Personalized approach in the treatment of mental disorders: Long-term prospects for the use of low doses of psychotropic drugs.

Abstract

Importance. Despite the fact that in recent decades a large number of new psychotropic medication have been developed and investigated, psychotherapy and other treatments for mental disorders, it became apparent that many patients are resistant to treatment or response only after repeated changes in therapy or its combinations. Having a diagnosis of mental disorder itself was not sufficient to choose the best treatment. In the medical field, there is a new approach to the treatment of mental disorders - "personalized approach", which will treat not "diagnosis" but "patient".

Materials and methods. In order to observe the prospects of using low doses of psychotropic drugs (and their combinations) to achieve more effective treatment results, a content analysis was conducted using Ukrainian and English publications for the last 15 years. The search was performed on the databases Pubmed, CrossRef.

Results. The most effective drug is selected by the doctor based on the clinical condition and symptoms of the patient, but the most important factor in achieving successful results is the individually selected effective dose. Timely dose adjustment to achieve the desired clinical response, combined with the prevention of adverse reactions, is an important factor in maintaining patient's adherence to treatment.

Reducing the dose of psychotropic drugs to levels below those recommended in the instructions for use can lead to significant positive results due to: improved health care in general with more effective therapeutic results, reduced side effects and reduced patient`s costs.

Personalized approach and judicious use of psychotropic drugs for other purposes is considered an integral part of the continuous development of science, taking into account the clinical experience of the use of drugs.

Conclusions. There is a need to adjust the dosage of psychotropic drugs to the minimum effective dose that will meet the individual needs of the individual patient, and will help to find a balance between efficacy and risk of side effects and will be a necessary basis for developing an effective personalized approach in psychiatric practice.

Optimizing the dosage of a psychotropic drug is an important factor in improving the efficiency of the health care system as a whole.

Background

Progress in the treatment of mental disorders has become noticeable with the development of psychopharmacology and psychotherapy. Numerous randomized clinical trials have confirmed the fact that these therapies are more effective than placebo. Although many new psychotropic drugs, psychotherapies, and other treatment methods of the mental disorders have been developed and researched in recent decades, it has become apparent that many patients still remain resistant to the treatment or respond only after repeated change of a therapy or combination thereof.

In addition to the fact that the process of a therapy selection takes a lot of time, many patients also experience serious side effects that negatively affect their quality of life and an adherence to a particular method of treatment.

In the existing situation, psychiatrists and other mental health professionals continue to rely on their "own" clinical experience with the patients in addition to the use of the generally accepted standardized protocols and the guidelines, which are often not perfect and do not take into account all the patient characteristics (biological, psychological and social).

This discrepancy arose due to the fact that the existence of a mental disorder diagnosis alone had become insufficient for a selection of the optimal treatment method. This fact simultaneously demonstrates a much more complex patient with the diversity of genes and their products, which are inextricably connected with the environment, cultural characteristics and psychology of the patient, and plays a crucial role in the response to the treatment [1].

In this regard a new approach to the treatment of mental disorders – a "personalized approach" evolved in the medical field the last few years.

Currently, a need for such an approach in psychiatry is obvious. Over the past few years, the number of the scientific publications on a personalized approach to mental health has increased. However, this approach has both supporters and opponents. Some professionals believe that an individual approach to treatment can be achieved [2,3], others say that psychiatry cannot be truly personalized because it can cost even more human and material resources [4].

New approaches always lead to contradictions and confrontations between the supporters and the opponents. The emergence of a personalized approach to the treatment of mental disorders will allow to resolve the long-standing dispute between the supporters of a "blind" following the protocols and the instructions (concerning the use of psychotropic drugs) and supporters of a "personalized" approach to the patient therapy based on his or her biological, psychological and social characteristics.

A personalized approach will allow to treat not the "diagnosis" but the "patient".

Possible deviation from the instructions offered by the manufacturers of pharmaceuticals will significantly reduce the distress of a psychiatrist when choosing treatment tactics.

In this article, in the light of a personalized approach, we consider it is necessary to pay special attention to the usage of "the small doses of the psychotropic drugs" in the mental disorders’ treatment.

Many years of clinical practice and observation jointly with colleagues have given us an idea that more careful prescription of psychotropic drugs in "Small Doses" may be more effective.

Our task is to study critically the multifaceted role which the optimization of the dose of psychotropic substances can play on the patient's health, in a view of the upward trend of the number of mental disorders, and, accordingly, an increasing consumption of psychotropic drugs.

According to our observations, less does not mean "Worse or Inefficient", perhaps in the long run "Better and More Effective"!

Materials and Methods

In order to study the prospects for using low doses of psychotropic drugs (and its combinations) to achieve the more effective treatment results, a content analysis was conducted using Ukrainian and English publications over the past 15 years. The initial search showed 120 articles (Pubmed, CrossRef), from which 43 were included into analysis. The search for English-language articles was conducted by keywords: "personalized therapy", "mental disorders", "low doses", "small doses", "psychotropic medications", "treatment", "off-label psychotropic medications". The search for Ukrainian-language articles was carried out by keywords: "personalized therapy", "mental disorders", "low doses", "small doses", "psychotropic drugs", "treatment", "use of psychotropic drugs not for prescription".

Results

Psychotropic drugs are widely prescribed throughout the world and in Ukraine in particular. The most important manufacturers of original psychotropic drugs are international pharmaceutical companies. In addition, most original psychotropic drugs undergo years of clinical trials before they are marketed. Furthermore, they must obtain the legislative approval of the relevant regulatory authorities in the countries where they will be sold and used as intended for the treatment of the relevant groups of patients and relevant nosologies.

For example, one of such an authority in the United States is the Food and Drug Administration (FDA), in the European Union it is the European Medicines Agency (EMA), and in Ukraine it is the State Pharmaceutical Committee [5, 6]. Despite the fact that each drug has a direct purpose, psychotropic medications are prescribed very often not for a prescription and outside the recommended doses, especially if there is no effective alternative for its use, such as in geriatric or child psychiatry, or in those cases, when the patient needs a new therapy for the disease with resistance to the main treatment plan.

According to the law, the manufacturers are not allowed to promote the use of drugs for off-label purposes and without specifying the range of doses. However, the scientific data may support the off-label prescriptions and go beyond the doses specified in the instructions to achieve the better clinical effects. In addition, the regulatory authorities do not directly regulate the clinical use of the psychotropic substances and do not limit the personalized use [7].

At the same time, making any new additions to the medication's instructions to expand its use is a longstanding and a very expensive process, as it will require a reconduction of long-term multi-stage clinical trials [8]. This may mean that there is a certain "effective clinical dose range", which is not taken into account and which is indicated meanwhile in the instructions of the psychotropic drug and its effectiveness in real clinical practice.

For example, most antidepressants (tricyclics, SSRIs, and SSNRIs) are equally effective in treating major depressive disorder [9]. The same is true for another group of the psychotropic medications, which is often prescribed – atypical antipsychotics. It is assumed that the most effective drug is selected by a mental health professional based on a clinical condition and the symptoms of the patient, but the most important factor in achieving the successful results is the individually selected effective dose. In addition, a timely dose adjustment to achieve the desired clinical response, combined with the prevention of the side effects, is an important factor in maintaining patient adherence to the treatment.

However, no less important is the fact that the dose of a psychotropic drug also plays an important role in a wide range of not only obvious but also hidden side effects, such as the increasing financial expenses of the patient [10].

Similarly, an excessive use of the unreasonably high doses of the psychotropic medications, or combinations thereof, may well be caused by an abuse or the misconceptions of patients about the effectiveness and safety of the drugs in the doses taken.

By reducing the dose of the psychotropic drugs to levels below those recommended in the instructions for the use, the therapeutic goals not only can be achieved, but in some cases, even exceeded by minimizing the side effects and, therefore, achieving a greater adherence to the treatment.

Despite its connection with the off-label use, a reasonable administration of the low doses of the psychotropic drugs can lead to the significant positive results due to: an improved health care in general with more effective therapeutic results, reduced side effects and reduced patient expenses.

What is the rationale behind a personalized approach in the selection of the psychotropic drugs?

Prescribed medications should provide the desired therapeutic result, minimizing the adverse side effects and treatment costs [11]. The side effects, dosage, frequency and the route of an administration, as well as the other factors connected to the prescribed regimen, should also not impair a compliance or interfere with the patient's adherence to the treatment regimen.

However, for a truly more effective treatment of the mental disorders, and for a comprehensive and reasonable process of prescribing the lower doses of the psychotropic drugs, the additional factors must be taken into account. (Table 1, [12]).

Table 1.

Table 1. The main characteristics related to the dosage, which can be optimized to reduce the side effects of the psychotropic drugs (mod. Daughton CG, 2013).
↗Characteristics	Example	Possible effects
Route of an administration	Orally, by injection, percutaneously	Medicines for a local application are highly concentrated and often are overused
Dose strength	The amount of a substance in the drug	The main variable in optimizing the effectiveness of the treatment; the reason for the patient's adherence to the treatment; the cause of the side effects
Dosage form (includes the main substance and excipients)	Capsules, tablets, drops, injections, special forms of prolonged action and slow release, etc.	Affects an adherence and determines a dosage of the drug
Dosing regime	Multiplicity of a dosage and time of an administration during a day; take into account the duration of action (half-life)	Excessive daily dose can cause an overdose; the complex schemes worsen the patient's adherence
Duration (course of treatment)	Long-term, short-term, supportive	Long-term treatment poses risks of over-treatment for patients and contributes to reduce of an adherence to the treatment, especially when the outcomes are not obvious to the patient; a long-term treatment may require periodic dose adjustments
Titration (speed of increasing from a lower dose)	The effect of the "first dose"	May lead to a discontinuation of the treatment
Medication intake time	Biological rhythms can affect the efficiency and the excretion	Wrong time of an administration may increase the excretion or reduce the efficiency (thereby requiring an increasing of the doses); circadian rhythms often control the biosynthesis of many proteins that serve as the drug receptors
The complexity of the regime	Complex, inhomogeneous, episodic dosing; polypharmacy; asynchronous dosing; combination therapy;	Drug interactions may worsen the symptoms; the patient may be confused in the complex prescriptions, which leads to a non-compliance with the treatment
Pharmacokinetic profile	Determines the degree of the excretion of the main substance and the associated metabolites	Some drugs are excreted more intensively than others; long-acting drugs, in contrast to short-acting drugs, improve an adherence to the treatment.
Sensory properties	Taste and smell	May provoke a resistance to the treatment, especially in children

Excessively prescribed number of the drugs or the complex treatment regimens, as a result of polypragmasy, can contribute to:

1. Development of the side (emotional, somatic and behavioral) effects;
2. Development of addiction, abuse or misuse;
3. Increased risk of poisoning (especially relevant in pediatric and geriatric practice);
4. Increasing financial expenses for a patient and a health care in general;
5. Low adherence with a subsequent premature discontinuation of the therapy.

The modern paradigm that exists in psychiatry is changing - when the doctors and the patients increasingly resort to the alternative approaches to the treatment, such as psychotherapy and the other methods [13, 14].

Despite the variety of the different approaches in the treatment of the mental disorders, pharmaceuticals are still considered as the first line of therapy.

However, for the treatment of the chronic conditions that require more control and adherence to the therapy, in contrast to the acute conditions that require rapid control of the symptoms, it is important to consider the non-standard approaches. And perhaps one of such approaches may be a personalized health-care, which may ultimately be more effective.

What can be done to optimize the decision-making process when prescribing the psychotropic drugs?

Prior to the advent of the standardized clinical trials, a medical professional was largely drawn on personal clinical experience in the treatment of the patient, and the patient's treatment depended more on the doctor's skill than on science [15]. Due to the fact that the clinical trials are based on a long-term, multi-stage assessment of the drug, we are increasingly guided in prescribing by an approach that does not always incorporate the evaluation of patient's personality, including biological, psychological features and social - environmental factors that affect individual, in this regard, we strive to strictly adhere to the "standard" doses specified in the medication instructions. We try not to treat the patient, but to adjust him or her to the standards of therapy. In addition, insurance medicine, as well, increasingly pushes us to do so [16].

Many doctors mistakenly believe that the standard dose should not be adjusted - to ensure a therapeutic efficacy. Sometimes doctors are afraid that a dose adjustment may have the legal consequences. These concerns are less than fully reasonable, as the treatment standards for the dosage of the most commonly used classes of drugs have not been established. For example, the FDA does not prohibit an unregulated prescription of a medicine (one aspect of which is a dosage) because it does not regulate a prescription of medicines in practice (controlled substances are an exception) [17].

In fact, a personalized approach and a reasonable off-label use of the psychotropic drugs is considered an integral part of the continuous development of science, taking into account the clinical experience of using the drugs. Due to the personalized approach when using not for its intended purpose it also plays a role in the re-profiling of the substance for the new purposes, expanding its indications [18]. And in this article, we are describing an alternative point of view, which is that the universal purpose of the standard dose, as stated in the instructions, remains unchanged and necessarily means that one or some categories of the patients or the individual patients are excessively treated. Instead, it would be wiser if these categories of patients received lower doses because they indicate a higher effect when using the lower doses than indicated in the instructions. Herewith the personalized approach to the treatment of the mental disorders inherently suggests that the doctor may offer a regular follow-up, which may take the form of the more frequent clinic visits or regular phone contacts to monitor the patient's response to a lower dose and continue a further dose titration.

Is it reasonable to prescribe the psychotropic drugs deviating from the instructions?

Nowadays, many psychotropic drugs are used not for the direct purposes, as defined by the instructions. Often, psychiatrists are guided by their own clinical experience in prescribing the drugs that go beyond those specified in the instructions, such as: the indications for use, a dosage, total daily amount, dosage frequency, duration, age.

Restrictions on the use of the drugs for the other purposes are particularly relevant for the children, adolescents and the other population groups (e.g., the pregnant women) who have been excluded from the clinical trials historically. And in such cases, the use of the medications for the other purposes is not considered unreasonable and unapproved. However, a daily clinical practice shows a different reality: in some cases, the approved drugs cause the side effects starting from the minimum doses prescribed in the instructions, or an unreasonable maintenance therapy with high doses can lead to a premature discontinuation of the medication.

At the same time, the practical use of the psychotropic drugs for the other purposes, in fact, opens the possibility for a constant updating of a more limited drugs database that had existed at the time of licensing the drug [19]. In addition, a reasonable off-label appointment, expands the clinical indications for a use. The growing number of the publications on the use of the psychotropic drugs for the other purposes provides an access to the information on the actual use [20]. For example, most antipsychotic drugs are licensed to treat psychosis, but they are also prescribed to control a behavior in the other mental disorders not for their intended purpose. In the UK, antipsychotics such as haloperidol, aripiprazole are licensed for the pediatric use (schizophrenia, bipolar mania), risperidone (for the behavioral disorders), but the drugs such as olanzapine, quetiapine and amisulpiride are considered off-label because they are not licensed for the pediatric use. Antipsychotics are used for children aged 5 to 18 years to correct a behavior [21]. In addition, the side effects of the modern (atypical) antipsychotic drugs include: weight gain, diabetes, obesity and a cardiovascular disease; they increase the risk of the seizures and may adversely affect a child's development. However, even if there is supporting evidence for the prescription, the doctor must document all the unregulated prescriptions to minimize the legal consequences of the prescriptions.

It is important to note that the published literature on an unregulated use focuses mainly on the drugs used in a non-compliant age group [22,23]. Relatively a little attention is paid to the use of the psychotropic medications not according to the instructions for a drug dosing.

Can a lower dose of a psychotropic drug be more effective?

At the beginning of the 21st century, a number of publications appeared on the topic "Less Means More" on improving the healthcare performance indicators, by reducing the excessive use of a medical care, for example by reducing (careless) prescribing of the drugs [24]. The study conducted (by Mojtabai R Olfson M, 2010) in a large and representative sample, 13,079 visits to psychiatrists in the United States between the mid-1990s and mid-2000s, identified a growing trend of the psychotropic polypharmacy. After analyzing the data, we found that the average number of the drugs prescribed at each visit increased by 40.1% [25].

Thus, when talking about a reasonable prescription of the medicine, we still understand the reduction of polypragmasy, but there is still no consideration for the reasonable doses.

A prescription of the psychotropic drugs may not be reasonable or even harmful if the substance is prescribed aimfully not for the purpose regulated by the instructions, as well as a non-compliance with the parameters specified in the instructions (e.g., exceeding specified ranges of the doses), in the absence of the sufficient evidence. On the other hand, it may also be unwise to strictly comply with the intended use of the drug.

A reasonable appointment of the psychotropic drugs in pediatric, geriatric practice and in cases of the somatically impaired patients is especially relevant. A systematic review of 80 studies published from January 2000 to October 2015 found that the older people take five or more medications a day and are treated by several doctors at once. More than 50% of the elderly people who take many drugs, as well as adhere to the complex therapeutic regimens, do not adhere to the prescribed therapy [26].

A study conducted (Garfinkel Mangin D, 2010) showed that reducing or stopping polypharmacothereapy for the elderly patients does not lead to the significant risks, but rather leads to reduced mortality, improved health and a quality of the life [27].

Another striking example is a study (Levinson, 2011), which documented the widespread careless and an off-label use of the atypical antipsychotic drugs at nursing homes. This study found an unnecessary use of the antipsychotic drugs, not for an indication, or an exceedance of the doses and a duration of the treatment, which shows that patients were at an unnecessary risk and the health care system was burdened with the additional costs [28]. In some cases, the lower doses may contribute to a greater adherence to the therapy, making the drug more affordable. It is also known that a high commitment to a therapy reduces the chronicity of diseases, reduces the frequency of the exacerbations and, accordingly, leads to a reduction in the overall health care costs.

According to the study (Cascade E. 2007), 45% of the atypical antipsychotic drugs are prescribed to the patients aged 40 to 64 years, 24% of the antipsychotic drugs are used by the patients aged 18 to 39 years. The other two age groups of the patients under 18 and ≥65 years accounted for 14% and 17% of the antipsychotic drugs, respectively [29].

The use of the antipsychotic medications that are not used for the patients is controversial due to the limited evidence base as well as the potential side effects. Children and the elderly are two risk groups for whom the antipsychotic drugs can be useful and potentially dangerous.

The pharmaceutical companies restrict the marketing use of their adult-only drugs in pediatric practice, as well as their misuse. However, the drugs are widely used and the potential risk is significant. The current prescription of these drugs for children, adolescents and the elderly should be carefully considered in terms of the potential risks and benefits. Additional studies in the form of the controlled clinical trials involving children, adolescents and the elderly should be performed on the grounds that show the significant prospects for the patient.

How can the dosage of a psychotropic drug affect the development of side effects?

Sometimes in clinical practice we observe a reaction after prescription of an excessive dose. The development of the side effects may be connected with the individual biological characteristics of the patient. For example, such a reaction can be caused by a rapid accumulation of the drug, as a result of an active binding of blood plasma to the proteins. A personalized selection of the minimum dose lower than the limit specified in the instructions (½ or ¼ from the minimum dose) can prevent a side effect.

The higher doses may also lead to the side effects sufficient to cause the behavioral disorders and the inadequate emotional responses that may be responsible for a discontinuation of the therapy.

For example, an incorrectly selected dose of an antidepressant or an antipsychotic can lead to an increase of the existing symptoms (mental and somatic), which also leads to an abrupt cessation of an intake or a non-compliance. In this regard, the effect of the "first dose" is extremely important for many psychotropic drugs [30].

Excessive doses can also lead to the side effects, which are misconstrued for the certain comorbidities, and mislead the doctor, lead to polypragmasy and the appointment of the additional drugs to improve the patient's condition, but, conversely, cause a deterioration. Often, the beginning of psychotropic therapy can cause anxiety, the symptoms of which can be mistakenly accounted for concomitant conditions or diseases.

An unreasonably high dose of the drug may also cause the patient to try to adjust the dose by oneself to a lower effective dose (e.g., by crushing tablets, or less frequent intake), although this may eventually lead the patient to the correct dose [31].

A noncompliance with regimes of the drug intake or an abrupt discontinuation thereof may prompt the doctor to change the prescribed drug to another (although the side effect was not caused by the wrong drug, but the inadequately selected dose). Finally, an aggravation of the existing symptoms (mental and somatic) caused by an overdose can cause a patient's distrust of the doctor, the search for a new specialist or the alternative treatments.

What do we mean when prescribing the "low" doses of the psychotropic drugs?

In order to avoid a confusion in the understanding of the term "low dose", it is important to distinguish between its two different meanings. One includes the lowest, and means below the allowable range, the other - the lowest dose specified in the instructions to the drug.

Clinical experience shows that the dosage of many psychotropic drugs can be reduced while maintaining a therapeutic efficacy. At the same time, there are situations when a dose reduction is not a reasonable idea, and an adherence to the dosage specified in the instructions for the use is quite reasonable. Especially in the situations where there is a threat to life, or in cases where the likelihood of the toxic or adverse events increases (e.g., toxic effects of Lithium in excess of the therapeutic dose range), experimenting with a titration up or down is unacceptable [32]. Conversely, the use of low doses may be unacceptable in the acute and urgent situations where an immediate therapeutic response is required. Examples include a non-use of the small doses in the emergencies in psychiatry [33].

In certain critical situations, the doses, that are higher than usual, may be reasonable at the beginning of the therapy for a rapid increase in the substance and its metabolities levels in plasma. In some situations, the doses, that exceed the ones indicated in the instructions, may be more effective, such as the antiepileptic drugs, which are prescribed for the seizure control [34].

Even when the standard doses or maximum dosing are required at the beginning of the therapy, further "titration downwards" may be appropriate for a longer treatment. Alternatively, "titration downwards" may eventually indicate that a drug is no longer needed, or can be effectively used for a maintenance therapy in amount less than the minimum dose stated in the instructions.

For some psychotropic drugs, the use of the lower doses may be more reasonable at the beginning of a therapy, especially in the chronic or mild conditions that do not require an immediate intervention. One of such examples, which is caused by an overdosing, is the mild to moderate depression [35], when a reasonable prescription may include the beginning of the therapy with the low doses of the antidepressants and only then, if necessary, a further titration.

Another example of an excessive drug prescription may be a borderline personality disorder. This disorder is associated with the long-term adverse effects, which include a persistent functional impairment, a lot of pressure on the family,comorbid psychosomatic diseases, premature mortality, including 8% of the suicides. People with borderline personality disorder need long-term treatment. For example, in Australia, a treatment of the borderline disorder is the most expensive and ranks second after schizophrenia. A psychotherapeutic treatment is the main therapy, but the availability of such treatment is limited. Despite the effectiveness of the psychotherapeutic treatment, the psychopathological symptoms such as depression and anxiety often remain. In addition, it is always easier to provide the prescriptions than a psychotherapeutic treatment [36].

The methods for predicting the medication’s effective doses based on the patient's personal pharmacokinetics are also available [37].

In some situations, when it is necessary to increase the dose of the drug, it is possible to use another effective method. For example, to use the psychotropic drugs from one class (two neuroleptics in a smaller dose), but with the different mechanisms of an action.

An interesting study in the direction of a personalized approach to the treatment of the mental disorders is the study of the biomarkers that reflect the disease. The patients with the absolute mRNA values ​​above those suggested may be referred in the early stages to the treatment with more effective antidepressants, including the addition of the other antidepressants or the anti-inflammatory drugs. Identification of the biomarkers that predict response to a treatment is crucial for reducing the social and economic losses from the depression and improving patients' life quality [38].

Alternatively, the low doses, combined with the lifestyle changes and other behaviors (e.g., a healthy eating, an exercise, or avoiding risky behaviors such as a smoking or an alcohol use), are often an effective approach to a treatment, although usually more difficult for the patient. Table 2 shows the personal characteristics of the patient, which may affect the dosage of the psychotropic drugs.

Table 2.

Table 2. Characteristics of the patient that may affect the dosage of the psychotropic drugs (mod. Daughton CG, 2013)
↗Characteristics	Example	Possible effects
Individual pharmacokinetic and pharmacodynamic features	Genetic polymorphism determines an accelerated or slowed metabolism; sensitivity or insensitivity to the drug	May lead to increased, reduced or otherwise unnecessary release of the bioactive chemicals depending on the substance
Commitment and adherence to the treatment	Non-compliance with the treatment regimen; causes a variety of the behaviors, from a purposeful adherence to the treatment to an unconscious discontinuation of the treatment	Compliance and adherence to the treatment are among the main factors determining the frequency and the severity of the side effects leading to an overdose or an addiction.
Polypharmacy	The excessive amounts of the different medications used for the several conditions; may be as the result of a multiple monotherapy or a combination therapy; or the result of accepting the prescriptions from the several doctors	An excessive medication contributes to a non-compliance and the discontinuation of the therapy; effective communication between a doctor and a patient can reduce the frequency of the polypharmacy
Diet, nutrition, connection with food intake	Alcohol, nicotine	An interaction of the medicinal substances and the nutrients affect the pharmacokinetics and the pharmacodynamics, reducing the efficacy or causing the side effects – all of which leads to a non-compliance with the treatment
Somatic condition	Renal, hepatic, pulmonary, cardiovascular dysfunction	A disordered function can have a profound effect on a drug excretion
Gender, age, race, ethnicity, body weight	The main indicators influencing the pharmacodynamics and the pharmacokinetics of the dose	Children and the elderly may require the smaller doses
Biomarkers of the specific mental disorders	Absolute values of mRNA	Allows to predict the prognosis of the disease and determine the effective treatment plan

What is the advantage of prescribing the lower doses of the psychotropic medications?

Not all the mental health professionals know about the benefits of prescribing the low doses of the psychotropic drugs. A large number of side effects, impaired quality of a life, and as a result a lower adherence to the therapy, usually occur as a result of a suboptimal drug administration, and at the same time an appointment of the lower doses may be a more effective therapeutic solution.

Prescribing the lower doses can be beneficial both for a patient (a reduction of the financial costs as a result of prescribing the lower doses, a reduction of the side effects) and a doctor (an improved therapeutic efficacy) [39].

According to the FDA, the recommended doses for many drugs are often adjusted downwards in the future. For example, an estimation of 71% of the new molecular substances approved by the FDA between 1980 and 1999 showed that in 21% of them the dosage was subsequently modified . From those, 79% were adjusted downwards. Most of them, 27%, were psychotropic drugs. [40].

One of the obvious factors, which is motivating to start a treatment with lower doses, is medications with a very narrow therapeutic range, where the therapeutic effects and the toxicity are closely related to a dose-response curve.

Despite this, a use of the lower doses has many potential benefits. Our mind is often slipped on such advantages as: an empowerment of patients, which allows to encourage a patient to self-titrate to the lowest effective doses. This, in turn, can cause the patient's commitment to a treatment, a sense of a greater security, and ultimately an achievement of the therapeutic goals. In addition, it is important to remember that when prescribing relatively low doses of the psychotropic drugs, a part of the effect of the drug may be caused by the placebo effect due to an effective communication between a doctor and a patient [41].

Some examples of the drugs that confirm a therapeutic efficacy of the low, lower, or subtherapeutic doses of the psychotropic drugs

The article provides many examples of the effectiveness and the benefits of the low-dose treatment, including the fact that "less can be better."

Certain classes of the psychotropic drugs are attracting attention due to a potential therapeutic importance of using the lower doses. The most commonly prescribed psychotropic drugs are antidepressants [42].

A review of the literature on the use of SSRIs by the family physicians, neurologists, and psychiatrists for the treatment of a mild to moderate depression indicates the inconsistencies in the dosages. SSRIs are often prescribed at the initial or maintenance doses below the lowest desired ones - often in the proposed subtherapeutic ranges [43]. Actual data often shows little additional therapeutic effect from SSRIs compared to a placebo in the mild to moderate depressive disorder, whereas both treatments provide the significant benefits compared to no treatment. In this situation, a treatment with the low doses of the drugs can serve as a practical implementation of the latent therapeutic effect of the placebo caused by attending the physician, and at the same time it can also be used to avoid side effects from the use of conventional doses.

Conclusion

1. It is necessary to adjust the dosage of psychotropic medications to the minimum effective level, which meets the individual needs of the patient, and helps to find a balance between the effectiveness and the risks of side effects and be a necessary basis for developing an effective personalized approach in the psychiatric practice.
2. Personalized dose selection of a psychotropic drug also improves the therapeutic outcomes, while reducing a frequency of side effects and reducing the financial costs of the treatment.
3. Optimizing a dosage of the psychotropic drug is an important factor in improving the success of the treatment, improving adherence to it, as well as improving the quality of the psychiatric care and the patient's life.
4. The results emphasize that therapeutic regimens and protocols are important but imperfect guidelines for the doctors when deciding on a drug. This is especially important in psychiatry, given that the diagnostic schemes that underlie these regimens and protocols are not always accurate.
5. One of the important problems is that during the clinical trials of the psychotropic drugs, the companies use the standardized diagnostic techniques that do not take into account all the individual characteristics of the patient.
6. Without an access to current data on the efficacy of the low doses, an ineffective treatment of the patient is obvious. This will require a significant improvement in the dissemination of data among the doctors concerning the new low-dose efficacy studies.
7. In addition, the psychiatrist or other mental health professional who writes a prescription should not forget that each of the drugs prescribed by him or her may have the unforeseen side effects that may go beyond the health care and move into the legal responsibility plane.

Additional Information

Conflicts of interest

The authors declare that they have no conflicts of interest to declare.