The need to improve current psychopharmacotherapy before developing new drugs

Abstract

CNS research has become unprofitable, and several pharmaceutical companies have reduced financial support for developing new CNS drugs. Until the situation can be changed, it is our duty to optimize the usage of the currently available psychoactive drugs. Several tools for optimizing pharmacotherapy are available, such as therapeutic drug monitoring and genotyping and phenotyping CYP enzymes. Further medical treatment and healthcare provision for patients with severe mental disorders should be improved. Knowledge of psychopharmacotherapy influences the choices of medication and outcomes; therefore, future psychiatrists should have a greater knowledge of pharmacodynamics, pharmacokinetics and pharmacogenetics.

Keywords::

• genotyping
• non-adherence
• phenotyping
• psychopharmacotherapy
• therapeutic drug monitoring
• treatment optimization

Although a number of psychoactive drugs are available (around 130 drugs have been detected and developed in the last 60 years), achieving optimal therapeutic responses can be challenging. In the past few years, several high-profile pharmaceutical companies have shut down major research of the CNS. The research for psychotherapeutic drugs has become unprofitable mainly because of dramatic increase in cost. The development of new drugs has become much more sophisticated and expensive. The time from the first molecule development to a drug’s placement on the market is typically 12 – 15 years. The cost of developing a new drug is 10 – 15 billion US dollars. Moreover, when CNS drugs fail, they tend to do so in late-stage clinical trials, after a significant investment has been made [1]. The drugs currently available have largely been developed based on the monoamine hypothesis. The most recent approaches use the development of new targets independent of the mechanisms of action of previous compounds.

However, 38.2% of the European Union population has a mental disorder [2]. Psychoactive drugs are used to treat most of them, even though for some psychiatric disorders psychotherapy is most effective and drugs should be used only as an adjunctive treatment. The most frequent anxiety disorders are commonly treated by primary care physicians who prescribe psychoactive drugs, most frequently specific serotonin reuptake inhibitors.

Until the situation can be changed, it is our duty to optimize the usage of the currently available psychoactive drugs.

There is consensus that treatment should be evidence-based, measurement-based, individualized (tailored to the patient) and complex (including physical healthcare and psychosocial intervention in addition to pharmacotherapy). Treatment aims are becoming more ambitious, for example, not only remission but also recovery, meaning the ability to function socially and vocationally [3]. Evidence-based practice recommendations are provided by guidelines intended for use by all clinicians. The aim of the guidelines is to improve standards of care, diminish unacceptable variations in the provision and quality of care, and support physicians in clinical decisions. The guidelines should be known, used and intrinsic in fulfilling these aims. Treatment guidelines can improve patient outcomes, but there are a number of challenges in adopting and implementing the current practical guidelines. Most psychiatrists are aware of treatment guidelines and they have clinical experience with them. Despite this, some psychiatrists make treatment decisions that are not in accordance with the guidelines [4].

In terms of measurement-based treatment, psychiatry does not yet have objective markers for mental disorders. Treatment efficacy can be evaluated by the presence and intensity of symptoms according to scales. Response and remission are well-defined according to the reduction of scale scores; however, psychiatrists in routine clinical practice are not very enthusiastic about using the scales. The scales help to objectify the dynamics of treatment response. It has been suggested that the absence of improvement within 2 weeks of treatment may predict the likely failure of subsequent pharmacological intervention. Patients who fail to demonstrate early improvement may benefit from a change in therapy [5,6]. Further, insurance companies want comparable documentation of clinical outcomes.

Individualized treatment is a hot topic in all fields of medicine. A necessary condition for treatment efficacy is the administration of an adequate dose for a sufficient amount of time to result in optimal therapeutic drug concentrations in the plasma. A further necessary step is crossing the blood– brain barrier and finally reaching the CNS. There is evidence that sufficiently high concentrations of psychoactive drugs in the blood are required to attain a response [7]. Patients differ in their ability to absorb, distribute, metabolize and excrete drugs due to concurrent disease, age, concomitant medication and genetic peculiarities. At the same dose, a more than 20-fold inter-individual variation in steady state concentrations may result. Therapeutic drug monitoring (TDM) is a valuable tool for tailoring the dosage to the individual characteristics of a patient [8]. Updated TDM consensus guidelines are now available [7].

Indications for TDM include dose optimization after the initial prescription/dose change, suspected non-adherence to medication, lack of improvement or adverse effects with adequate dosing, genetic peculiarities concerning drug metabolism, prevention of relapses/recurrences under long-term therapy, critical drug combinations and avoidance of intoxication [8]. Considering the variability of plasma concentrations that may result at a given dose and the even larger variability of clinical effects ranging from lack of response to intoxication, it seems plausible that the pharmacokinetic variability may at least be reduced by measuring drug concentrations in the plasma to find the dosage that is required in order to attain the therapeutic reference range for the individual patient. Another aspect of pharmacotherapy that profits from TDM is monitoring patient compliance. Most psychiatric disorders are chronic, life-long diseases. Many patients with psychiatric diseases, such as patients with chronic somatic diseases, are able to live outside psychiatric hospitals with continuous psychopharmacotherapy. In psychiatry, non-adherence is a well-known problem, especially among schizophrenia patients. Depots, now preferentially called long-acting injectable (LAI) antipsychotics, are among the pharmacological options available to address adherence problems. In spite of their well-known advantages, LAI antipsychotics remain an underutilized option in many countries [9,10].

Achieving optimal therapeutic outcomes can be challenging. Before changing a treatment strategy, pseudoresistance to the treatment should be excluded. In our hospital, due to the lack of clinical improvement under recommended doses of clozapine, we measured the plasma concentrations of the drug in all of the hospitalized patients. More than half of patients had plasma levels of the drug outside the optimal range. Very similar results were found in depressed patients who were hospitalized for a lack of clinical improvement in out-patient settings [11]. For effective TDM, the availability of appropriate analytical methods that produce results within a reasonable time is essential. Abnormal values may indicate pharmacokinetic abnormalities as well as other problems such as poor compliance. The complete medication has to be considered before making an interpretation.

The benefits of TDM for the optimization of psychopharmacotherapy can be further enhanced by genotyping and phenotyping CYP enzymes. These enzymes are highly polymorphic and involved in the metabolism of most psychotherapeutic drugs. In a patient who is genotyped as a poor metabolizer or ultra-rapid metabolizer, the dose can often be adapted, using clinical judgement and TDM [12]. Phenotyping measures the metabolic situation of the patient at the moment of the test and allows its evolution to be followed. The measurement may be influenced by environmental factors, such as smoking, co-medications or the presence of other comorbidities such as liver diseases.

TDM and probe drug phenotyping and genotyping enable sophisticated analyses of the pharmacokinetic situation of an individual patient. Phenotyping and genotyping methods are becoming increasingly available for clinical practice. Optimal outcomes require a joint effort between laboratory specialists, pharmacologists, physicians and the patient [8,13]. It is to be hoped that, as the costs of TDM and pharmacogenetic testing decrease and their effectiveness becomes well documented, individualized drug treatment will become more widely available.

Many physical disorders have been identified that are associated with severe mental health disorders and alcohol abuse, and medical disorders account for more than half of the excess mortality found in these patients. The increased somatic comorbidity is due to many factors, such as the side effects of pharmacological treatment, unhealthy diet and high levels of cigarette smoking, as well as inadequate medical treatment or healthcare provision. Greater attention should be paid to modifiable risk factors [14].

Many patients with major mental illnesses already have high risk factors for cardiovascular disease. According to conservative suggestions, every patient over 40 with clinically significant low-density lipoprotein cholesterol elevation should receive a statin if 3 months of simpler interventions (e.g., diet and exercise) do not result in satisfactory improvement. After 50 years of age, every patient who meets two or more criteria for the metabolic syndrome should receive a statin. The age itself is a risk factor for cardiovascular disease, and so is male gender. Other approaches to primary prevention should not be neglected, including appropriate changes in diet and activity levels [15].

Professional requirements for future psychiatrists will demand a greater knowledge of pharmacodynamics, pharmacokinetics, the structure and functioning of the brain and genetics than is currently available in most training programs. Knowledge about psychopharmacotherapy may influence the choices of medication offered to patients. Patients must be encouraged to participate in the treatment decisions and given the confidence to take control of their own treatment.

Expert opinion

Therapeutic outcomes are still not satisfactory for many patients. TDM provides a useful and available tool for addressing interindividual variability in patient pharmacokinetic properties. Following the consensus guidelines for TDM will help to overcome problems of non-response or adverse reactions due to pharmacokinetic abnormalities and improve the outcomes of psychopharmacotherapy for many patients. Pharmacogenetics is one of the first clinical applications of the post-genomic era.

However, the application of TDM and pharmacogenetic testing is still limited, mainly due to availability and cost. In the current situation, these methods should be available at least for hospitalized patients, that is, pharmacoresistant psychiatric patients, to exclude pseudoresistance caused by partial/non-adherence and metabolic abnormalities. The recommended treatment strategies for pharmacoresistance are not very successful and evidence-based. Choosing an optimal treatment for these patients may be cost-effective.

Pharmacogenetics promises personalized medicine. The consequences that arise from genotyping may be the adjustment of dosage according to genotype, choices of therapeutic strategies or even choices of drug. However, the routine application of pharmacogenetic dose adjustment in clinical practice requires prospective validation. Genotyping of the polymorphic CYP 2D6 gene is used increasingly in clinical practice. Several psychiatric hospitals already use CYP2D6 testing before treating a patient with antidepressant or antipsychotic drug therapy.

The implementation of pharmacogenomics in routine clinical practice presents significant challenges. No study has yet investigated if the adjustment of clinical doses according to the patient’s genetic variability results in a reduction of side effects or in improved response. Prospective trials are required to prove the clinical and economic benefits of pharmacogenetic testing.

It is strongly believed that in the near future, the position of psychiatry in society will improve. Current trends of decreased investments in CNS drug development will be reversed as we better integrate knowledge from basic, translational and clinical neuroscience.

Polymorphic drug-metabolizing enzymes (DMEs) are responsible for the metabolism of the majority of psychotropic drugs, explaining a large portion of variability in individual drug metabolism. However, DME polymorphisms are relevant not only for clinical pharmacology and practice but also for research in psychiatry and neuroscience. Several DMEs, above all the CYP enzymes, are expressed in the brain, where they may contribute to the local biochemical homeostasis playing a physiological role through their action on endogenous substrates.

Declaration of interest

This paper was supported by the project CEITEC – Central European Institute of Technology (CZ.1.05/1.1.00/02.0068) from European Regional Development Fund. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.