The use of psychotropic medications has dramatically increased over the past two decades ( Pincus et al., 1998 ). In the United States, in 2005, people treated with antidepressants were approximately 27 million, as compared to 13.3 million in 1996, corresponding to an overall increase of 74% ( Olfson and Marcus, 2009 ). Recent available data (for calendar year 2009) indicate that total US retail prescriptions for psychotropic drugs exceeded US$380 million, corresponding to a net dollar cost of US$22 billion ( Greenblatt et al., 2011 ). The largest share of psychotropic drug prescriptions occurs at the primary care level ( Mojtabai and Olfson, 2008 ); usually for anxiety and depressive symptoms and their physical correlates ( Linden et al., 1999 ). Given the extensive use of these agents, carcinogenic risk should be carefully weighed when prescribing long-term drug therapies. From a public health perspective, even a small increased risk factor, when applied to a large population, will produce many preventable cases of disease ( Rose, 1981 ).

No data were available for some agents, mostly older drugs which entered the US market before current FDA efficacy and safety procedures were implemented in the 1960s and 1970s: amitriptyline, desipramine, nortriptyline (tricyclic antidepressants—TCAs); phenelzine, tranylcypromine (monoamine oxidase inhibitors—MAOIs); chlorpromazine (typical antipsychotic) and paliperidone (atypical antipsychotic); bromazepam, clonazepam (benzodiazepines) and chlordiazepoxide (sedative-hypnotic); dextroamphetamine, hydroxyamphetamine, methamphetamine (amphetamines); and lithium.

Data on carcinogenicity outcomes including tumor promoting activity and frequency of tumor incidence were retrieved from animal studies conducted in vivo. Descriptive analysis was carried out and findings pooled by drug class. The following drug categories were considered: antidepressants, antipsychotics, benzodiazepines/sedative-hypnotics, amphetamines and stimulants, lithium and anticonvulsants. For each drug, the number of studies reporting positive or negative risk of carcinogenicity was compiled ( Tables 1 – 5 ).

A systematic review of the FDA preclinical evidence was conducted to retrieve unpublished preclinical studies on carcinogenicity of the most common marketed psychotropic drugs. Data were obtained from the final package insert approved by the Center of Drug Evaluation and Research of the FDA and available on the official website of the FDA ( www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm347877.htm ).

Among anticonvulsants ( Table 5 ), 85.7% (6/7) of examined agents were associated with carcinogenicity, with 64.3% (9/14) of all studies being positive for carcinogenicity. The only agent not associated with carcinogenicity was lamotrigine. Specific agents associated with carcinogenicity were valproate, carbamazepine, gabapentin, pregabalin, oxcarbazepine and topiramate. No data were available for lithium in the FDA-based safety information.

Among amphetamines and stimulants ( Table 4 ), 25% (1/4) of examined agents were associated with carcinogenicity, with 10% (1/10) of all studies being positive for carcinogenicity. Only methylphenidate was associated with carcinogenicity, in one-third studies of that agent. Amphetamine salts, modafinil and atomoxetine were unassociated with carcinogenicity.

Among benzodiazepines and sedative-hypnotics ( Table 3 ), 70% (7/10) of examined agents were associated with carcinogenicity, with 55% (11/20) of all studies being positive for carcinogenicity. Specific agents associated with carcinogenicity were clonazepam, zolpidem, zaleplon, diazepam, eszopiclone, oxazepam and midazolam. Agents unassociated with carcinogenicity were lorazepam, alprazolam and triazolam.

If all examined psychotropic agents are combined, 71.4% (30/42) of agents had some preclinical evidence of carcinogenicity. Among antidepressants ( Table 1 ), 63.6% (7/11) of examined agents were associated with carcinogenicity, with 45% (9/20) of all studies being positive for carcinogenicity. Specific agents associated with carcinogenicity were mirtazapine, sertraline, paroxetine, citalopram and escitalopram, duloxetine and bupropion. Agents unassociated with carcinogenicity were fluoxetine, venlafaxine, trazodone and imipramine. Among antipsychotics ( Table 2 ), 90% (9/10) of examined agents were associated with carcinogenicity, with 69.6% (16/23) of all studies being positive for carcinogenicity. All agents were associated with carcinogenicity except clozapine.

Discussion

Among psychotropic drugs classes, new generation (atypical) antipsychotics and anticonvulsants showed the highest evidence of carcinogenicity, with almost all agents (with the exception of clozapine and lamotrigine) being carcinogenic in FDA-based preclinical studies. A majority of antidepressants (63.6%), benzodiazepines and sedative-hypnotics (70%) were also found to be carcinogenic. Among the amphetamines/stimulant drug class, only methylphenidate had some evidence of carcinogenicity. If all examined psychotropic agents are combined, about 71% of agents had some preclinical evidence of carcinogenicity.

These results need to be interpreted in the context of the standards of assessment of potential human carcinogenicity with animal-based studies, as well as available evidence in human studies. Each aspect, standards of study of animal carcinogenicity and human studies themselves, will be considered in turn.

Animal species and strains FDA preclinical in vivo studies to evaluate the carcinogenic potential of drugs are performed in mice and rats, in both sexes, and often extended over the average lifetime of the species (18 to 24 months for mice; 24 to 30 months for rats) (Hayes et al, 2011). To ensure that 30 rats per dose survive the 2-year study, 60 rats per group per sex are often started in the study. It is important to differentiate between different strains of rats and mice. As reported by recent National Toxicology Program (NTP) studies, Fisher 344 (F344) rats and B6C3F1 mice present high incidence of testicular tumors and leukemias, and liver tumors respectively (Casarett and Klaassen, 2008). Important choices also include the number of drug doses, and dose levels, and details of the required histopathology. Both gross and microscopic pathological examinations are performed not only on animals that survive the drug exposure but also on those that die prematurely.

Drug doses To test the carcinogenic potential of drugs high drug doses are necessary. This is because of statistical and experimental design limitations of chronic bioassays. Identifying with statistical confidence a 0.5% incidence of cancer (over 1 million additional cancer deaths per year in the United States) in a group of experimental animals would require a minimum of 1000 test animals, this assuming no tumors were present in the absence of exposure. To test the potential carcinogenicity of a drug at the doses usually encountered by people would require using an impractically large number of animals. One alternative to this is to assume that there is a relationship between the administered dose and the carcinogenic response and administer to animals doses of drugs that are high enough to produce a measurable tumor response in a reasonable size test group (40 to 50 animals per dose) (Casarett and Klaassen, 2008).

Methodological rigor FDA-required preclinical in vivo studies follow the Organisation for Economic Co-operation and Development (OECD) Guidances for Testing of Chemicals and the Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies Guidelines (http://www.fda.gov/Drugs/DrugSafety/default.htm). This guarantees their methodological rigor.The OECD Guidances for the testing of chemicals are a collection of the most relevant internationally agreed testing methods used by governments, industry and independent laboratories to assess chemical products’ safety. They are primarily applied in regulatory safety testing and subsequent chemical notification and registration. OECD test guidelines should not be confused with data requirements, which are the prerogative of national authorities.The GLP for Nonclinical Laboratory Studies regulations set the minimum basic requirements for study conduct, personnel, facilities, equipment, written protocols, operating procedures, and study reports. Facilities conducting studies in accordance with the GLP regulations are required to have a Quality Assurance (QA) Unit to monitor each study so as to guarantee the quality and integrity of safety data in support of FDA-regulated products. The final study report should include a signed statement from the QA Unit with the dates the study was inspected and findings reported. In addition, since 1990, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) bring together the regulatory authorities and pharmaceutical industry of Europe, Japan and the US to discuss scientific and technical aspects of drug registration and to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.

Relevance to humans Transposing animal studies’ findings to humans remains controversial (Hackam and Redelmeier, 2006). Rats and mice give concordant positive or negative results in only 70% of preclinical studies; it is therefore unlikely that the concordance between studies conducted on, respectively, rodents and humans would be higher (Lave et al., 1988). In addition, the rodents that are commonly used to study experimental tumors’ growth have relevant genetic, molecular, immunologic and cellular differences as compared to humans. Further, despite the recent development of transgenic mouse models to better identify carcinogens and mechanisms of action (Bucher, 1998), animal models are unable to entirely replicate the complex physiological changes that occur in humans’ physiopathology (Mak et al., 2014). However, preclinical studies in animal are still a key component of the hazard identification process. All human carcinogens that have been adequately tested in animals produce positive results in at least one animal model. Thus, “although this association cannot establish that all agents and mixtures that cause cancer in experimental animals also cause cancer in humans, nevertheless, in the absence of adequate data on humans, it is biologically plausible and prudent to regard agents and mixtures for which there is sufficient evidence of carcinogenicity in experimental animals as if they presented a carcinogenic risk to humans”. (International Agency for Research on Cancer (IARC) and World Health Organization, 2000).