Azapirones for the treatment of anxiety - an overview - World Scientific News

 
Azapirones for the treatment of anxiety - an overview - World Scientific News
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WSN 109 (2018) 14-25                                                                   EISSN 2392-219

               Azapirones for the treatment of anxiety
                           – an overview

            Bartosz Knap1,*, Stanisław Kwiatkowski2, Karolina Kolasińska2,
            Karolina Knap-Czop3, Dawid Przystupski2, Sylwia Roguzińska4,
                                   Ewa Kędzierska1
   1
    Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin,
                             4a Chodzki Str., 20-093, Lublin, Poland
                             2
                               Faculty of Medicine, Wroclaw Medical University,
                          5 J. Mikulicza-Radeckiego Str., 50-345 Wroclaw, Poland
                      3
                      Department of Clinical Genetics, Medical University of Lublin,
                            1 Radziwiłłowska Str., 20-080, Lublin, Poland
    4
       Faculty of Dentistry, Wroclaw Medical University, 26 Krakowska Str., 50-425 Wroclaw, Poland
                                 *E-mail address: knapbartek@gmail.com

ABSTRACT
       Anxiety disorders belong to the most common psychiatric diagnosis. Over the years,
benzodiazepines were considered the gold standard for pharmacological treatment of anxiety. They are
effective anxiolytics, but unfortunately the long-term use of benzodiazepines is accompanied by many
adverse events. An alternative to classical anxiolytics is a relatively new class of psychotherapeutic
drugs – azapirones. They are 5-HT1A partial agonists commonly used in the treatment of generalized
anxiety disorder and as augmentation for SSRI in social anxiety disorder and depression. Due to the
high ratio of benefits to risk, azapirones are extensively studied for their use in other disease entities.
The aim of this article was to overviewed current information on azapirones. Their history of
development, mechanism of action, pharmacokinetics, interactions , clinical use and their role in the
modern pharmacotherapy of anxiety.

Keywords: azapirones, buspirone, gepirone, ipsapirone, tandospirone, anxiety disorder

          ( Received 12 August 2018; Accepted 27 August 2018; Date of Publication 29 August 2018 )
World Scientific News 109 (2018) 14-25

1. INTRODUCTION

       Anxiety disorders are one of the most common mental complaints in the world. They
can self-exist, however, their presence in the image of other psychological illness is very often
noted, among others in depression [61]. According to epidemiological studies, it is estimated
that over 42% of all depressive disorders are mixed anxiety-depressive syndromes, and in the
case of over 19%, depression is described with coexisting anxiety [53].
       Moreover the presence of anxiety in the course of depressive disease translates into
greater severity of symptoms, stronger impairment of psychosocial functions and less
optimistic prognosis [27]. It is associated with a weaker response to treatment and a higher
risk of suicidal episodes [14].
       The coexistence of anxiety with other psychological illness and numerous somatic and
autonomic symptoms – especially in the case of panic disorder – make correct diagnosis and
treatment of anxiety disorders still pose a challenge for modern medicine [46]. Also from a
pharmacological point of view, the treatment of anxiety disorders is problematic. Although
drugs used in the treatment of anxiety constitute a large group of agents with different
mechanisms of action, there is still a lack of complex preparations. Most of the drugs used are
not very specific and often have a more sedation-oriented effect than anxiolytic properties.
Others, despite their higher specificity (e.g. benzodiazepines) generate problems of addiction
and tolerance [47, 57].
       A relatively new class of psychotherapeutic drugs - azapirones – may be the answer to
the problem of the proper pharmacotherapy of anxiety. Azapirones are a great advance in the
design of drugs with anxiolytic and antidepressant properties. Due to the high ratio of benefits
to risk, azapirones are widely used and examined in the treatment of anxiety, mixed anxiety-
depressive disorder, as well as other psychiatric diseases related to dysfunctions of serotonin
mechanisms [7].

2. MATERIALS AND METHODS

      A literature search was performed using PubMed, Scopus, Web of Science, Google
Scholar databases. The following terms were searched: “azapirones”, “buspirone”,
“gepirone”, “ipsapirone”, “tandospirone”, “(anxiety OR anxiety disorder OR anxiety
treatment) AND azapirones” and limited to the English or Polish language.

2. 1. History of development
      First attempts to treat anxiety disorders have their origins in ancient times. Over the
centuries, anxiolytic drugs have gradually evolved from simple, non-selective substances like
alcohol, opioids or bromides, through barbiturates and meprobramat, to a breakthrough in
1958 - the patenting of the first benzodiazepine, i.e. chlordiazepoxide.
      This discovery introduced pharmacotherapy of anxiety in the era of modern medicine,
and benzodiazepines themselves became one of the most frequently prescribed drugs in
history. With the popularity of benzodiazepines, more and more problems related to their use
have begun to be revealed: tolerance, addiction, mass consumption - resulting from self-
medication - leading to numerous dangerous and often fatal overdoses [30, 32].

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      This phenomenon forced intensified attempts to search for and design new substances
with anxiolytic activity. The FDA (Food and Drug Administration) approval of a new drug
for the treatment of GAD (General Anxiety Disorder) – buspirone – in 1986, marked a new
age of psychotherapeutic drug therapy [13]. Among other substances belonging to the class of
azapirones, alphabetically, alnespirone, binospirone, enilospirone, eptapirone, gepirone,
ipsapirone, revospirone tandospirone, umespirone, zalospirone can be mentioned [7, 23].
They remain at various stages of development or research on them has been abandoned. The
three most promising agents – gepirone, ipsapirone, tandospirone (Table 1.) – are undergoing
clinical trials for the treatment of GAD [58]. Nowadays, tandospirone is also registered in
China as an antidepressant and anxiolytic drug [3].

                   Table 1. Structures of azapirones. Modified from: [58]

                         R                                     Name of compound

                                                                    Buspirone

                                                                    Gepirone

                                                                    Ipsapirone

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                                                                      Tandospirone

2. 2. Pharmacotherapy of anxiety disorders
      From a pharmacological point of view, the treatment of anxiety disorders can be
characterized according to two main directions of action of used drugs. One of them is the
agonistic effect of ligands on the GABA-ergic system – more precisely on the GABAA
receptors [45]. The most well-known representatives of this mechanism are benzodiazepines
being the gold standard for the treatment of anxiety disorders. The second direction of action
of anxiolytics is affecting the functioning of the serotonin system. This mechanism underlies
therapeutic efficacy, among others azapirone anxiolytics and a variety of antidepressant drugs
[23].

2. 3. Mechanism of action
      The exact mechanism of the anxiolytic action of azapirones still remains unclear.
However, it is known, that it results from the partial agonism toward the serotonin 5-HT1A
receptor [26]. These receptors belong to the G protein coupled receptors (GPCR) superfamily.
Their activation inhibits adenylyl cyclase and decreases the amount of cAMP (3',5'-cyclic
adenosine monophosphate) thanks to the Gi and Go proteins (Figure 1.) [25]. The highest
concentration of 5-HT1A receptors in human body is observed in the limbic areas of the brain
(including hippocampus, amygdala, lateral septum) and raphe nuclei. In smaller amounts,
they are also located in the cortical areas (especially prefrontal cortex and entorhinal cortex),
thalamus, hypothalamus and basal ganglia (e.g. in the striatum) [41].
      5-HT1A receptors exist as both presynaptic autoreceptors as well as postsynaptic
heteroreceptors. As autoreceptors, they are located on the bodies and dendrites of serotonin
neurons in the area of the raphe nuclei. They inhibit the activity of the system, causing
suppression of endogenous serotonin secretion into the synaptic space by means of negative
feedback. The effect is a weakening of the transmission in serotonin neurons. Due to this
mechanism, 5-HT1A receptors control the general tone of serotonin activity [1, 9].
Postsynaptic 5-HT1A receptors (heteroreceptors) are located in the terminal nerves of the
CNS. They regulate the sensory, motor, autonomic and psychoemotional processes. Their
stimulation causes an increase in the activity of serotonin neurons, while inhibiting the
transmission in other neurons, in different areas of the brain (e.g. hippocampus or celebral
cortex) [1].
      Numerous scientific studies suggest that the insufficient activity of 5-HT1A receptors
plays a key role in the pathomechanism of anxiety. In studies conducted on knockout mice –
with an inactivated gene coding the 5-HT1A receptor – it was found that animals with

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a receptor deficiency, have a greater tendency to avoid the fearful environment and stressful
situations compared to mice with an intact receptor [42].
       Also observations conducted on patients suffering from anxiety disorders confirm the
participation of 5-HT1A receptors in the etiology of anxiety. Nash and collogues found that the
positron emission tomography (PET) scan of untreated patients with panic disorder shows
significant changes in the 5-HT1A receptor domain. In comparison with healthy volunteers,
both presynaptic and postsynaptic 5-HT1A receptor binding was reduced in untreated patients.
The most significant reductions has been observed in the raphe, orbitofrontal cortex, temporal
cortex and amygdala [38].
       Azapirones, in the presynaptic 5-HT1A autoreceptors, behave as total agonists. They
stimulate the activity of 5-HT1A presynaptic autoreceptors, and thus inhibit the release of
endogenous serotonin from synaptic terminals. However, with long-term administration of
azapirones, down-regulation (desensitization) of these receptors and enhanced serotonin
release occurs. In the case of postsynaptic 5-HT1A heteroreceptors, azapirones are partial
antagonists, i.e. they act as antagonists when serotonin levels at receptor area are high, and as
agonists when serotonin levels are low [22, 51]. Stimulation of postsynaptic 5-HT1A
heteroreceptors in corticolimbic structures causes an increase in the activity of monoamine
system and, as a result, produces anxiolytic and antidepressant-like effect. Additionally, these
receptors have a modulatory effect on other neurons (e.g. glutamatergic) in various brain
regions, which can also contribute to this effect [1].

                                                Synaptic cleft                              Na+ channel        K+ channel

                                 5-HT1A partial                         Protein            Na+
                                                      Adenylate                                           K+
                                    agonist                             kinase C
                                                       cyclase
 Serotonin                        (buspirone)

                         !
                                                  #                                                         K+
                     "
                     #
                                      !
                                  "       ATP                          cAMP                  Ca2+ channel
               Inhibitory
               G-protein

  Post-synaptic membrane

             Cytoplasm                                                               Ca+
                                                             Endoplasmic reticulum

   Figure 1. 5-HT1A partial agonist (buspirone) mechanism of action. Modified from: [43]

      Besides the effects on serotonin mechanisms, scientific reports are increasingly focusing
on two alternative mechanisms of action of azapirones. One of them is the dopaminergic
theory of azapirones. Buspirone is an antagonist of dopamine receptors with high affinity for

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the D3 and D4 receptor and lower for D2 [28]. Recent studies on animal models indicate the
involvement of dopamine D3 receptors in the occurrence of anxiety behavior [12, 37]. The
above results may suggest that at the base of the anxiolytic effects of buspirone lies its affinity
for the D3 receptor. Another alternative mechanism of action of azapirones is based on their
affinity for adrenergic receptors. The 2 adrenergic receptors located on serotoninergic
neurons modulate the release of serotonin from synaptic terminals [49]. Buspirone as an
antagonist of 2 adrenergic receptors increase secretion of endogenous serotonin [20].

2. 4. Pharmacokinetics
       Azapirones are generally admnistered orally and rapidly absorbed, with a very short
half-lives of approximately 1-3 hours. As a result, they must be administered several times a
day (e.g. buspirone and tandospirone – 3 times daily) [17, 33]. The exception is umespirone
with a long duration of action up to 23 hours [24]. Unfortunately, umespirone has not been
comercialized, but research is currently ongoing on the development of extended-realease
formulation of buspirone [48].
       Azapirones are metabolized mainly in the liver and excreted in urine and feces. Most
azapirones including buspirone, gepirone, ipsapirone, tandospirone have common metabolite
1-(2-pyrimidinyl)-piperazine (1-PP). 1-PP has 5-HT1A partial agonist and α2-adrenoceptor
antagonist activity, but mostly it is associated with the occurrence of side effects [34, 60].

2. 5. Clinical use
      To date, the main and only registration indication for azapirones is GAD. At the same
time, buspirone still remains the only one (apart from tandospiron, registered only in Asian
countries) commercially used azapirone. Its use in the treatment of GAD is often questioned,
however, numerous studies confirm its effectiveness in eliminating anxiety symptoms [8, 15,
59]. It is also effective in the treatment of GAD with coexisting depressive symptoms [19,
50]. In addition to GAD, azapirones have a wide range of so-called off-label use. Buspirone is
used, among others, to potentiate the SSRI (selective serotonin reuptake inhibitors) action in
the treatment of social anxiety disorder [35]. Azapirones also demonstrate antidepressant
efficacy, both in studies conducted on rodents as well as in human clinical trials [4, 5, 29, 44].
Unfortunately, their usefulness in this context is limited and occurs only in the case of milder
forms of depression. Nevertheless, they are commonly employed as an augmentation of SSRI
[52]. Buspirone can also be effective in the treatment of panic disorder [26], functional
dyspepsia [21], ADHD (attention-deficit hyperactivity disorder) [10], ADD (attention deficit
disorder) [40] or even alcoholism [6, 31]. However, in these cases the results are not clear, so
further studies are needed. Azapirones can also be effective as augmentation agent in
treatment of schizophrenia. Studies on buspirone and tandospirone have shown that they may
have a possible benefits in enhancing some types of cognitive performance in patients
suffering from this mental disorder. [55, 56].

2. 6. Interactions
      Buspirone turns out to be relatively safe in combination with a wide variety of different
agents. Most common interaction of buspirone is observed with MAO (monoamomino
oxidase) and is responsible for occurrence of hypertension. Significant adverse interaction
have also been observed during concomitant administration with cyclosporine, haloperidol,

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clomipramine and disulfiram. Buspirone can be safely used with wide range of
antidepressants, hypertensives, H2-blockers, anticonvulsants and anti-diabetic medications.
Furthermore comparing to benzodiazepines buspirone does not exhibit serious interactions
with alcohol [33, 54, 60].

2. 7. Comparison to benzodiazepines
      Azapirones are generally well tolerated class of drugs with very wide therapeutic index
and small range of side effects. Thus, with relatively safe profile, buspirone can be an
alternative to other anxiolytics with a lower ratio of benefits to risk, such as benzodiazepines.
The most common side effects of buspirone are: dizziness and lightheadedness, headache,
nervousness, nausea, diarrhea, paresthesia, excitation and sweating [11, 16]. Compared to
benzodiazepines (Table 2.), patients treated with buspirone are less likely to experience
fatigue and weakness and less frequent depressive episodes [39]. In addition, buspirone does
not induce sedation and has no addiction potential. Therefore no withdrawal symptoms or
rebound anxiety following discontinuation occurs. Buspirone also does not affect cognitive
performance and driving skills and does not interact with alcohol [16].
      However, the results of the studies are not clear whether azapirones are as effective as
benzodiazepines in the treatment of GAD [8, 18, 36]. In addition, in the case of patients
previously treated with benzodiazepines, buspirone may prove insufficiently effective. The
reason for this phenomenon is unknown [8, 18]. Moreover, buspirone has a slow onset of
action with latency around 1-3 week [16]. For this reason it is not recommended as a first-line
agent in treatment of GAD [2].

          Table 2. Comparison of clinical effects of azapirones and benzodiazepines
                         (+ effect occurs; – effect does not occur)

                     Effect                            Azapirones          Benzodiazepines

                                                            -
              Fast onset of action                                                 +
                                                       (1-3 weeks)
            Direct effect on anxiety                         -                     +
             Antidepressant effect                          +                      -
             Anticonvulsant effect                           -                     +
                Hypnotic effect                              -                     +
                Sedative effect                              -                     +
              Myorelaxant effect                             -                     +
                Amnestic effect                              -                     +
                                                                                   +
            Impact on panic attacks                          -
                                                                             (alprazolam)

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      Strong impact on psychomotor functions                  -                     +
           Impact on respiratory center                       -                     +
                                                                                    +
              Interaction with alcohol                        -              (potentiation of
                                                                                 action)
           Paradoxical stimulant effects                      -                     +
Withdrawal syndrome after discontinuation of
                                                              -                     +
                treatment
                Addictive potential                           -                     +

3. CONCLUSIONS

      Azapirones are a popular and widely used class of drugs in the treatment of anxiety
disorders. Numerous scientific studies confirm effectiveness of buspirone in the treatment of
GAD. It also turns out to be effective as an augmentation of SSRI in the treatment of social
anxiety disorder and depression. Due to its relatively safe pharmacological profile and few
adverse effects, buspirone is extensively studied in its use in other disease entities, such as:
panic disorder, functional dyspepsia, ADHD and ADD, alcoholism or schizophrenia. Despite
many advantages, buspirone does not meet all expectations, such as the lack of direct
antidepressant action or in some cases debatable anxiolytic action. For this reason, new
compounds from the class of azapirone derivatives are persistently designed and tested.
Unfortunately, today buspirone still remains the only azapirone used on a wider scale.

References

[1]     Artigas F, Developments in the field of antidepressants, where do we go now?,
        European Neuropsychopharmacology, 25(5) (2015) 657–70.
[2]     Bandelow B, Zohar J, Hollander E, et al., World Federation of Societies of Biological
        Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety,
        Obsessive-Compulsive and Post-Traumatic Stress Disorders – First Revision, The
        World Journal of Biological Psychiatry, 9(4) (2008) 248–312.
[3]     Belmer A, Patkar OL, Lanoue V, Bartlett SE, 5-HT1A receptor-dependent modulation
        of emotional and neurogenic deficits elicited by prolonged consumption of alcohol,
        Scientific Reports, 8(1) (2018) 2099.
[4]     Bielski RJ, Cunningham L, Horrigan JP, Londborg PD, Smith WT, Weiss K, Gepirone
        extended-release in the treatment of adult outpatients with major depressive disorder: a
        double-blind, randomized, placebo-controlled, parallel-group study, The Journal of
        clinical psychiatry, 69(4) (2008) 571–7.
[5]     Blier P, Ward NM, Is there a role for 5-HT1A agonists in the treatment of depression?,
        Biological Psychiatry, 53(3) (2003) 193–203.

                                               -21-
World Scientific News 109 (2018) 14-25

[6]   Bruno F, Buspirone in the Treatment of Alcoholic Patients, Psychopathology, 22(1)
      (1989) 49–59.
[7]   Cadieux RJ, Azapirones: an alternative to benzodiazepines for anxiety, American family
      physician, 53(7) (1996) 2349–53.
[8]   Chessick CA, Allen MH, Thase M, et al., Azapirones for generalized anxiety disorder,
      The Cochrane database of systematic reviews, 3 (2006) CD006115.
[9]   Chilmonczyk Z, Bojarski A, Pilc A, Sylte I, Functional Selectivity and Antidepressant
      Activity of Serotonin 1A Receptor Ligands, International Journal of Molecular
      Sciences, 16(8) (2015) 18474–506.
[10] Davari-Ashtiani R, Eslami Shahrbabaki M, Razjouyan K, Amini H, Mazhabdar H,
     Buspirone Versus Methylphenidate in the Treatment of Attention Deficit Hyperactivity
     Disorder: A Double-Blind and Randomized Trial, Child Psychiatry & Human
     Development, 41(6) (2010) 641–8.
[11] Davidson JRT, Feltner DE, Dugar A, Management of generalized anxiety disorder in
     primary care: identifying the challenges and unmet needs, Primary care companion to
     the Journal of clinical psychiatry, 12(2) (2010).
[12] Diaz MR, Chappell AM, Christian DT, Anderson NJ, McCool BA, Dopamine D3-Like
     Receptors Modulate Anxiety-Like Behavior and Regulate GABAergic Transmission in
     the Rat Lateral/Basolateral Amygdala, Neuropsychopharmacology, 36(5) (2011) 1090–
     103.
[13] Eison AS, Azapirones: history of development, Journal of clinical
     psychopharmacology, 10(3 Suppl) (1990) 2S–5S.
[14] Fawcett J, Barkin RL, Review of the results from clinical studies on the efficacy, safety
     and tolerability of mirtazapine for the treatment of patients with major depression,
     Journal of Affective Disorders, 51 (1998) 267–85.
[15] Feighner JP, Buspirone in the long-term treatment of generalized anxiety disorder, The
     Journal of clinical psychiatry, 48 Suppl (1987) 3–6.
[16] Feighner JP, Boyer WF, Serotonin-1A anxiolytics: an overview, Psychopathology, 22
     Suppl 1 (1989) 21–6.
[17] Fuhr U, Staib AH, Harder S, et al., Absorption of ipsapirone along the human
     gastrointestinal tract, British journal of clinical pharmacology, 38(1) (1994) 83–6.
[18] Gale CK, Millichamp J, Generalised anxiety disorder, BMJ Clinical Evidence, 2011
     (2011).
[19] Gammans RE, Stringfellow JC, Hvizdos AJ, et al., Use of buspirone in patients with
     generalized anxiety disorder and coexisting depressive symptoms. A meta-analysis of
     eight randomized, controlled studies, Neuropsychobiology, 25(4) (1992) 193–201.
[20] Gobert A, Rivet J-M, Cistarelli L, Melon C, Millan MJ, Buspirone modulates basal and
     fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the
     frontal cortex of freely moving rats: activation of serotonin1A receptors and blockade of
     α2-adrenergic receptors underlie its actions, Neuroscience, 93(4) (1999) 1251–62.

                                             -22-
World Scientific News 109 (2018) 14-25

[21] Grover M, Camilleri M, Effects on gastrointestinal functions and symptoms of
     serotonergic psychoactive agents used in functional gastrointestinal diseases, Journal of
     Gastroenterology, 48(2) (2013) 177–81.
[22] Heiser JF, Wilcox CS, Serotonin 5-HT1A Receptor Agonists as Antidepressants, CNS
     Drugs, 10(5) (1998) 343–53.
[23] Hensler JG, Regulation of 5-HT1A receptor function in brain following agonist or
     antidepressant administration, Life sciences, 72(15) (2003) 1665–82.
[24] Holland RL, Wesnes K, Dietrich B, Single dose human pharmacology of umespirone,
     European Journal of Clinical Pharmacology, 46(5) (1994) 461–68.
[25] Hoyer D, Hannon JP, Martin GR, Molecular, pharmacological and functional diversity
     of 5-HT receptors, Pharmacology Biochemistry and Behavior, 71(4) (2002) 533–54.
[26] Imai H, Tajika A, Chen P, et al., Azapirones versus placebo for panic disorder in adults,
     The Cochrane database of systematic reviews, (9) (2014) CD010828.
[27] Keller MB, Hanks DL, Anxiety symptom relief in depression treatment outcomes, The
     Journal of clinical psychiatry, 56 Suppl 6 (1995) 22–9.
[28] Kim SW, Fowler JS, Skolnick P, et al., Therapeutic doses of buspirone block D3
     receptors in the living primate brain, The International Journal of
     Neuropsychopharmacology, 17(8) (2014) 1257–67.
[29] Koek W, Patoiseau JF, Assié MB, et al., F 11440, a potent, selective, high efficacy 5-
     HT1A receptor agonist with marked anxiolytic and antidepressant potential, The
     Journal of pharmacology and experimental therapeutics, 287(1) (1998) 266–83.
[30] Konopka A, Wroński M, Samochowiec J, The medicine’s potentiality in the area of
     anxiety treatment — history and the present day, Psychiatria, 10(2) (2013) 55–62.
[31] Kranzler HR, Buspirone Treatment of Anxious Alcoholics, Archives of General
     Psychiatry, 51(9) (1994) 720-31.
[32] López-Muñoz F, Álamo C, García-García P, The discovery of chlordiazepoxide and the
     clinical introduction of benzodiazepines: Half a century of anxiolytic drugs, Journal of
     Anxiety Disorders, 25(4) (2011) 554–62.
[33] Mahmood I, Sahajwalla C, Clinical Pharmacokinetics and Pharmacodynamics of
     Buspirone, an Anxiolytic Drug, Clinical Pharmacokinetics, 36(4) (1999) 277–87.
[34] Manahan-Vaughan D, Anwyl R, Rowan MJ, The azapirone metabolite 1-(2-
     pyrimidinyl)piperazine depresses excitatory synaptic transmission in the hippocampus
     of the alert rat via 5-HT1A receptors, European journal of pharmacology, 294(2–3)
     (1995) 617–24.
[35] Masdrakis VG, Turic D, Baldwin DS, Pharmacological treatment of social anxiety
     disorder, Modern trends in pharmacopsychiatry, 29 (2013) 144–53.
[36] Mitte K, Noack P, Steil R, Hautzinger M, A Meta-analytic Review of the Efficacy of
     Drug Treatment in Generalized Anxiety Disorder, Journal of Clinical
     Psychopharmacology, 25(2) (2005) 141–50.

                                             -23-
World Scientific News 109 (2018) 14-25

[37] Moraga-Amaro R, Gonzalez H, Pacheco R, Stehberg J, Dopamine receptor D3
     deficiency results in chronic depression and anxiety, Behavioural Brain Research, 274
     (2014) 186–93.
[38] Nash JR, Sargent PA, Rabiner EA, et al., Serotonin 5-HT1A receptor binding in people
     with panic disorder: positron emission tomography study, British Journal of Psychiatry,
     193(03) (2008) 229–34.
[39] Newton RE, Marunycz JD, Alderdice MT, Napoliello MJ, Review of the side-effect
     profile of buspirone, The American journal of medicine, 80(3B) (1986) 17–21.
[40] Niederhofer H, An open trial of buspirone in the treatment of attention-deficit disorder,
     Human Psychopharmacology: Clinical and Experimental, 18(6) (2003) 489–92.
[41] Ohno Y, Therapeutic Role of 5-HT1A Receptors in The Treatment of Schizophrenia
     and Parkinson’s Disease, CNS Neuroscience & Therapeutics, 17(1) (2011) 58–65.
[42] Parks CL, Robinson PS, Sibille E, Shenk T, Toth M, Increased anxiety of mice lacking
     the serotonin1A receptor, Proceedings of the National Academy of Sciences of the
     United States of America, 95(18) (1998) 10734–9.
[43] Penington NJ, Fox AP, Effects of LSD on Ca++ currents in central 5-HT-containing
     neurons: 5-HT1A receptors may play a role in hallucinogenesis, The Journal of
     pharmacology and experimental therapeutics, 269(3) (1994) 1160–5.
[44] Robinson DS, Rickels K, Feighner J, et al., Clinical effects of the 5-HT1A partial
     agonists in depression: a composite analysis of buspirone in the treatment of depression,
     Journal of clinical psychopharmacology, 10(3 Suppl) (1990) 67S–76S.
[45] Rupprecht R, Eser D, Zwanzger P, Möller H-J, GABA A receptors as targets for novel
     anxiolytic drugs, The World Journal of Biological Psychiatry, 7(4) (2006) 231–237.
[46] Rzewuska M, Leczenie zaburzeń nerwicowych, Farmakoterapia w Psychiatrii i
     Neurologii, 99(1) (1999) 47–75.
[47] Rzewuska M, Pużyński S, Jarema M, et al., Standardy i algorytmy farmakoterapii w
     zaburzeniach lękowych i obsesyjno-kompulsyjnych, Farmakoterapia w Psychiatrii i
     Neurologii, 99(1) (1999) 7–18.
[48] Sakr A, Andheria M, Pharmacokinetics of buspirone extended-release tablets: a single-
     dose study, Journal of clinical pharmacology, 41(7) (2001) 783–9.
[49] Scheibner J, Trendelenburg A-U, Hein L, Starke K, α 2 -Adrenoceptors modulating
     neuronal serotonin release: a study in α 2 -adrenoceptor subtype-deficient mice, British
     Journal of Pharmacology, 132(4) (2001) 925–33.
[50] Sramek JJ, Tansman M, Suri A, et al., Efficacy of buspirone in generalized anxiety
     disorder with coexisting mild depressive symptoms, The Journal of clinical psychiatry,
     57(7) (1996) 287–91.
[51] Stahl S, 5HT1A receptors and pharmacotherapy. Is serotonin receptor down-regulation
     linked to the mechanism of action of antidepressant drugs?, Psychopharmacology
     bulletin, 30(1) (1994) 39–43.

                                             -24-
World Scientific News 109 (2018) 14-25

[52] Stahl SM, Lee-Zimmerman C, Cartwright S, Morrissette DA, Serotonergic drugs for
     depression and beyond, Current drug targets, 14(5) (2013) 578–85.
[53] Stein MB, Kirk P, Prabhu V, Grott M, Terepa M, Mixed anxiety-depression in a
     primary-care clinic, Journal of Affective Disorders, 34 (1995) 79–84.
[54] Steinberg JR, Anxiety in elderly patients. A comparison of azapirones and
     benzodiazepines, Drugs & aging, 5(5) (1994) 335–45.
[55] Sumiyoshi T, Matsui M, Nohara S, et al., Enhancement of Cognitive Performance in
     Schizophrenia by Addition of Tandospirone to Neuroleptic Treatment, American
     Journal of Psychiatry, 158(10) (2001) 1722–5.
[56] Sumiyoshi T, Park S, Jayathilake K, Roy A, Ertugrul A, Meltzer HY, Effect of
     buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: A
     randomized, double-blind, placebo-controlled study, Schizophrenia Research, 95(1–3)
     (2007) 158–68.
[57] Świȩcicki Ł, Praktyczne aspekty farmakoterapii lȩku - Pozycja opipramolu, Psychiatria,
     10(2) (2013) 63–6.
[58] Taylor DP, Moon SL, Buspirone and related compounds as alternative anxiolytics,
     Neuropeptides, 19 Suppl (1991) 15–9.
[59] Wittchen H-U, Generalized anxiety disorder: prevalence, burden, and cost to society,
     Depression and Anxiety, 16(4) (2002) 162–171.
[60] Azapirones have potential in a wide variety of CNS disorders, Drugs & Therapy
     Perspectives, 5(1) (1995) 5–7.
[61] WHO | The world health report 2001 - Mental Health: New Understanding, New Hope,
     WHO, (2013).

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