Lakhasly

INTRODUCTION
Anxiety refers to a group of disorders characterized by a wide range of somatic and psychiatric disorders including changes in behavior and cognition, which arise as a result of irrational fear (1). Anxiety disorders represent the group of the most prevalent mental diseases with a prevalence of 7.4% in the general population (2). Anxiety is a significant medical condition which has serious negative consequences on the mental and social sphere of life (3). According to the Fifth International Classification of Mental Illness (DSM-5) (4), anxiety disorders are comprised of several groups of disor- ders: the generalized anxiety disorder, social phobia, specific phobia, panic disorders with/without agoraphobia, secondary anxiety, acute stress disorder, anxiety induced by drugs, while according to the last classification, obsessive-compul- sive disorder and posttraumatic stress disorder are excluded from the group of anxiety disorders. Anxiety, in addition, can occur as a dominant symptom in a number of other psychiat- ric disorders, such as autism spectrum disorders, bipolar dis- order and addiction diseases, also in chronic diseases, as rheumatoid arthritis, cancer or similar diseases are (5-7).
Different types of the anxiety disorder are treated in vari- ous ways, but anxiety is generally treated with a combination of the psychotherapeutic treatment and pharmacotherapy. From the group of psychotherapeutic treatment options, the most important is cognitive-behavioral therapy, which can be applied with significant efficacy for all forms of anxiety dis- order (8). Pharmacotherapy of the anxiety implies the use of anxiolytics and antidepressants. The pharmacotherapy core for anxiety disorders are antidepressants: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and noradrenergic and specific serotoninergic antidepressants (NaSSAs) (9). In addition to antidepressants, benzodiazepines and buspirone are also used to treat anxiety. Anxiolytics are used as an adjuvant therapy with antidepressants, at the very beginning of treatment of anxiety, since antidepressants require time for achieving their maximum effect, while the long-term use of anxiolytics is considered unjustified due to the possibility of developing addiction (10). However this therapeutic approach in the treatment of anxiety disorders is accompanied by significant limitations. In the case of patients suffering from depressive disorders, it has been shown that the adherence of patients to antidepressants is worryingly low (11). Although the initia- tion of benzodiazepines has a positive impact on patients’ ad- herence to the antidepressant, this therapeutic approach may be accompanied with an abuse of these drugs, most often through undue prolonged use (12-13). The insufficient effec- tiveness of antidepressant therapy in patients with anxiety disorders is often the result of application of low doses of anti-depressants. Also, a significant problem in the treatment of anxiety disorders is the fact that cognitive-behavioral ther- apy is combined with pharmacotherapy in only one-quarter of patients with anxiety (14). All of these factors significantly diminish the treatment of anxiety, so it seems realistic the rates of 50% to 60% of responding patients to the treatment
of anxiety disorders, which is found in several clinical trials (5).
On the other hand, it has been proven that problems re- lated to abuse of anxiolytics and insufficient adherence of pa- tients towards antidepressants can be successfully prevented with improving the quality of an advice that health workers, especially Pharmacists pass to patients suffering from mental illness (15). Results of the research conducted by the World Health Organization especially highlight the role that Phar- macists, as health workers who are most accessible to pa- tients, should have in order to improve the treatment of all mental disorders (16). After the World Health Organization made its recommendations, a large number of studies were conducted to investigate the efficacy of pharmaceutical health care in the treatment of depression (17-19). The aim of this review article was to evaluate, through a detailed presentation of therapeutic options for the treatment of anxi- ety disorders, perspectives in which Pharmacists would more actively participate in the treatment of patients with anxiety.
PHARMACOTHERAPY OF ANXIETY
Anxiety is a complex mental disorder that can have its cognitive, phobic, and physiologically-autonomic symptoms (5). From this, it can be concluded that an adequate treatment for the anxiety in most cases requires a combination of dif- ferent skills and techniques of treatment, primarily the phar- macotherapy and cognitive-behavioral therapy (20). One of the most important problems in the treatment of anxiety is the absence of cognitive-behavioral therapy, so that the effi- ciency of pharmacotherapy should be seen through the prism of the mentioned fact in most patients. For the treatment of anxiety, a great number of medications have been used throughout history, starting from herbal medicines, such as valerian preparations, to various groups of synthetic drugs. In the meantime, knowledge of a nature of the disease has be- come greater, so it has been found that there are different types of anxiety disorders with the prevalence of different symptoms. Because of this, certain types of drugs, such as benzodiazepines and beta-blockers, have lost relevance in the treatment of anxiety, as they do not affect all symptoms that accompany anxiety disorders. Antidepressants nowadays form the basis of pharmacotherapy of anxiety disorders, with the growing use of pregabalin (5).
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)
SSRIs have been the first line of anxiety therapy for years. It has been shown that SSRIs achieve their anxiolytic effect by the inhibition of serotonin transport and subsequent de- sensitization of serotonin receptors, although it is possible that the anxiolytic effects contribute to the ability of some representatives of this group of drugs to be the partial ago- nists of 5HT1 receptor, as exemplified by buspirone (21). There is no difference between the different representatives of this group of drugs in terms of efficacy in the treatment of anxiety disorders (20). The efficacy of these drugs in the
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   treatment of anxiety depends on a large number of different factors, but it can be said with certainty that they act on all three groups of symptoms that may occur in anxiety disor- ders. In addition, symptoms of anxiety can often be inter- twined with symptoms of accompanying depression, which can also be successfully treated with SSRIs which is the main advantage of SSRIs comparing to benzodiazepines, since benzodiazepines do not affect cognitive symptoms of anxiety and accompanying depression (5). These drugs achieve their anxiolytic effect only after the initial period, which usually lasts from 2 to 4 weeks, and in some patients this period may be even longer - from 6 to 8 weeks (22). Doses of antidepres- sants are adapted to the individual characteristics of patients and the type of anxiety disorder, but are usually in the fol- lowing ranges: escitalopram 10-20 mg, citalopram 20-60 mg, fluoxetine 20-40 mg, paroxetine 20-60 mg, sertraline 50-200 mg, fluvoxamine 100-300 mg (23). SSRIs have low affinity for the muscarinic, adrenergic, and histamine receptors, for their use is not accompanied by the adverse effects such as the orthostatic hypotension, sedation, dry mouth and blurred vision, which are characteristic for tricyclic antidepressants (24). At the beginning of treatment with SSRIs headache or insomnia may occur, wherein the incidence of these side ef- fects can be reduced by the introduction of the lower initial dose of these drugs. However, the most important side effects of these drugs are the sexual disorder and weight gain, which usually arise in chronic therapy (9). The use of SSRIs during pregnancy and lactation is not associated with the onset of major congenital malformations, but there is not much data on the long-term developmental outcomes of children ex- posed to SSRIs (25).

PREGABALIN
Pregabalin is a structural analog of the inhibitory neuro- transmitter gamma amino butyric acid which in Europe is successfully used to treat two types of anxiety disorders: gen- eralized anxiety disorder and social anxiety. In addition to anxiety disorders, pregabalin is also used to treat the neuro- pathic pain (26) and a certain forms of the partial epilepsy (27). Pregabalin has the similar efficacy with benzodiaze- pines, while on the other hand it has a significant advantage as there is a significantly lower risk of addiction (5). Similar to antidepressants, the pregabalin successfully affects on the physical and psychological symptoms of anxiety, as well as on symptoms of possible accompanying depression (28). Pregabalin is currently used as the first line of therapy in the treatment of generalized anxiety disorder, but can also be used successfully as the second line therapy in patients who have not successfully responded to therapy with antidepres- sants (29). For the acute treatment of generalized anxiety dis- order the pregabalin is used in a dose of 200 mg daily, while for the prevention of relapse the pregabalin is used in a dose of 450 mg daily (30). The main advantage that the pregabalin has in relation to antidepressants is significantly increasing the anxiolytic effect, while the main advantage over benzo- diazepines is an importantly lower risk of addiction (5). The most common side effects that accompany the pregabalin use are somnolence and dizziness (9). When it comes to the
potential use of pregabalin in pregnancy, most recent results of clinical studies have not indicated the existence of a tera- togenic effect, although it can not be excluded with certainty (31).
BENZODIAZEPINES
Benzodiazepines have a significant place in the treatment of anxiety disorders for years, but it seems that their use is slowly losing its importance when it comes to this kind of treatment of mental disorders. Results of clinical trials have shown that this group of drugs have no effect on the cognitive symptoms of anxiety or on the accompanying depression (5). Also, benzodiazepines are not effective in the treatment of obsessive-compulsive disorder and post-traumatic stress dis- order. Finally, an important limitation of benzodiazepine re- fers to the fact that their prolonged application is very often accompanied by the development of a serious psychic and physical dependence that is later relied upon by the severe abstinence syndrome (32). On the other hand, it is important to note that benzodiazepines have significant advantages compared to other anxiolytics. In contrast to SSRIs, benzodi- azepines achieve their anxiolytic effect through enhanced and facilitated activity of the gamma-amino-buteric acid, so after their administration it is necessary only a few minutes until the aforementioned anxiolytic effect is observed (33). Also, benzodiazepines compared to SSRIs have a signifi- cantly better safety profile, because they even in very high toxic doses rarely lead to complete CNS depression; on the other hand, benzodiazepines in combination with other CNS depressants, and especially with an alcohol, exhibit the addi- tive depressive effect on CNS (34). Beside this additive de- pressive effect with other sedatives and hypnotics, benzodi- azepines do not have the tendency to engage in more serious drug-drug interactions, which also makes them more suitable for use than SSRIs (5). When taking into account the afore- mentioned advantages and limitations of the benzodiaze- pines, it is difficult to define a real position that these drugs should have in the treatment of anxiety disorders. It seems that the most realistic is the currently applicable practice, ac- cording to which benzodiazepines are used for the initial phase of treatment of anxiety disorders, while antidepressants do not exhibit their anxiolytic effect (35). The most important representatives of benzodiazepines used to treat anxiety dis- orders are the alprazolam and clonazepam (33). An usual starting dose of alprazolam ranges from 0.25 to 0.5 milli- grams 2 to 3 times a day, and the maximum allowed dose is 2 milligrams 2 to 3 times daily, whereas the clonazepam can be administered at the same doses but twice daily (36). The use of benzodiazepine is contraindicated in the pregnancy and lactation (37).
OTHER DRUGS THAT CAN BE USED TO TREAT ANXIETY DISORDERS
Beta-blockers, primarily the proporanolol, can be used as an adjuvant therapy for the symptomatic treatment of somatic symptoms (tachycardia, palpitations) in the certain types of anxiety disorders (38), although results of recently
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   conducted meta-analysis from 2016 do not recommend the routine use of propranolol in the treatment of any type of anx- iety disorders (39). For the prevention of autonomic symp- toms of anxiety, it is advisable to use the propranolol at a dose from 20 to 40 milligrams an hour before the stressful event (40).

Tricyclic antidepressants have been proven to be effective in treating certain types of anxiety disorders (41), but because of serious adverse effects should be applied only in those pa- tients in whom SSRIs have not been shown to be effective (9). Trimipramine and imipramine at doses of 75 to 250 mg are used to treat panic disorders and agoraphobia, while for the treatment of the generalized anxiety disorder, the imipra- mine is used in doses from 75 to 200 mg. Clomipramine at doses from 75 to 300 milligrams is used for the treatment of obsessive-compulsive disorder, and the amitriptyline at doses from 75 to 200 mg for the treatment of post-traumatic stress disorder (23). There is no clear evidence that tricyclic antide- pressants are teratogen, although the probability is still high, especially for the clomipramine (42).
For the treatment of anxiety in practice some OTC prod- ucts and herbal medicines are often used. The use of such preparations for the treatment of anxiety may be accompa- nied by serious negative consequences. In most cases, these preparations are not effective enough to treat all symptoms of anxiety disorders, so the therapy is suboptimal. In addition, there is very little documented data of potential adverse ef- fects and drug-drug interactions of these preparations (43). Kava kava is a herbal medicine that has previously been used to treat anxiety (44), but recent research has shown that it has a serious hepatotoxic potential (5). Also, for the other herbal medicines, such as the root of valerian, randomized clinical studies and a meta-analysis have not shown significant effi- cacy when it comes to the treatment of anxiety disorders (45- 46).
ROLE OF PHARMACISTS IN TREATMENT OF PATIENTS WITH ANXIETY
According to the World Health Organization, Pharma- cists are labeled as health workers who are most accessible to all patients, including patients suffering from anxiety disor- ders. For this reason, modern trends imply more active and more important role that Pharmacists should have in the treat- ment of all mental disorders. It is evident that the role that Pharmacists have in the health care system is constantly evolving, so Pharmacists have a growing responsibility. It is certain that Pharmacists have a significant place in the opti- mizing therapy and dosing regimen, advising patients and controlling and improving adherence. According to recom- mendations of the WHO, Pharmacists should be the equal members of collaborative medical teams who successfully function in the treatment of depression, so something similar could be expected when it comes to the treatment of anxiety (47).
There are many critical points in the pharmacotherapy of anxiety disorders that could be significantly overcome through the more active role of Pharmacists. Question of the efficacy of anxiolytic therapy is very often imposed and re- quires a very careful approach from all healthcare profession- als involved in the treatment. It is especially important to de- termine the reason for the inadequate efficiency of pharma- cotherapy and this is perhaps the most important area within which Pharmacists can improve the treatment of anxiety. In- sufficient efficacy of pharmacotherapy of anxiety may be the result of a true resistance or pseudo-resistance (5). True re- sistance to the anxiety pharmacotherapy can be the result of an incorrect diagnosis (5), where the Pharmacist has no abil- ity to correct an error, or it may be the result of the action of certain exogenous factors (5), in which detection the Pharma- cist can certainly participate. It is known that certain exoge- nous factors, such as excessive use of coffee (48), smoking of marijuana (49), sleep disorders (50) and personal prob- lems, such as family problems or financial problems (5), can exacerbate anxiety and make it more difficult to treat it. As the part of regular communication with anxiety patient, the Pharmacist should to, through questions related to risk fac- tors, disclose their presence and provide adequate warning to the patient about consequences that may occur if the patient does not stop with a harmful life.
When it comes to the pseudo-resistance to anxiolytic ther- apy, it is mainly due to an insufficient adherence of patients. It is known that patients suffering from anxiety disorders of- ten show the reduced adherence to prescribed pharmacother- apy (5). Patients suffering from mental disorders often deny the existence of the disease and may have a disrupted relation with the medical staff, which is why their relation to the pre- scribed pharmacotherapy may be negative (51). However, it seems that reasons for the weaker adherence of anxiety pa- tients are related to the objective disadvantages of pharma- cotherapy, such as delayed start of the anxiolytic effect of an- tidepressants and the occurrence of adverse events (5). Im- proving the adherence of patients with mental disorders is designated as an area in which Pharmacists could play a key role (52). It is particularly important that Pharmacists, within the first several weeks before antidepressants show effect, in- dicate to patients this antidepressant therapy specific quality.
Common mistake that can be encountered in the treat- ment of patients with anxiety refer to the suboptimal treat- ment of patients (5), so the optimization of the dosing regi- men is another important role that Pharmacists should accept in the treatment of anxiety disorders (53).
Pharmacists have to take great responsibility when they prescribe benzodiazepines as an additional therapeutic line in the treatment of anxiety disorders. Benzodiazepines are used during the first few weeks of anxiety therapy as an adjunct to antidepressants due to the rapid manifestation of their anxio- lytic effect (35). A major problem with the use of benzodiaz- epines is related to the occurrence of strong psychic and physical dependence that follows their chronic administra- tion (32), and this is something that Pharmacists should
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   constantly warn their patients at each presription of benzodi- azepines. The problem could be results of some studies indi- cating that Pharmacists, as a rule, do not have enough time to provide more detailed information on benzodiazepines (53). Also, research of some authors suggest that benzodiazepines have the potential to exacerbate anxiety if they are not dosed appropriately (54).

Study conducted in Germany (43) has shown that patients suffering from anxiety disorders are very often opt for the application of specific OTC medicines. Treatment of anxiety patients using the OTC preparation is often suboptimal. Be- side that, a great problem in self-medication is the fact that patients consider that the OTC preparations are completely safe and therefore they prefer to use them at the expense of conventional drugs (55). Since it is known that some herbal preparations used to treat anxiety have a serious potential for the drug-drug interactions and adverse effects (56-57), it is important that Pharmacists, with their warnings, influence the patients’ attitudes who can be too benevolent in terms of the OTC preparations.
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