such as the hypothalamic–pituitary–adrenal (HPA) axis (Guerin, Schmoutz, & Goeders, 2014). Cortisol is a glucocorticoid steroid hormone produced and released from the adrenal gland in response to stress. Oxazepam suppresses cortisol secretion in healthy individuals and patients with depression (Christensen, Lolk, Gram, & Kragh-Sørensen, 1992). Pretreatment with oxazepam, alprazolam, or chlordiaz-epoxide (Librium®), as well as other drugs that modulate HPA axis activity, can reduce drug self-administration in animal studies (Guerin et al., 2014; Schmoutz, Guerin, & Goeders, 2014).
Metyrapone (Metopirone®), a glucocorticoid biosynthesis inhibitor drug, has been demonstrated to reduce the psychomotor stimulant, reinforcing, and discriminative stimulus effects of cocaine in animal studies (Schmoutz, Guerin, et al., 2014). Of particular interest is that the combination of oxazepam and metyrapone has been shown in controlled studies to attenuate drug-seeking and drug self-administration of cocaine, methamphetamine, and nicotine in animals (Goeders et al., 2012; Keller, Cornett, Guerin, & Goeders, 2013; Schmoutz, Guerin, Runyon, Dhungana, & Goeders, 2015). A double-blind, placebo-controlled pilot study also found that this combination tended to attenuate cocaine craving and cocaine use in humans, especially in a high-dose group (Kablinger et al., 2012).
The attenuating effect of oxazepam/metyrapone on cocaine self-administration is demonstrated in animals whose adrenal glands have been removed, suggesting that the effect is not dependent on suppressing cortisol secretion (Guerin et al., 2014). In addition to suppressing cortisol synthesis, metyrapone increases the synthesis of neurosteroids via a mechanism outside of the adrenal gland (Schmoutz, Guerin, et al., 2014). Benzodiazepine drugs bind to the gamma-aminobutyric acid (GABA) receptor complex GABA-A, which mediates their anti-anxiety, sedative-hypnotic, and anticonvulsant effects. Neurosteroids also can positively modulate GABA-A receptor activity, and this can have antidepressant, anticonvulsant, anti-anxiety, and anti-stress effects (Reddy, 2010). Increased synthesis of GABA-active neurosteroids may be the mechanism by which metyrapone attenuates the effects of cocaine (Schmoutz, Guerin, et al., 2014; Schmoutz, Runyon, & Goeders, 2014).
In addition to binding to GABA-A receptors, oxazepam binds to the translocator protein (TSPO) in the brain (Howland, 2016). Activation of TSPO stimulates neurosteroid biosynthesis. Hence, the combination of oxazepam and metyrapone appears to have a synergistic effect on GABA-A receptors, TSPO, and the production of neurosteroids. Such a synergistic effect may explain the attenuating effects of oxazepam/metyrapone on drug-seeking and drug self-administration behaviors.
Oxazepam and the Treatment of Depression
Sleep disturbances and comorbid anxiety are commonly present in various subgroups of patients with depression (Howland et al., 2008; Jindal et al., 2003; Klein et al., 1999). Studies have demonstrated that insomnia increases the risk of new onset depression and the risk of recurrence of depression (Howland, 2011a). Patients with depression who experience insomnia are more likely to have suicidal thoughts than patients with depression without significant insomnia. Disturbed sleep also is associated with a less than optimal response to antidepressant medication.
Although some types of antidepressant drugs can improve sleep (Howland, 2011b), selective serotonin reuptake inhibitor drugs can interfere with sleep (Jindal et al., 2003). The co-administration of various benzodiazepine drugs or zolpidem (Ambien®) improves the sleep of patients with depression without impairing the antidepressant response (Howland, 2011a). A placebo-controlled study found that augmentation of fluoxetine (Prozac®) with eszopiclone (Lunesta®) improved sleep and resulted in a significantly greater antidepressant remission rate (Howland, 2011a).
Abnormal regulation of the HPA axis, leading to persistent elevations in cortisol levels, is implicated in the pathophysiology of depression (Sigalas, Garg, Watson, McAllister-Williams, & Ferrier, 2012). As described previously, oxazepam suppresses cortisol secretion in patients with depression and also binds to brain TSPO, which can stimulate the biosynthesis of neurosteroids having anti-depressant, anxiolytic, and anti-stress effects. These neurobiological effects suggest that oxazepam may be beneficial for treating anxious depression.
Many phenylpiprazine derivative drugs are marketed for depression, including vilazodone (Viibryd®), vortioxetine (Brintellix®), nefazodone (Serzone®), trazodone (Desyrel®, Oleptro®), aripiprazole (Abilify®), and brexpiprazole (Rexulti®). A double-blind, randomized study comparing oxypertine (i.e., a phenylpiperazine drug) to oxazepam in anxious depression demonstrated similar benefits for both drugs (Faidherbe, 1976). A double-blind, randomized study comparing the combination of oxazepam plus prolintane (i.e., a norepinephrine–dopamine reuptake inhibitor) to the tricyclic antidepressant opipramol found that both treatments were effective and well tolerated in patients with depression (Gmür & Angst, 1977). The combination of oxazepam and monoamine oxidase inhibitors was safe and effective among 1,600 patients with anxious depression (Bailey, Davies, & Morrison, 1981). In a randomized, double-blind treatment study of anxious depression, alprazolam and oxazepam were similarly effective at relieving anxiety, whereas alprazolam was somewhat more effective overall (Rimon et al., 1991). Better mood-elevating and anxiolytic effects were found for oxazepam compared to the psychotropic plant medicine kava in a placebo-controlled study (Sarris et al., 2012).
Alprazolam and clonazepam (Klonopin®) each have been demonstrated to have significant antidepressant effects in placebo-controlled studies (Howland, 2011a), but these benzodiazepine drugs have a greater abuse liability than oxazepam. Moreover, alprazolam and clonazepam have little binding affinity for TSPO, unlike oxazepam. Because GABA-active neurosteroids may attenuate drug-seeking and drug self-administration behaviors, oxazepam may have a lower abuse liability because of its TSPO-binding affinity. Judicious use of benzodiazepine drugs or other sedative-hypnotic agents can be beneficial for treating anxiety or insomnia in patients with depression, and can enhance the overall effectiveness of antidepressant drugs. Among benzodiazepine drugs, however, oxazepam may be a safer choice, especially when concerns exist for comorbid substance abuse.
Depression is an independent risk factor for the development of cardiovascular disease, including cardiac arrhythmias, and comorbid depression increases the morbidity and mortality of patients with pre-existing heart disease. Concerns have been raised for potential adverse cardiac effects of certain antidepressant drugs (Vieweg et al., 2012). TSPO is found in the heart, the expression of cardiac TSPO is altered by different stress conditions, and drugs binding to TSPO may have cardioprotective effects (Morin, Musman, Pons, Berdeaux, & Ghaleh, 2015). Whether oxazepam used alone or together with antidepressant drugs has a positive effect on cardiac function in patients with depression is an interesting question that should be studied.
Preclinical studies and some open-label and controlled clinical studies of drugs that directly suppress or inhibit HPA axis function, including metyrapone, have shown benefit for the treatment of depression (Sigalas et al., 2012). Because the combination of oxazepam and metyrapone has synergistic effects on GABA-A receptors, TSPO, and the production of neurosteroids, and because each drug can suppress cortisol secretion, an oxazepam/metyrapone combination product warrants investigation as an antidepressant therapy for depression, similar to its investigational use in cocaine-dependent patients (Kablinger et al., 2012). Patients in the study by Kablinger et al. (2012) had low baseline depression and anxiety ratings, but there was a non-significant trend toward improvement in mood and anxiety in the high-dose group compared to placebo.
Oxazepam not only has a reduced abuse liability, but may be potentially useful in the treatment of substance abuse, especially in conjunction with metyrapone. In addition, because of its pharmacological effects, oxazepam can be considered an appropriate medication for the treatment of depression. The oxazepam/metyrapone combination has been piloted in cocaine-dependent patients, and should be studied in patients with depression. Oxazepam has an interesting pharmacological and clinical profile that distinguishes itself from other benzodiazepine drugs. For this reason, it should be used more.
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