Available online at www.worldscientificnews.com

( Received 12 August 2018; Accepted 27 August 2018; Date of Publication 29 August 2018 )

WSN 109 (2018) 14-25 EISSN 2392-2192

Azapirones for the treatment of anxiety – an overview

Bartosz Knap1,*, Stanisław Kwiatkowski2, Karolina Kolasińska2,

Karolina Knap-Czop3, Dawid Przystupski2, Sylwia Roguzińska4,

Ewa Kędzierska1

1Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, 4a Chodzki Str., 20-093, Lublin, Poland

2Faculty of Medicine, Wroclaw Medical University, 5 J. Mikulicza-Radeckiego Str., 50-345 Wroclaw, Poland

3Department of Clinical Genetics, Medical University of Lublin, 1 Radziwiłłowska Str., 20-080, Lublin, Poland

4Faculty 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

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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].

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

Synaptic cleft

Cytoplasm

Serotonin

Na+

K+

Ca+

5-HT1A partial agonist

(buspirone)

K+

Adenylatecyclase

Protein kinase C

Na+ channel K+ channel

Ca2+ channel

Endoplasmic reticulum

Post-synaptic membrane

cAMPATP

!

"

#

#

!

"

Inhibitory G-protein

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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.

World Scientific News 109 (2018) 14-25

-22-

[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.

World Scientific News 109 (2018) 14-25

-23-

[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.

World Scientific News 109 (2018) 14-25

-24-

[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.

World Scientific News 109 (2018) 14-25

-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).