Psychopharmacology (2010) 211:113122 DOI 10.

1007/s00213-010-1874-z

ORIGINAL INVESTIGATION

Are the colors and shapes of current psychotropics designed to maximize the placebo response?
Arif Khan & Eswara Prasad Bomminayuni & Amritha Bhat & James Faucett & Walter A. Brown

Received: 23 February 2010 / Accepted: 20 April 2010 / Published online: 22 May 2010 # Springer-Verlag 2010

Abstract Rationale Patient expectations are an important aspect of the placebo response. Color and shape of a medication lead to perceptions that an agent is stimulating or calming, strong or weak. Objectives We assessed the degree to which central nervous system medications match the perceived drug action and thereby harness the placebo response. Methods We consulted the 2009 Physicians Desk Reference and recorded the formulation and color of each referenced dose of central nervous system therapeutics approved for sale in the USA. On the basis of the expectations they engender, orange, yellow, and red pills were categorized stimulating; green, blue, and purple pills calming. White and gray pills were considered neutral. Results The majority of the 176 unique doses that were included in the study were in tablet (55%) and capsule (33%) form. Stimulants (75%) were the only drug category
A. Khan (*) : E. P. Bomminayuni : A. Bhat : J. Faucett Northwest Clinical Research Center, 1951 152nd Pl NE #200, Bellevue, WA 98007, USA e-mail: akhan@nwcrc.net A. Khan Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA W. A. Brown Department of Psychiatry and Human Behavior, Brown University, Box G-BH, Providence, RI 02912, USA W. A. Brown Tufts University School of Medicine, Boston, MA 02111, USA

primarily formulated as capsules. Of the 176 unique doses included, 43% were stimulating, 23% calming, 23% neutral, and 12% were a formulation other than pill or capsule. There were no instances in which over 50% of the pills of an indication were stimulating or calming in color. Discussion Our study did not confirm the hypothesis that pharmaceutical companies color and formulate the shape of drugs to enhance the treatment response. In several instances, each approved dose of a given medication was a different color, and the majority of doses were in tablet form. Further research into the effect of different colors and formulations of medications on perceptions and efficacy evaluations should be considered. Keywords Drug . Antipsychotic . Antidepressant . Anxiolytic . Placebo-response . Colors

Introduction A portion of any drugs benefit comes from the placebo response. In some conditions (e.g., pain, depression, anxiety), half or more of a drugs benefit can be attributed to the placebo response (Khan et al. 2005; Ridgway et al. 2007). Although the mechanisms that underlie the placebo response are not fully understood, a number of processes that contribute to the placebo response have been identified. These include expectation, therapeutic alliance, classical conditioning, and regression to the mean (Frank and Frank 1991). Expectation plays a major part. What patients expect to experience as a result of treatment has a profound effect on what they actually do experience. For example, clinical trial design features associated with higher patient expectations for improvement (e.g., probability of randomization to drug

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arm, length of trial) have been shown to influence the placebo response (Khan et al. 2004; Rutherford et al. 2009). Lower likelihood of patient receipt of placebo is associated with higher expectation for the treatment and a higher treatment response, for those assigned to placebo as well as those assigned to drug. Expectations arise from multiple sources including general information about a treatments effects and, most importantly, what patients hear about treatment from a clinician. The physical properties of a medication can also create expectations. A series of studies have shown that perceptions of placebo medications vary based on the color of the pill (Buckalew and Coffield 1982a, b; Jacobs and Nordan 1979; Sallis and Buckalew 1984). As summarized in the review by de Craen et al. (1996), blue and green pills were perceived to have a depressant or calming effect, whereas red, orange, and yellow pills were perceived as stimulating. But the effects of these colors go beyond perception. Researchers have manipulated the pill color of ingested medications and placebos and identified trends similar to those noted above (Blackwell et al. 1972; Schapira et al. 1970). Schapira et al. noted that green oxazepam pills were rated more effective at treating anxiety than yellow or red pills whereas yellow pills were rated most effective at treating depression. Similarly, Blackwell et al. gave pink and blue placebo pills to medical students and found that the recipients of the pink pill reported more stimulating effects in contrast to those who received blue pills who reported more sedating effects. The shape of a medication also influences expectations. Central nervous system (CNS) therapeutics are formulated as oral solutions, tablets, transdermal patches, capsules, and injections. Research into the influence of shape on perceived strength of a medication has been conducted showing that capsules are perceived to be stronger than tablets (Buckalew and Coffield 1982a,b). The findings of Hussain (1972) supported these perceptions as patients given chloradiazepoxide in capsule form noted greater improvement of anxiety symptoms than did those given the same dosage in tablet. More recently, Fallowfield et al. (2005) reported that female breast cancer patients who preferred to receive endocrine therapy by injections rather than tablets more frequently mentioned adherence and efficacy as the reason for their preference as compared to those who preferred tablets over injections. Although both Fallowfield et al. and Duric et al. (2005) reported trends towards a higher percentage of patients favoring tablets over injections, close to 50% of patients in the Fallowfield et al. study who preferred tablets also mentioned missing doses on occasion. Paradoxically, as the number of approved medications has increased, there has been remarkably little additional research into the effect of increasing patient expectations

through drug color and formulation. In this context, we wondered to what extent the pharmaceutical industry has made use of the existing body of research. We, therefore, undertook a review of CNS agents currently for sale in the USA using the 2009 Physicians Desk Reference (PDR) (Thomson Reuters 2009). The research reviewed above suggests that pharmaceutical companies, by coloring medications to correspond with patients expectations, might enhance response to the drug. In fact, a study by de Craen et al. (1996) concluded that Dutch manufacturers of CNS drugs appeared to formulate pill colors to match medicinal action. We hypothesize that industry follows these guideline such that the colors of drugs will be designed to enhance their intended medicinal action. Stimulants and antidepressants will, therefore, be primarily bright in color. Medications with calming properties (anxiolytics, sedatives (and hypnotics), anti-panic, anti-mania, and anti-psychotic agents) will be primarily darker in color.

Methods Overview We consulted the PDR product category index (PCI) to identify approved doses of non-generic CNS medications: anxiolytics, antidepressants, anti-mania, anti-panic and antipsychotic agents, stimulants, and sedatives (and hypnotics). For each referenced dose, we identified the shape of the medication as formulated in an oral solution, tablet, transdermal patch, capsule, or injection. After recording the shape, we categorized each dose delivered in tablet or capsule form as stimulating, calming, or neutral. Inclusion criteria Each FDA-approved dose of non-generic CNS medication referenced in the PDR PCI was included in the study. In the case of medications approved for multiple CNS disorders, all doses were included under each disorder. Approved products not listed in the PCI were not included. For example, Risperidone was not referenced in the PCI and was, therefore, not included. Generic drugs brought to market after patent of approved agent expired were also excluded. Shape Prior to assessing color of medication, we noted the number of drug doses formulated as a liquid, tablet, transdermal patch, capsule, or injection. Doses prescribed as liquids, patches, or injections were not attributed a color category.

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Color coding Two authors (EB, JF) reviewed the 2009 PDR and recorded formulation and color of each pill. For referenced medications not pictured in the product reference guide, we consulted product labeling for a physical description of each approved dose. Each dose was classified into one of three expectancy categories: calming, stimulating, and neutral. Red, orange, and yellow were categorized stimulating; blue, purple, and green calming. Shades of white and gray were put into a separate neutral category. For two-colored capsules, the pill was categorized stimulating if either part of the pill was red, orange, or yellow; calming if either part of the pill was blue, purple, or green, and the other part was neutral. For each product, listed colors were recorded for all approved doses. Analysis of data Because of the categorical nature of the data, we used a descriptive approach during the analysis. Doses of drugs approved for multiple indications were included in each drug class for which they were approved; however, these doses were counted only one time for the sample totals. The number of doses of drugs for each indication as well as the number of unique doses included in the study was totaled. Percentages of stimulating, calming, or neutral tablets or capsules were calculated for doses approved for each indication as well as all of the unique doses.

doses), six anti-panic agents (21 doses), 11 anti-psychotics (45 doses), 12 anti-mania agents (43 doses), and 10 stimulants (43 doses). Tables in the Appendix present the list of medications included by indication, approved dose, formulation, and summary description of color. Investigator determined color expectancy (stimulating, calming, neutral) can also be seen in Tables in the Appendix. A total of 176 unique doses were included in the study (50 doses were approved for more than one indication). Of these 176 unique doses, 89% were formulated as capsules or tablets. As shown in Table 1, 43% of capsules and tablets were stimulating in color, 23% calming, and 23% were neutral. Tablets (53%) were more common than capsules (36%). Injections (5%), transdermal patches (4%), and oral solutions (3%) accounted for a small percentage of the doses. Figure 1 presents the percentages of CNS drugs for each included indication that were formulated as oral solutions, tablets, transdermal patches, capsules, or injections. The formulation of 32/43 (75%) stimulants was capsule. Stimulants were the only pill class with over 50% of the doses formulated as capsules. On the other hand, over 80% of sedatives were formulated as tablets whereas none of the sedatives were capsules. Figure 2 presents the percentages of CNS drugs that were stimulating, calming, or neutral capsules and tablets or other formulations. Fewer than 20% of drugs for each indication were formulated in shapes other than capsules or tablets. There were no instances in which greater than 50% of approved and referenced doses for any indication were stimulating or calming in color.

Results The 2009 PDR PCI referenced 16 antidepressants (48 doses), five anxiolytics (16 doses), seven sedatives (12

Discussion We set out to assess the degree to which CNS medication colors appear designed to enhance the expected medicinal

Table 1 Number (percentage) of stimulating, calming, and neutral pills by drug class Drug class Anti-anxiety Anti-depressant Anti-mania Anti-panic Anti-psychotic Sedative Stimulant Totalsa Doses 16 48 43 21 45 12 41 176 Red, orange, yellow (stimulating) 6 22 16 8 22 3 19 75 (38) (46) (37) (38) (49) (25) (46) (43) Blue, purple, green (calming) 8 10 10 6 7 4 11 40 (50) (21) (23) (29) (16) (33) (27) (23) White/gray (neutral) 1 10 13 6 8 3 7 41 (6) (21) (30) (29) (17) (25) (17) (23) Not tablet or capsule 1 6 4 1 8 2 4 20 (6) (12) (9) (5) (17) (17) (10) (11)

a Drugs approved for multiple indications counted once in column total. Bold denotes number (percentage) of doses corresponding with expected medicinal action

116 Fig. 1 Percentage of CNS drugs formulated as oral solutions, tablets, transdermal patches, capsules, and injections

Psychopharmacology (2010) 211:113122

action of the drug. We hypothesized that industry would utilize data from previous studies, indicating that the physical properties of a medication influence patient expectancies and may enhance medication response. To assess the degree to which the colors of these medications correspond with the intended drug effects, we first recorded the formulation of each dose. The majority (88%) of doses included in our study took the form of tablet or capsule and could be categorized as calming, stimulating, or neutral. Stimulants, which were 75% capsules, appeared to be formulated differently (and more strongly) than medications for all other indications. Antidepressants, sedatives, anti-psychotic, anti-mania, and anti-panic agents were all formulated more frequently as tablets. Injections (the strongest formulation) were available for only three out of seven drug classes included in our study.

Surprisingly, the colors of medications (tablet and capsule) did not appear to consistently correspond with intended medicinal action for any of the indications. In no instances did the colors of over 50% of any medications correspond with the expected drug action. In fact, doses of several medications were a variety of colors. For example, antidepressant buproprion doses are available in yellow, red, blue, purple, pink, and white tablets. Antidepressant/anxiolytic paroxetine is available in yellow, pink, blue, and green tablets and additionally as an oral solution. Anti-psychotic/anti-mania treatment aripiprazole doses come in green, blue, pink, yellow, and white tablets. These are but a few examples of medications with multiple doses made with different, sometimes contradicting, colors (see Appendix). Additionally, several medications are approved for multiple indications (i.e., fluoxetine, paroxetine, aripiprazole, olanzapine, ziprasi-

Fig. 2 Percentage of CNS drugs categorized as stimulating, calming, and neutral tablets or capsules

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done). None of the doses approved across indications were available in specific colors for an indication. To our knowledge, one other study has examined the relationship between the color of pills and the CNS indications which they treat. Although de Craen et al. (1996) concluded that Dutch manufacturers appeared to take CNS indication into account during pill manufacturing, 23 of the 49 pills included in the study were white. From this perspective, 50% or fewer of the 49 stimulants and antidepressants in the de Craen study were colored to correspond with the drug effect. Our study did not confirm the hypothesis that pharmaceutical companies factor patient expectancies into drug formulation by coloring pills to correspond with the drug action. This finding is surprising, considering that the placebo effect can account for a considerable portion of the drug response (Khan et al. 2005) and that research dating back to the 1970s has consistently shown that pill colors and shapes are associated with perceptions of medicinal effect and potency. Although the studies designed to assess the actual effect of pill colors and formulations on perceived drug efficacy have limitations, the trends identified are consistent. This regularity in the perceived effectand actual effectsof pills based on their color is consistent with the fact that colors have universal meanings and similar psychological associations across cultures. For example, red is regarded as strong and active, black as bad and strong, blue and green as good (Adams and Osgood 1973). Whether the universality of these attributes of color arises from innate physiological responses to these colors, shared environmental associations (e.g., blue sky and green plants are good, darkness is more dangerous than light) or common cultural beliefs is as yet unclear. What is clear is that the color of a pill creates expectations as to the effects that the pill will have on psychological state and that those expectations are generally consistent with the affective meaning of the color. Over the past two decades, the placebo response has evolved from being strictly a nuisance obscuring the evaluation of new treatments to being a phenomenon worthy of study in its own right. Research has identified some of the mechanisms behind the placebo effect and the processes that engender it. Recent studies have identified brain changes associated with the placebo effect (Leuchter et al 2002; Oken 2008). These findings have brought about a shift in beliefs about placebo. Symptomatic improvement with placebo can no longer be attributed simply to a patients imagination or desire to report what is expected. It seems that the response to a placebo is as authentic as the response to real treatment and involves some of the same physiological processes. Some researchers and clinicians are now

suggesting that rather than ignoring the placebo response, we should harness it to enhance the benefit of all treatments. Along these lines, further research into the perceived effect of different colored medications and formulations and the way that different colored medications and formulations influence drug efficacy seems warranted.

Appendix

Table 2 Dose, formulation, color, and expectancy of FDA-approved antidepressants referenced in 2009 Physicians Desk Reference product classification index Antidepressant Dose Shape/ formulation Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Oral Solution Tablet Tablet Tablet Tablet Capsule Capsule Capsule Transdermal Transdermal Transdermal Tablet Tablet Tablet Oral solution Capsule Capsule Tablet Capsule Capsule Capsule Color Expectancy

Buproprion

75 mg 100 mg Buproprion SR 100 mg 150 mg 200 mg Buproprion XL 150 mg 300 mg Citalopram 10 mg 10 mg 20 mg 40 mg Desvenlafaxine 50 mg 100 mg Duloxetine 20 mg 30 mg 60 mg Emsam Transdermal Escitalopram 6 mg 9 mg 12 mg 5 mg 10 mg 20 mg 5 mg/5 ml 20 mg 90 mg (weekly) 10 mg 3/25 mg 6/25 mg 6/50 mg

Yellow Red Blue Purple Pink White White Peach Pink White Pink Orange Green Blue/White Blue/Green White White White N/A Green/ White Green/ Transparent Orange Pink/Yellow Yellow Yellow/

Stimulating Stimulating Calming Calming Stimulating Neutral Neutral Stimulating Stimulating Neutral Stimulating Stimulating Calming Calming Calming Neutral Neutral Neutral Calming Calming Stimulating Stimulating Stimulating Stimulating

Fluoxetine

Isocarboxazid Olanzapine/ Fluoxetine

118 Table 2 (continued) Antidepressant Dose Shape/ formulation Color Expectancy

Psychopharmacology (2010) 211:113122 Table 4 Dose, formulation, color, and expectancy of FDA-approved sedatives referenced in 2009 Physicians Desk Reference product category index Sedative 12/25 mg Capsule 12/50 mg Capsule 15 mg Tablet 30 mg 45 mg 15 mg 30 mg 45 mg 10 mg 20 mg 30 mg 40 mg 5 mL Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Oral solution Tablet Tablet Tablet Capsule Capsule Capsule White Red/Yellow Red/White Yellow Red-Brown White White White White Yellow Pink Blue Green Orange Yellow Pink Blue Gray/Peach Peach Orange/ Orange Stimulating Stimulating Stimulating Stimulating Neutral Neutral Neutral Neutral Stimulating Stimulating Calming Calming Stimulating Stimulating Calming Stimulating Stimulating Stimulating Dose Shape/ formulation Tablet Tablet Tablet Tablet Tablet Injection Injection Tablet Tablet Tablet Tablet Tablet Color Expectancy

Bevitamel

Mirtazapine

Mirtazapine SolTab Paroxetine

400 1,000 mcg Diphenhydramine 25 mg Eszopiclone 1 mg 2 mg 3 mg Pentobarbitol 20 ml 50 ml Ramalteon 8 mg Zolpidem 5 mg 10 mg Zolpidem CR 6.25 mg 12.5 mg

Peach Stimulating Green Blue White Blue White Pink White Peach Blue Calming Calming Neutral Calming Neutral Stimulating Neutral Stimulating Calming

Paroxetine CR 12.5 mg 25 mg 37.5 mg Venlaxafine 37.5 mg XR 75 mg 150 mg

Table 5 Dose, formulation, color, and expectancy of FDA-approved anti-panic agents referenced in 2009 Physicians Desk Reference product classification guide Antipanic agent Clonazepam Dose Shape/ formulation Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Capsule Color Expectancy

Table 3 Dose, formulation, color, and expectancy of FDA-approved anxiolytics referenced in 2009 Physicians Desk Reference product classification index Anxiolytic Dose Shape/ formulation Tablet Tablet Tablet Capsule Capsule Capsule Capsule Capsule Tablet Tablet Tablet Tablet Oral Solution Capsule Capsule Capsule Color Expectancy

Clonazepam Wafers

Diazepam

Duloxetine

Fluvoxamine CR Paroxetine

2 mg 5 mg 10 mg 20 mg 30 mg 60 mg 100 mg 150 mg 10 mg 20 mg 30 mg 40 mg 10 mg 37.5 mg 75 mg 150 mg

White Yellow Blue Green Blue/White Blue/Green Blue/White Blue Yellow Pink Blue Green Gray/Peach Peach/Peach Orange/ Orange

Neutral Stimulating Calming Calming Calming Calming Calming Calming Stimulating Stimulating Calming Calming Stimulating Stimulating Stimulating

Fluoxetine

0.5 mg 1 mg 2 mg 0.125 mg 0.25 mg .5 mg 1 mg 2 mg 20 mg

90 mg (weekly) Paroxetine 10 mg 20 mg 30 mg 40 mg 10 mg Paroxetine CR 12.5 mg 25 mg 37.5 mg 37.5 mg 75 mg 150 mg

Orange Blue White White White White White White Green/ White Capsule Green/ White Tablet Yellow Tablet Pink Tablet Blue Tablet Green Oral Solution Tablet Yellow Tablet Tablet Capsule Capsule Capsule Pink Blue Gray/Pink Peach/ Peach Orange/ Orange

Stimulating Calming Neutral Neutral Neutral Neutral Neutral Neutral Calming Calming Stimulating Stimulating Calming Calming Stimulating Stimulating Calming Stimulating Stimulating Stimulating

Venlaxafine XR

Venlaxafine XR

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Table 6 Dose, formulation, color, and expectancy of FDA-approved anti-mania agents referenced in 2009 Physician Desk Reference product classification index Anti-manic agent Aripiprazole Dose 2 mg 5 mg 10 mg 15 mg 20 mg 30 mg 10 mg 15 mg 1 mg 9.75 mg 100 mg 200 mg 300 mg 250 mg 500 mg 25 mg 100 mg 150 mg 200 mg 2 mg 5 mg 25 mg 2.5 mg 5 mg 7.5 mg 10 mg 15 mg 20 mg 10 mg 5 mg 10 mg 15 mg 20 mg 3 mg/25 mg 6 mg/25 mg 6 mg/50 mg 12 mg/25 mg 12 mg/50 mg 20 mg 40 mg 60 mg 80 mg 20 mg Shape/formulation Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Oral solution Injection Capsule Capsule Capsule Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Injection Tablet Tablet Tablet Tablet Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Injection Color Green Blue Pink Yellow White Pink Pink Yellow White/Blue White/Blue White/Purple White Gray White Peach Cream Blue White White White White White White White Blue Pink Yellow Yellow Yellow Yellow Pink/Yellow Yellow/Yellow White/Yellow Yellow/Red Red/White Blue/White Blue/Blue White/white Blue/White Expectancy Calming Calming Stimulating Stimulating Neutral Stimulating Stimulating Stimulating N/A Calming Calming Calming Neutral Neutral Neutral Stimulating Neutral Calming Neutral Neutral Neutral Neutral Neutral Neutral Neutral Calming Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Calming Calming Neutral Calming

Aripiprazole Discmelt

Aripiprazole Intramus Carbamezapine ER

Divalproex ER Lamotrigine

Lamotrigine Chew

Olanzapine

Olanzapine IM Olanzapine Discmelt

Symbyax

Ziprasidone

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Table 7 Dose, formulation, color, and expectancy of FDA-approved antipsychotics referenced in 2009 Physicians Desk Reference product category index Antipsychotic Aripiprazole Dose 2 mg 5 mg 10 mg 15 mg 20 mg 30 mg 10 mg 15 mg 1 mg 9.75 mg 5 mg 10 mg 25 mg 50 mg 2.5 mg 5 mg 7.5 mg 10 mg 15 mg 20 mg 10 mg 5 mg 10 mg 15 mg 20 mg 3 mg 6 mg 9 mg 12.5 mg 25 mg 37.5 mg 50 mg 1 mg 2 mg 5 mg 10 mg 10 mg 25 mg 50 mg 100 mg 20 mg 40 mg 60 mg 80 mg 20 mg Shape/formulation Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Oral solution Injection Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Tablet Injection Tablet Tablet Tablet Tablet Tablet Tablet Tablet Injection Injection Injection Injection Capsule Capsule Capsule Capsule Tablet Tablet Tablet Tablet Capsule Capsule Capsule Capsule Injection Color Green Blue Pink Orange White Pink Pink Yellow Orange Pink White Purple White White White White Blue Pink Yellow Yellow Yellow Yellow White Yellow Pink Carmel/Blue Carmel/Yellow Carmel/White Carmel/Orange Orange Orange Orange Orange Blue/White Blue/Blue White/White Blue/White Expectancy Calming Calming Stimulating Stimulating Neutral Stimulating Stimulating Stimulating Stimulating Stimulating Neutral Calming Neutral Neutral Neutral Neutral Calming Stimulating Stimulating Stimulating Stimulating Stimulating Neutral Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Calming Calming Neutral Calming

Aripiprazole Discmelt

Aripiprazole Intra. Molindon

Olanzapine

Olanzapine IM Olanzapine Discmelt

Paliperidone ER

Risperidone Long Acting

Thiothixene

Thioridazine

Ziprasidone

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Table 8 Dose, formulation, color, and expectancy of FDA-approved stimulants referenced in 2009 Physicians Desk Reference product category index CNS stimulant Atomoxetine Dose 10 mg 18 mg 25 mg 40 mg 60 mg 80 mg 100 mg 5 mg 10 mg 15 mg 20 mg 5 mg 5 mg 10 mg 15 mg 20 mg 30 mg 40 mg 50 mg 60 mg 70 mg 5 mg 10 mg 15 mg 20 mg 25 mg 30 mg 18 mg 27 mg 36 mg 54 mg 10 20 30 40 50 60 10 15 20 30 mg mg mg mg mg mg mg mg mg mg Shape/Formulation Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Tablet Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Capsule Tablet Tablet Tablet Tablet Capsule Capsule Capsule Capsule Capsule Capsule Transdermal Transdermal Transdermal Transdermal Color White/White Orange/White Blue/White Blue/Blue Blue/Orange Orange/White Orange/Orange Blue Orange Green White Yellow Brown/Transparent Brown/Transparent Brown/Transparent Yellow/Yellow Orange/White Green/White Blue/White Blue/Blue Orange/Blue Gray/Orange Blue/Green White/Gray Orange/Orange White/Orange Orange/Orange Yellow Gray White Orange Green/White Blue/White Red/White Yellow/White Purple/White White Expectancy Neutral Stimulating Calming Calming Stimulating Stimulating Stimulating Calming Stimulating Calming Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Stimulating Calming Calming Calming Neutral Stimulating Calming Neutral Stimulating Stimulating Stimulating Stimulating Neutral Neutral Stimulating Calming Calming Stimulating Stimulating Calming Neutral

Dexmethylphenidate XR

Dextroamphetamine Dextroamphetamine Spanules

Lisdexamphetamine

Methamphetamine Salts XR

Methylphenidate ER

Methylphenidate CD

Methylphenidate Transdermal

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Psychopharmacology (2010) 211:113122 Jacobs KW, Nordan FM (1979) Classification of placebo drugs: effect of color. Percept Mot Skills 49:367372 Khan A, Kolts RL, Thase ME, Krishnan KRR, Brown W (2004) Research design features associated with the outcome of antidepressant clinical trials. Am J Psychiatry 161:20452049 Khan A, Kolts RL, Rapaport MH, Krishnan KRR, Brodhead AE, Brown W (2005) Magnitude of placebo response and drugplacebo differences across psychiatric disorders. Psychol Med 35:743749 Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M (2002) Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 159:122129 Oken BS (2008) Placebo effects: clinical aspects and neurobiology. Brain 131:28122823 Thomson Reuters (2009) Physicians Desk Reference, 63rd edn. Thomson Reuters, Montvale Ridgway D, Khan A, Cierpial MA, Lineberry CG (2007) Subject numbers and placebo outcome variability in clinical trials of new CNS medications. Drug Inf J 41:701708 Rutherford BR, Sneed JR, Roose SP (2009) Does study design influence outcome? The effects of placebo control and treatment duration in antidepressant trials. Psychother Psychosom 78:172 181 Sallis RE, Buckalew LW (1984) Relation of capsule color and perceived potency. Percept Mot Skills 58:897898 Schapira K, McClelland HA, Griffiths NR, Newells DJ (1970) Study on the effects of tablet colour in the treatment of anxiety states. BMJ 2:446449

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