Exploring psychotherapeutic issues and agents in clinical practice
The introduction of clozapine (Clozaril®) in 1989 ushered in the era of newer so-called second-generation antipsychotic drugs referred to as “atypical.” Based on perceptions of superior safety and broader clinical applications, the allure of prescribing atypical drugs is so great that recent generations of prescribers have little or no experience with the use of older drugs (Owens, 2012a,b).
Trifluoperazine (Tfp), a contemporary of the first antipsychotic drug chlorpromazine (Thorazine®), was developed in the mid-1950s and introduced in 1959 as an anxiolytic and antipsychotic agent (Phillipson, 1960). The drug is commonly known by its original trade-name Stelazine®. Although Stelazine is no longer manufactured under this name, it is available as a generic drug in the United States and around the world. I have used Tfp fairly often and colleagues wonder why I would use such an old drug. Am I behind the times, or is there a method to my madness? In this month's column, I describe some interesting things about Tfp.
Trifluoperazine for Anxiety and Depression
Most clinicians who have heard of Stelazine think of it as a treatment for schizophrenia, which is one of its indications approved by the U.S. Food and Drug Administration (FDA), but the drug also has an approved indication for non-psychotic anxiety. Extensive clinical studies of Tfp were performed beginning in 1957 (Phillipson, 1960). Controlled and open-label trials demonstrated efficacy for Tfp in patients with schizophrenia, severe persistent nausea and vomiting, and various forms of psychoneurosis. The category of psychoneurosis encompassed non-psychotic patients who experienced various maladaptive or reactive emotional states, such as anxiety, depression, or psychosomatic symptoms. The effective dose of Tfp for psychotic patients was 10 to 50 mg per day, whereas doses of 1 to 6 mg per day were used for psychoneurosis. Subsequent placebo-controlled studies demonstrated benefit for low-dose Tfp in the treatment of anxiety (Mendels et al., 1986; Weiss, 1977). The current FDA-recommended Tfp dose range is 15 to 40 mg per day for schizophrenia and 1 to 6 mg per day for non-psychotic anxiety.
Borderline personality disorder is characterized by labile affective symptoms (e.g., depression, anxiety, rage, dysphoria), cognitive disturbances (e.g., brief psychosis, interpretive distortions), and behavioral dyscontrol. Cowdry and Gardner (1988) conducted a series of sequential 6-week, double-blind, placebo-controlled, crossover trials of alprazolam (Xanax®), carbamazepine (Tegretol®), Tfp, and tranylcypromine in 16 women with borderline personality. Tfp was used in doses of 2 to 12 mg per day (average dose = 7.8 mg per day). Tranylcypromine and carbamazepine trials had the highest completion rates. Physicians rated patients as significantly improved relative to placebo while receiving tranylcypromine and carbamazepine. Patients rated themselves as significantly improved relative to placebo only while receiving tranylcypromine. Patients who tolerated a full trial of Tfp (for >3 weeks) showed significant improvement on physician-rated anxiety and suicidality and patient-rated depression, anxiety, and rejection sensitivity. All other ratings showed favorable, but nonsignificant changes for Tfp versus placebo. Those receiving carbamazepine demonstrated a marked decrease in the severity of behavioral dyscontrol, and those receiving alprazolam had an increase in the severity of episodes of serious dyscontrol (Cowdry & Gardner, 1988).
Today, adding atypical antipsychotic drugs to antidepressant medications is a common clinical practice for treatment-resistant depression, and some of these uses are FDA approved (i.e., aripiprazole [Abilify®], quetiapine [Seroquel®], brexpiprazole [Rexulti®], and olanzapine [Zyprexa®]). Interestingly, Tfp was also introduced as part of a combination product containing the monoamine oxidase inhibitor antidepressant tranylcypromine (Parnate®) in 1960. Each tablet contained 1 mg of Tfp and 10 mg of tranylcypromine. Up to four tablets per day were used. This combination product, known as Parstelin®, was found to be rapidly and highly effective for treating depression, including patients who had shown a poor response to other therapies (Hemphill & Foster, 1962; Straker, 1960). The manufacture of Parstelin was discontinued in 1999, but tranylcypromine-Tfp is still available in Argentina (known as Cuait-D) and Italy (known as Parmodalin).
Trifluoperazine and P-Glycoprotein Inhibition
P-glycoprotein 1 (Pgp), also known as MDR1 (multidrug resistance protein 1) or ABCB1 (ATP-binding cassette sub-family B member 1), is a cell membrane protein that operates as an efflux pump transporting organic compounds from inside to outside the cell. Pgp is widely distributed in many cell types, including intestine, liver, kidney, and capillary cells of the blood–brain barrier (BBB). The BBB is a major impediment to the entry of many drugs into the brain, partly because drugs that are Pgp substrates are extruded from the brain across the BBB (Linnet & Ejsing, 2008).
Some psychotropic drugs, including many antidepressant agents, are substrates for Pgp (O'Brien, Dinan, Griffin, & Cryan, 2012). There is developing evidence from preclinical studies that Pgp efflux of antidepressant agents may be clinically relevant. Increased Pgp-mediated efflux of antidepressant agents at the BBB may result in reduced brain drug concentrations and decreased antidepressant-like activity in animals (O'Brien, Clarke, Dinan, Cryan, & Griffin, 2013). Administering Pgp inhibitor drugs together with antidepressant drugs may be a novel therapeutic approach for improving treatment response (O'Brien et al., 2012). For example, the cardiovascular drug verapamil (Calan®) is a Pgp inhibitor and has been used anecdotally to augment antidepressant agents in treatment-resistant depression (Clarke, O'Mahony, Cryan, & Dinan, 2009). Other Pgp inhibitors have not as yet been used in this way in humans.
Tfp also inhibits Pgp (Silva et al., 2015). Given the long clinical use of Tfp in psychotic and non-psychotic patients since the late 1950s, it would be a more appropriate drug than verapamil to use for antidepressant augmentation. As described previously, the combination product tranylcypromine-Tfp has been used for the treatment of depression (albeit in a limited way) for more than 50 years. Tranylcypromine is not a substrate for Pgp; therefore, the clinical effect of this combination cannot be attributed to this mechanism. Controlled studies investigating the use of Tfp for antidepressant augmentation in treatment-resistant depression are warranted.
Trifluoperazine and Calmodulin Inhibition
The calcium ion acts as a global second messenger in cell physiology, and this role is mediated by intracellular proteins that sense calcium concentrations and subsequently regulate the activity of other proteins and enzymes (Audran et al., 2013). Calmodulin is the prototypical calcium sensor that has been widely studied in normal and abnormal physiological states. Regulation of calmodulin is important for understanding cellular proliferation, inflammation, neurodegeneration, and other pathological processes. Tfp is an extensively studied drug molecule that has been used as a calmodulin inhibitor (Feldkamp, Gakhar, Pandey, & Shea, 2015).
Because of its inhibitory effects on calmodulin, Tfp has been actively investigated in preclinical and clinical cancer research studies (Berchtold & Villalobo, 2014; Brosius et al., 2014). Tfp may also have neuroprotective effects in neurodegenerative conditions (Lauterbach, 2013). Calmodulin inhibitors, including Tfp, can ameliorate tissue damage due to ischemia/reperfusion in the heart, liver, and brain (Kuroda, Nakai, Kristian, & Siesjo, 1997). Tfp has been shown to decrease hyperalgesia and treat neuropathic pain (Molokie et al., 2014). Tfp also can reverse and prevent the development of analgesic tolerance to morphine (Tang, Shukla, & Wang, 2006).
Antipsychotic drugs differ in their pharmacological properties. They have a wide range of different and overlapping clinical and side effect profiles. Despite their contemporary reputation, atypical drugs as a group are no more efficacious, do not improve specific symptoms, have no clearly different side effect profiles, and are less cost-effective than the group of older typical antipsychotic drugs (Tyrer & Kendall, 2009). Nurses who do not know much about the older drugs should become familiar with them; those who have forgotten about them should become reacquainted (Owens, 2012a,b). My review of the past, present, and potential future use of Tfp is not exhaustive, but is intended to remind us that we should be grateful that this old drug is still alive.
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- Berchtold, M.W. & Villalobo, A. (2014). The many faces of calmodulin in cell proliferation, programmed cell death, autophagy, and cancer. Biochimica et Biophysica Acta, 1843, 398–435. doi:10.1016/j.bbamcr.2013.10.021 [CrossRef]
- Brosius, S.N., Turk, A.N., Byer, S.J., Longo, J.F., Kappes, J.C., Roth, K.A. & Carroll, S.L. (2014). Combinatorial therapy with tamoxifen and trifluoperazine effectively inhibits malignant peripheral nerve sheath tumor growth by targeting complementary signaling cascades. Journal of Neuropathology and Experimental Neurology, 73, 1078–1090. doi:10.1097/NEN.0000000000000126 [CrossRef]
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- Cowdry, R.W. & Gardner, D.L. (1988). Pharmacotherapy of borderline personality disorder. Archives of General Psychiatry, 45, 111–119. doi:10.1001/archpsyc.1988.01800260015002 [CrossRef]
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- Hemphill, R.E. & Foster, A.R. (1962). Parstelin in anxiety states and depression. Journal of the College of General Practitioners, 5, 238–245.
- Kuroda, S., Nakai, A., Kristian, T. & Siesjo, B.K. (1997). The calmodulin antagonist trifluoperazine in transient focal brain ischemia in rats: Anti-ischemic effect and therapeutic window. Stroke, 28, 2539–2544. doi:10.1161/01.STR.28.12.2539 [CrossRef]
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- Mendels, J., Krajewski, T.F., Huffer, V., Taylor, R.J., Secunda, S., Schless, A. & Melmed, A.S. (1986). Effective short-term treatment of generalized anxiety disorder with trifluoperazine. Journal of Clinical Psychiatry, 47, 170–174.
- Molokie, R.E., Wilkie, D.J., Wittert, H., Suarez, M.L., Yao, Y., Zhao, Z. & Wang, Z.J. (2014). Mechanism-driven phase I translational study of trifluoperazine in adults with sickle cell disease. European Journal of Pharmacology, 723, 419–424. doi:10.1016/j.ejphar.2013.10.062 [CrossRef]
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