583893

research-article2015

AOPXXX10.1177/1060028015583893Annals of PharmacotherapyKaminsky et al

Review Article

Alternate Routes of Administration of Antidepressant and Antipsychotic Medications

Annals of Pharmacotherapy 1­–10 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028015583893 aop.sagepub.com

Bonnie M. Kaminsky, PharmD1,2, Jolene R. Bostwick, PharmD1,2, and Sally K. Guthrie, PharmD1,2,3

Abstract Objective: To review the administration of antidepressant and antipsychotic medications via inhaled, intranasal, buccal, sublingual, transdermal, and rectal routes. Data Sources: A PubMed search was conducted for all data through March 31, 2015 to identify pertinent literature. Search terms included the generic name of each antidepressant and antipsychotic medication in combination with the following terms: alternate routes of administration, inhaled, intranasal, buccal, sublingual, transdermal, and rectal. Study Selection and Data Extraction: English-language case reports, studies, and reviews describing medication administration in human subjects were included. Data Synthesis: Commercially available products that use an alternative route of administration include loxapine for inhalation, asenapine for sublingual administration, and selegiline for transdermal administration. Case reports and studies describe intranasal, sublingual, and transdermal routes of administration of antipsychotic medications as well as buccal, sublingual, transdermal, and rectal administration of antidepressant medications. The concordance between the physicochemical properties possessed by some antipsychotic and antidepressant agents and the physicochemical properties required for nontraditional routes of administration suggest that administration via alternative routes may be feasible for some of these drugs. Further exploration of drug absorption via alternative routes in addition to consideration of patient and formulation factors may yield improvements in medication therapy for patients with psychiatric illnesses. Conclusions: For patients unable to tolerate oral or injectable therapy, administration of psychotropic medications via nontraditional routes may be feasible. The development of alternative routes of drug delivery could prevent discontinuation of needed medication therapy. Keywords antidepressants, antipsychotics, psychotropics, pharmacokinetics, and drug delivery Advances in available drug formulations and alternate routes of administration may improve patient medication therapy through multiple mechanisms. Drug formulations may be utilized to develop targeted therapy, and alternate routes may serve to enhance patient convenience, adherence, and comfort.1 For medications in the antidepressant and antipsychotic drug classes, the development of extended or controlled release oral products, orally disintegrating tablets (ODTs), and long-acting injectable products has increased treatment options.2-4 However, these formulations still require that patients tolerate the traditional routes of oral and injectable administration. Although oral and injectable routes of drug delivery are relatively well tolerated and result in therapeutic management, they are not practical or feasible in certain patient populations. Patients unable to receive oral therapy may include those who are unconscious, have difficulty swallowing medications, or have gastrointestinal abnormalities or patients requiring bowel rest. Furthermore, intravenous

or intramuscular administration of medications is not available for all medications and may not be the optimal choice in certain situations. Alternative routes of drug administration would allow maintenance of drug therapy in patients when the inability to tolerate traditional drug formulations might otherwise necessitate discontinuation of the drug. Consequently, the development and use of alternative routes of administration for therapeutic drug delivery of psychotropic agents is highly desirable.

1

University of Michigan Health System, Ann Arbor, MI, USA University of Michigan College of Pharmacy, Ann Arbor, MI, USA 3 University of Michigan Medical School, Ann Arbor, MI, USA 2

Corresponding Author: Bonnie M. Kaminsky, Department of Pharmacy, University of Michigan Health System, Victor Vaughan House, Room 322, 1111 E Catherine St, Ann Arbor, MI 48109, USA. Email: [email protected]

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TableI 1.  Commercially Available Antidepressant Drug Formulations.5

Drug

Oral Tablet/ Capsule

Amitriptyline

X

Bupropion

X

Citalopram

X

Desipramine

X

Oral Extended/ Delayed Release Tablet/Capsule

Topical Cream

Transdermal Patch  

X

  X

   

Desvenlafaxine Doxepin

Oral Solution/ Suspension/ Syrup

X X

  X

Duloxetine

X

Escitalopram

X

Fluoxetine

X

Xa

Fluvoxamine

X

X

Imipramine

X

Isocarboxazid

X

X

   

X

 

X

       

Levomilnacipran

X

 

Milnacipran

X

 

Mirtazapine

X

b

 

Nortriptyline

X

Paroxetine

X

Phenelzine

X

X

X

 

X

   

b

X

Selegiline

X

Sertraline

X

Tranylcypromine

X

Trazodone

X

Vilazodone

X

 

Vortioxetine

X

 

Venlafaxine

X

X

   

X

 

X

 

a

Once-weekly extended release capsule. Also available as an oral disintegrating tablet.

b

Currently Available Products The available dosage forms for antidepressants and antipsychotics that are listed in the FDA Orange Book are summarized in Tables 1 and 2.5 Therapeutic advances have occurred, particularly in the antipsychotic medication class, through the development of various oral and long-acting injectable medication formulations. However, despite the variety of commercially available drug preparations, there remains a lack of drug delivery options for patients unable or unwilling to accept oral or injectable therapies.

Alternative Routes of Administration The opportunity for the development of alternative treatment options exists for drugs possessing the pharmacokinetic and

physicochemical properties that allow for efficient provision of drug via inhaled, intranasal, buccal, sublingual, transdermal, or rectal routes of administration. The optimal properties required for these routes and considerations for drug administration have been previously described.6 Relevant drug properties for absorption via each of these routes include the degree of lipophilicity (log P) needed to promote adequate drug absorption and the acid dissociation constant (pKa) that would most favorably affect the drug ionization at the site of drug delivery. Drug properties for antipsychotic and antidepressant medications are summarized in Tables 3 and 4.6-8 Theoretically, based on these chemical properties, several of the medications could be administered via alternative routes. Despite this, the literature surrounding the use of alternative routes of administration for these medications remains sparse. This article will describe pharmacokinetic

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Kaminsky et al Table 2.  Commercially Available Antipsychotic Dosage Forms.5

Drug Aripiprazole

Oral Tablet/ Capsule

Oral Extended Release Tablet/ Capsule

Sublingual Tablet

Powder for Inhalation

Oral Solution/ Suspension/ Syrup

ShortActing Injection

Long-Acting Depot Injection

X

X

X

Xa

Asenapine

X

 

Chlorpromazine

X

X

Clozapine

Xa

X

Fluphenazine

X

X

X

X

Haloperidol

X

X

X

X

Iloperidone

X

Loxapine

X

Lurasidone

X

Olanzapine

a

 

  X

   

X

Paliperidone

 

X X

X X

Perphenazine

X

 

Pimozide

X

 

Quetiapine

X

Risperidone

Xa

Thioridazine

X

 

Thiothixene

X

 

Trifluoperazine

X

 

Ziprasidone

X

X

  X

X

X

X

 

a

Also available as an oral disintegrating tablet.

and physicochemical properties required for alternative routes of administration in addition to summarizing current evidence regarding their use in the delivery of the antidepressant and antipsychotic medication classes.

Methods Relevant evidence included in this review was identified through an English-language literature search of the PubMed database for all data through March 31, 2015. Search terms included the generic name of each compound identified in the antidepressant and antipsychotic medication classes listed in Tables 1 and 2 in combination with the following terms: alternate routes of administration, inhaled, intranasal, buccal, sublingual, transdermal, and rectal. All case reports, trials, and reviews matching search criteria were identified and those that described medication use in human subjects were selected for inclusion.

Inhalation The administration of drugs via the lungs is a well-established route, in particular for local therapeutic effects in disease states of the pulmonary system. However, because of the large surface area of the lungs and the good relative permeability of vasculature, inhaled drug administration has been identified as a potentially beneficial route for systemically acting medications. Absorption via this route is most rapid and results in highest bioavailability with smaller, lipophilic compounds. In general, a dose of approximately 20 mg may be administered via inhalation. Ideal properties of drugs administered via this route include a molecular weight of less than 10 000 g/mol, a log P of −1 to 2, and a pKa of 4 to 9.6 However, several challenges exist in developing a drug formulation for administration via the lungs. The drug’s absorption must not be subject to significant interference by mucociliary clearance, lung surfactants, enzymatic degradation, or macrophage uptake. Furthermore, the drug delivery system used for inhaled

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Table 3.  Physicochemical Properties of Antidepressant Medications.6-8 Drug Amitriptyline Bupropion Citalopram Desipramine Desvenlafaxine Doxepin Duloxetine Escitalopram Fluoxetine Fluvoxamine Imipramine Isocarboxazid Levomilnacipran Milnacipran Mirtazapine Nortriptyline Paroxetine Phenelzine Selegiline Sertraline Tranylcypromine Trazodone Vilazodone Vortioxetine Venlafaxine

Usual Adult Oral Daily Dose

Molecular Weight of Parent Molecule

Log Pa

Basic pKaa

75-300 mg 150-450 mg 20-40 mg 75-300 mg 50-100 mg 75-300 mg 40-60 mg 10-20 mg 20-80 mg 50-300 mg 75-300 mg 20-60 mg 40-120 mg 100-200 mg 15-45 mg 50-150 mg 20-50 mg 45-90 mg 5-30 mg 50-200 mg 30-60 mg 50-400 mg 40 mg 10-20 mg 75-375 mg

277.4 239.7 324.4 266.4 263.4 279.4 297.4 324.4 309.3 318.3 280.4 231.3 246.4 246.4 265.4 263.4 329.4 136.2 187.3 306.2 133.2 371.9 441.5 298.5 277.4

4.77 3.12 3.72 3.85 2.80 3.91 3.85 3.72 4.03 2.55 4.39 1.16 1.29 1.29 3.09 4.24 3.23 0.92 3.79 5.00 1.19 2.42 4.54 4.50 3.02

9.18 7.16 9.57 10.4 9.33 9.19 10.02 9.57 10.05 9.39 9.49 3.32 10.36 10.36 8.1 10 9.68 8.02 7.53 9.47 8.24 7.52 Nonionizable 8.85 9.27

Possible Alternative Formulationsb SL SL, TD Nasal, SL None likely Nasal, SL Nasal, SL None likely Nasal, SL None likely Nasal, SL None likely None likely None likely None likely Nasal, SL, TD None likely Nasal, SL Inhalation Nasal, SL, TD None likely Inhalation, Nasal Nasal, SL, TD TD None likely Nasal, SL

Abbreviations: SL, sublingual; TD, transdermal. a Log P presented as the predicted log P. Basic pKa presented as predicted pKa. b Nasal (maximum dose 20 mg), inhalation (maximum dose ~20 mg); SL (maximum dose 20-30 mg); TD (maximum dose 10-20 mg).

Table 4.  Physicochemical Properties of Antipsychotic Medications.6-8 Drug Aripiprazole Asenapine Chlorpromazine Clozapine Fluphenazine Haloperidol Iloperidone Loxapine Lurasidone Olanzapine Paliperidone Perphenazine Pimozide Quetiapine Risperidone Thioridazine Thiothixene Trifluoperazine Ziprasidone

Usual Adult Oral Daily Dose 10-30 mg 10-20 mg (SL only) 50-300 mg 12.5-900 mg 1-40 mg 0.5-30 mg 2-24 mg 20-250 mg 20-160 mg 5-20 mg 6-12 mg 4-64 mg 2-10 mg 300-800 mg 2-8 mg 50-800 mg 6-60 mg 4-40 mg 40-160 mg

Molecular Weight of Parent Molecule 448.4 285.8 318.9 326.8 437.5 375.9 426.5 327.8 492.7 312.4 426.5 404 461.6 383.5 410.5 370.6 443.6 407.5 412.9

Log Pa

Basic pKaa

Possible Alternative Formulationsb

5.0 3.88 4.74 3.42 4.44 3.89 4.02 3.43 4.9 2.69 2.53 4.16 5.52 2.66 3.32 5.56 3.53 4.98 4.26

7.67 9.5 9.41 7.33 7.39 8.04 8.43 7.32 8.25 7.78 8.07 7.39 9.26 6.74 8.07 9.84 7.62 7.66 8.25

TD Nasal, SL None likely Nasal, SL, TD Nasal, SL, TD Nasal, SL, TD Nasal, SL, TD Nasal, SL, TD TD Nasal, SL, TD Nasal, SL, TD Nasal, SL, TD None likely Nasal, SL, TD Nasal, SL, TD None likely Nasal, SL, TD Nasal, SL, TD Nasal, SL, TD

Abbreviations: SL, sublingual; TD, transdermal. a Log P presented as the predicted log P. Basic pKa presented as predicted pKa. b Nasal (maximum dose 20 mg), inhalation (maximum dose ~20 mg); SL (maximum dose 20-30 mg); TD (maximum dose 10-20 mg).

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Kaminsky et al drug delivery must have the appropriate particle size and molecular weight. Drug solubility and lung disease may also affect drug absorption.9 Drugs administered via this route may result in bronchospasm and may not be appropriate for patients with lung disease.4 Patient administration technique and reproducibility of drug delivery also warrant careful consideration with the development of drug formulations for pulmonary delivery. Currently, the only psychotropic medication available for administration via oral inhalation into the lungs is the first-generation antipsychotic loxapine. Loxapine for inhalation (ADASUVE) is marketed for the acute treatment of agitation associated with schizophrenia and bipolar I disorder. A 10 mg dose is contained within a single-use, disposable inhaler, with an indicator light that confirms dose delivery. In clinical trials, reduction in agitation with inhaled loxapine resulted in clinical improvement within 10 minutes of the initial dose, and the most common adverse effects were dysgeusia and sedation.10,11 Because of the risk for bronchospasm and related complications, inhaled loxapine is only available through a Risk Evaluation and Mitigation Strategy program. This program restricts the use of inhaled loxapine to enrolled health care facilities that have the capability to manage bronchospasm, including the ability to provide advanced airway management (intubation and mechanical ventilation).12

Intranasal Drug administration via the nasal cavity is capable of providing rapid drug absorption and therapeutic effects. Absorption through the nasal passages bypasses the gut and also allows transport of drugs into the central nervous system via the olfactory and trigeminal nerve pathways.13-15 Intranasal administration can be used to deliver doses of up to approximately 20 mg, with volumes up to 150 µL per actuation. Ideal drug characteristics for administration via this route include a molecular weight less than 1000 g/mol, a log P of 1 to 4, and pKa of 4 to 9.6 Whereas intranasal administration avoids systemic dilution and first-pass metabolism, drug absorption via this route can be limited by low lipophilicity, enzymatic degradation within the nasal cavity, large molecular size, and rapid mucociliary clearance from the nasal passages.16 The potential for irritation and unpleasant odor of either the drug itself or inactive excipients are also important factors that need to be considered when developing drugs for administration via this route.15 Although there is currently no information about the use of any intranasal antidepressant, a small pharmacokinetic study has examined the potential intranasal administration of the antipsychotic haloperidol. The crossover design included 4 healthy volunteers who received a single 2.5 mg dose of haloperidol administered via intravenous, intramuscular, and intranasal routes, with each dose separated by a

2-week washout period. Serial blood samples were obtained over the first 48 hours after administration. Intranasal haloperidol exhibited a peak concentration similar to that obtained by intramuscular administration, with mean time to peak concentration of 15 minutes compared with an intramuscular time to peak concentration of 30 minutes. In this study, intranasal drug administration had a relative bioavailability of 48.6% when compared with intramuscular administration. Adverse effects following intranasal administration included mild local irritation and watering eyes.17

Buccal Buccally administered drugs are absorbed through the lining of the cheek for either local or systemic effects. The bioavailability of some medications may be increased when administered via the oral cavity because they undergo less hepatic or gastrointestinal first-pass metabolism.18 Compared with sublingual tissue, buccal tissue is less readily permeable and results in slower absorption. If the medication can be retained in the buccal cavity, this route of administration could be used for sustained medication delivery. Medications with a long half-life and wide therapeutic range are best suited for buccal administration, and termination or a decrease in pharmacological effect can be accomplished through removal of the medication from this area. Consumption of food and drink shortly before or after the time of administration can affect drug absorption and therapeutic effects, necessitating patient adherence with appropriate administration.19 Additionally, although administration via this route represents a convenient and noninvasive method for medication delivery, patients must be able to maintain the drug in contact with the buccal tissue for therapeutic effect. When formulating a buccal product, attention must be paid to bitterness of taste or the propensity to cause gastric intolerance or nausea.20 Currently, there are no commercially available antipsychotic or antidepressant buccal formulations. This literature review identified a case report describing the use of buccal amitriptyline in an adult patient with short-bowel syndrome and depression. Amitriptyline tablets were crushed, and the patient was instructed to allow the drug to dissolve in her mouth to promote buccal absorption. Dosing was initiated at 25 mg nightly and titrated up to a daily dose of 125 mg. The amitriptyline and nortriptyline serum concentrations were measured to determine the extent of absorption. Treatment initially resulted in a supratherapeutic combined amitriptyline and nortriptyline concentration of 677 ng/mL. With downward dose titration to 75 mg daily, serum concentrations were maintained within a range of 53 to 223 ng/ mL. The authors also describe a decrease in the patient’s depression, suggesting that buccal administration may be a viable option for patients with erratic or inconsistent oral absorption.21

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Additionally, a study of selegiline ODT administration for buccal absorption described the potential feasibility of this route of administration for the treatment of depression. A total of 28 healthy individuals were enrolled in the study, which examined the tolerability and effects on monoamine oxidase-A (MAO-A) with high-dose selegiline ODT, a product currently marketed for the management of Parkinson’s disease, in comparison with the selegiline transdermal delivery system, a product currently marketed for the treatment of major depressive disorder. Participants were treated with the selegiline ODT formulation at doses of 2.5, 5, and 10 mg daily and were instructed to allow the medication to dissolve on the tongue and to avoid swallowing the formulation to increase the degree of buccal absorption. Treatment was continued for a period of 28 days. Brain MAO-A inhibition increased significantly from baseline with the 10 mg selegiline ODT dosage and was similar to the MAO-A inhibition that resulted with the selegiline transdermal delivery system. The results of this study indicate that further exploration of buccal delivery of selegiline is warranted.22

Sublingual With sublingual administration, the drug is placed between the tongue and the lower surface of the mouth. The sublingual mucosa is relatively permeable and provides access to an expansive network of capillaries, promoting rapid drug absorption.19 Sublingual administration avoids first-pass metabolism, and cessation of drug absorption can be easily achieved by removal of drug from the site of action.18,20 However, sublingual mucosa possesses greater permeability and salivary flow than buccal mucosa, so sublingual administration provides a more rapid and less sustained delivery of the drug.19 Sublingual drug delivery can be used to administer small doses, up to 20 to 30 mg per dose and small vehicle volumes of 500 µL or less. Ideal drug properties for sublingual administration include a molecular weight of less than 500 g/mol, a log P of 2 to 4, and a pKa of 4 to 9.6 As with buccal drug delivery, patient tolerability of taste or local irritation may limit sublingual medication administration. The second-generation antipsychotic asenapine (Saphris) represents the only FDA-approved sublingual dosage form for antipsychotic or antidepressant medications. The sublingual formulation of asenapine enhances drug bioavailability; the absolute bioavailability of asenapine is 35% with sublingual administration, compared with only 2% when taken orally.23 Sublingual asenapine administration provides greater bioavailability than oral, but the time to maximum serum concentration (Tmax) is still 1 hour. This delay in Tmax may be a result of asenapine rapidly moving into oral mucosal tissue, then more slowly partitioning into the systemic circulation.24 Absorption of asenapine is also affected

by oral intake, and the manufacturer recommends avoidance of both food and drink within a 10-minute period of drug administration.23 Although not commercially available as sublingual tablets, the administration of sublingual olanzapine and haloperidol has been described. One clinical study was conducted in 10 healthy volunteers and used a 3-way crossover design, with participants receiving olanzapine 5 mg oral tablets, 5 mg ODT administered in the standard fashion, and 5 mg ODT administered sublingually. The administration of olanzapine ODT via standard and sublingual routes resulted in earlier detectable serum concentrations compared with traditional oral tablets, with levels detected as early as 10 minutes after administration with ODT administration compared with 30 minutes after oral tablet dosing. Tmax was also reduced in both routes of ODT administration compared with standard oral tablet administration, with reported mean Tmax values of 3.47, 3.77, and 4.37 hours, respectively, for the oral ODT, sublingual ODT, and oral standard tablet. Also, sublingual administration of the ODT provided similar maximum plasma concentrations compared with oral tablets and standard administration of olanzapine ODT.25 Three reports describe the use of sublingually administered antipsychotics for the management of agitation in terminally ill patients. In one case report, a 64-year-old male patient received sublingual olanzapine ODT following a total gastrectomy and splenectomy. Both olanzapine ODT and an unspecified form of alprazolam were administered sublingually, and the treatment regimen was associated with clinical improvement in agitation, anxiety, and insomnia within 2 days of initiating treatment.26 A second case report describes the administration of high-dose olanzapine (formulation not specified) sublingually in a 63-year-old terminally ill patient with refractory agitated delirium. Sublingual olanzapine was initiated after treatment failure with several other agents, and improvement in agitation and level of sedation was described with therapy.27 The third report describes a comfort care kit containing haloperidol ampules that were designed for sublingual administration for agitation in terminally ill patients.28 These reports suggest the potential feasibility of using antipsychotic medications administered sublingually in end-of-life care. Finally, a case report describes the use of sublingual fluoxetine in 2 patients unable to be treated with oral antidepressant therapy because of gastrointestinal complications. The patients were treated with fluoxetine liquid (20 mg/5 mL) administered sublingually via dropper by a trained staff member. Fluoxetine was initiated at 10 mg daily and titrated up to 20 mg daily in both patients. Although the administration of up to 5 mL sublingually may prove difficult, in this case, serum levels of fluoxetine and its major metabolite norfluoxetine were within a therapeutic range by week 4 of treatment, and both patients were maintained on

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Kaminsky et al the sublingually administered antidepressant until transition to an oral formulation was appropriate.29

Transdermal Transdermal drug delivery devices have been developed for multiple medications. Advantages of transdermal drug administration include the avoidance of first-pass metabolism, the ability to provide controlled drug delivery over a longer period of time, and the ability to modify sites of drug delivery.30 Prior to systemic availability, transdermally administered drugs are released from the transdermal device, partition into subcutaneous tissue, diffuse into epidermal and dermal tissue, and drain into capillaries.6 Although removal of the delivery system will halt absorption, some drug will continue to be absorbed from the drug depot that has collected within dermal tissues.30 Transdermal application can only provide therapeutic effects for drugs with small doses, ideally those with therapeutic effects at a dose of 10 mg or less, and a larger application site is required for additional drug delivery.31 Necessary physicochemical properties of drugs administered via this route also include a molecular weight of less than 500 g/mol and a log P greater than 2 to 5; also, the drug needs to be in the nonionized state.6 This route is not associated with a rapid onset of action. However, it is potentially useful for drugs requiring a slow, sustained delivery. Additionally, because the stratum corneum acts as a significant barrier, the delivery of medications via the transdermal route requires ideal pharmacokinetic drug properties or the use of penetration enhancers. Finally, although transdermal drug delivery may provide a convenient route for patients because the patch application is noninvasive and can often reduce the frequency with which a drug needs to be taken, an important consideration with this route is the potential for skin irritation that sometimes requires the patch to be discontinued.6 The selegiline transdermal system (Emsam) is the only FDA-approved transdermal delivery formulation of an antidepressant drug. The selegiline patch is applied once daily for the treatment of major depressive disorder.32 Transdermal delivery avoids gastrointestinal tract exposure, which enhances the safety of the selegiline given at standard doses because it minimizes food-drug interaction risks associated with MAO inhibition in the gut. Thus, this route of administration provides a potentially beneficial treatment option for patients who require an alternative route of drug delivery for major depressive disorder.33 Transdermal administration of other antidepressant drugs, including fluoxetine, amitriptyline, and doxepin, has been described in the literature. A single case report examines the use of topical fluoxetine in an 8-year-old child who received treatment with a compounded formulation of fluoxetine 100 mg/mL in Lipoderm base. Prior to admission, 20 mg of fluoxetine was applied

to alternating wrists every morning, and treatment was continued during the inpatient stay. After 30 days of transdermal administration of fluoxetine in an inpatient setting, serum levels were drawn, and fluoxetine and norfluoxetine levels were undetectable.34 Topical application of amitriptyline has been described in a case report of a 42-year-old man with a history of depression and Crohn’s disease who did not tolerate treatment with intramuscular amitriptyline. In this case, 150 mg of amitriptyline was compounded in a lecithin organogel base and applied topically to the patient’s chest each night. Serum concentrations were determined to be within a therapeutic range of 50 to 250 ng/mL following 7 days of therapy, and the patient reported improvement in mood. However, the psychiatrist assessing the patient concluded that the patient did not respond adequately to the topical treatment.35 Doxepin is a tricyclic antidepressant with strong antihistaminergic activity, and topical doxepin 5% cream is commercially available for the treatment of pruritis.36 Because tricyclic antidepressants have also been effective in the treatment of neuropathic pain syndromes, topical doxepin administration has been examined in a 32-year-old patient with complex regional pain syndrome. The cream was applied to the left wrist, where the patient experienced chronic pain, twice daily and resulted in significant reduction of symptoms, including improvements in pain, allodynia, and discoloration.37 The use of doxepin for neuropathic pain was also examined in a randomized, placebo-controlled trial of topical doxepin, topical capsaicin, or a combination of the 2 agents. Patients enrolled in the study experienced symptoms of neuropathic pain that were unresponsive to codeine-containing analgesics or nonsteroidal anti-inflammatory drugs. Topical creams containing 3.3% doxepin, 0.025% capsaicin, a combination of the 2 agents, or a placebo aqueous cream were applied daily for 4 weeks, and pain was assessed daily. Following 2 weeks of treatment, all 3 treatment groups reported greater improvement in pain compared with placebo, with more rapid initial reduction in overall pain in the group treated with the combination product.38 Although these cases dealt with treatment of neuropathic pain, which may respond to lower antidepressant doses than depression, it is possible that a topical formulation could be used to treat depression. Two pharmacokinetic studies have evaluated the absorption of antipsychotic drugs from topical formulations. The administration of ABH gel (consisting of lorazepam, diphenhydramine, and haloperidol), an agent that is typically used for nausea in hospice care, was examined in a study of 10 healthy volunteers. A 1 mL dose, containing 2 mg of haloperidol, was applied to the wrists of volunteers, and serum concentrations were assessed over the first 240 minutes following drug administration. Haloperidol was not detectable in the serum over the measured time period.39

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Chlorpromazine absorption from gel formulation was assessed in 11 healthy volunteers who received topical chlorpromazine applied to the wrist. One volunteer received a 100 mg dose, and the remaining 10 received a 25 mg dose. Serum levels were assessed up to 4 hours after a single dose of the drug, and chlorpromazine was undetectable in all samples.40

Rectal The rectum represents the last 15 to 19 cm of the large intestine, and medications can be administered rectally as suppositories, enemas, or foams. Bioavailability of rectally administered medications is dependent on multiple factors, including the rate of drug dissolution, surface area over which the drug can be absorbed, the amount of nonionized drug at the site of absorption, and the retention time of the medication.20,41 Because of the variability of these factors, less predictable absorption is achieved with rectal compared with oral drug administration. However, rectal drug administration can result in reduced first-pass metabolism because approximately half of the drug dose will bypass the liver.42 Although this route represents a viable option for many medications, some patients prefer to avoid this route of administration; it can sometimes be difficult to retain the drug in the rectum long enough for absorption, and it can cause rectal irritation when used over prolonged periods of time.41,43 No commercially available rectal preparations exist for antidepressants or antipsychotics, but the use of rectally administered antidepressants has been described. One case report describes the use of trazodone suppositories in a patient requiring bowel rest postoperatively. Trazodone was administered rectally for 4 days prior to the resumption of oral dosing, and clinical improvement in mood and sleep was noted within 2 days of initiating treatment with the suppositories.44 A woman unable to receive oral therapy because of bowel obstruction was treated with 50 mg amitriptyline suppositories that were compounded from amitriptyline paste and cocoa butter and administered twice daily. Clinical improvement in sleeplessness, myoclonus, anxiety, nausea and vomiting, and dysphoria was noted within the first week of initiating therapy and was maintained with continued treatment.45 Although the authors described clinical improvement with rectally administered trazodone and amitriptyline in the cases described above, serum drug levels were not sampled in the individuals treated. However, in additional reports of doxepin and fluoxetine administration, serum levels were obtained during treatment with rectally delivered drug. In the first case, 4 patients with severe cancer-related pain received doxepin capsules inserted rectally, 2 at a time,

without the use of a suppository base. Serum concentrations were measured after 2 to 5 days of treatment at a consistent dose. According to the authors’ description, all patients experienced improvement in comfort. The patient receiving 25 mg daily dosing of rectal doxepin did not achieve therapeutic drug levels (150-500 µg/mL), but the patients receiving 50 mg twice daily and 50 mg 3 times daily achieved serum levels within or above the therapeutic range.46 The use of rectally administered fluoxetine has been more thoroughly characterized in both a case report and a bioavailability trial conducted in healthy volunteers. In the case report, the patient treated with rectal fluoxetine suffered from major depression but could not absorb oral medications because of the lack of a stomach and small intestine. Fluoxetine 20 mg in 30 mL of sterile water was administered as an enema once daily. Serum drug levels were measured. The therapeutic fluoxetine and norfluoxetine plasma ranges are not well established, but the authors described a therapeutic range defined as 30 to 40 ng/mL of fluoxetine and 37 to 43 ng/mL of norfluoxetine. The levels remained subtherapeutic during the 18 hours following administration. However, the authors commented that the patient experienced some improvement in mood. An attempt to increase serum levels through higher doses of medication was unsuccessful as a result of abdominal cramping.20 The bioavailability trial of rectal fluoxetine was conducted as a single-dose, crossover trial in 6 normal volunteers, comparing the rectal to oral administration of the marketed fluoxetine oral capsules. Each phase of the study lasted a month, and serum concentrations were measured serially over the first 24 hours and then over the 28 days postdose. The overall relative bioavailability of rectally administered fluoxetine in capsule form was determined to be 15%, and most patients in the study reported favorable tolerability of rectal treatment.47

Future Directions Despite the variety of oral and injectable formulations of antidepressant and antipsychotic medications, there is a lack of commercially marketed products for administration of these medications via alternate routes. Although the drugs within these 2 classes are generally small molecules, additional factors that need to be considered include lipophilicity, the fraction of drug ionization at the site of absorption, the amount of drug and volume of product that needs to be delivered, and the tolerability of the formulation. Based on the available literature concerning these drugs and their physicochemical properties, possible drug candidates for drug delivery via inhalation, nasal instillation, or sublingual or transdermal routes are identified and summarized in Tables 3 and 4. Because only the nonionized drug will be absorbed transdermally, a drug possessing a pKa of roughly 8.5 would likely be the upper limit that could be delivered

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Kaminsky et al via this route, because at a pH of 7, this drug would only be approximately 3% nonionized. We were not able to find specific information identifying optimal criteria for buccal or rectal drug formulations, although it is likely that criteria would be similar for sublingual and buccal formulations.

Conclusion Being able to provide nontraditional, alternate routes of administration of psychotropic drugs could greatly facilitate the provision of optimal patient care for those suffering from mental illness. Currently, there are few options for antidepressant or antipsychotic treatment via routes other than oral or injectable delivery. However, studies examining the delivery of these medications through inhaled, intranasal, buccal, sublingual, transdermal, and rectal routes suggest potential for future drug development. The development of alternative formulations of psychotropic medications would allow clinicians to treat those suffering from psychiatric diseases who cannot take oral or injectable forms of medications. Additionally, if such alternatives were available, the discontinuation of necessary drug therapy and the resulting decompensation of patients suffering from mental illness could be avoided. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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