Anxiety Disorders – A Review

 

Vidya Raju*, Jasmine Joy Bell, Merlin. N. J, Shaiju S. Dharan

Department of Pharmacology, Ezhuthachan College of Pharmaceutical Sciences, Marayamuttom, Neyyattinkara, Thiruvananthapuram, Kerala.

 

ABSTRACT:

Anxiety is defined as the state of fear, apprehension, tension, panic and restlessness. If the symptoms of anxiety interfers the daily life activities then these are called anxiety disorders. Nowadays, anxiety became an important symptom of various mental disorders such as major depressive disorders, obsessive compulsive disorders, panic disorders, post traumatic stress disorders and various phobias. These disorders mainly affects one-eighth of the total population worldwide and became an important area in the psychopharmacology. The management of anxiety disorders results in high expenditure and negative impact on quality of life. Currently allopathic drugs became the major scenario in the anxiety treatments but these treatments produce large amounts of adverse effects. Use of herbal remedies for the treatment of anxiety is in fast progress.  The phytoconstituents of these medicinal plants are found to be acting through the serotonin and GABA neurotransmitters.

 

 

 

 

INTRODUCTION:

Anxiety is a state of fear, panic, restlessness, apprehension and tension.⁽¹⁾ Anxiety disorders are the most common mental, emotional and behavioral problems. These may affect one-eighth of the total population worldwide and became an important area in the psychopharmacology.⁽²⁾ These behavioral changes occurs mainly due to exteroceptive or interoceptive stimuli that passes through the endocrine and autonomic nervous systems.⁽¹⁾ The management of anxiety disorders results in high expenditure and negative impact on quality of life.⁽⁴⁾ Generally, anxiety is an adaptive response which may disturb homeostasis.⁽⁵⁾

 

Monoamines, Neuropeptides, GABA, Neurosteroids, Serotonin, Acetyl choline and Adenosine are the important biomodulators of anxiety.⁽⁵⁾ Under pharmacotherapy, benzodiazepines, selective serotonin inhibitors are widely used.⁽⁷⁾ Moreover these drugs are associated with various adverse effects like teratogenicity, sedation, dizziness and cognitive impairment⁽⁸⁾ However in response to this adverse effects, herbal remedies for anxiety treatment have similar action to that of synthetic drugs are in fast progress.⁽¹⁰⁾

 

CLINICAL CATEGORIES OF ANXIETY DISORDERS:

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria categorized anxiety disorders into ^(1-3):

·        Generalized anxiety Disorders

·        Panic Disorders

·        Post- traumatic Disorders

·        Social Anxiety Disorders

·        Obsessive Compulsive Disorders

·        Phobias

 

Generalized Anxiety Disorders:

Generalized anxiety disorder (GAD) is a syndrome of ongoing anxiety and worry about many events that the patient generally recognizes as excessive and inappropriate.^(1-2) Physical symptoms that often accompany with this anxiety disorders mainly include fatigue, headaches, muscle tension, muscle aches, difficulty swallowing, trembling, twitching, irritability, sweating, nausea, light headedness, feeling out of breath, and hot flashes.^(2-3)

 

Panic Disorder:

Panic Disorder is an attack of overwhelming fear. ⁽¹⁾Physical symptoms associated with this disorders are: sweating, unexpected recurrent panic attacks, tachycardia, chest pains, trembling and chocking.^(2-3)

 

Post-Traumatic Stress:

Post‐ traumatic Stress Disorder (PTSD) occurs due to insistent recall of past stressful experiences such as mugging, rape, torture, being kidnapped, child abuse, car accidents, natural disasters etc.^(1-3) Physical symptoms associated with PTSD are: night mares, irritability, mental tupors and relieving trauma.⁽⁴⁾

 

Social Anxiety Disorder:

Social anxiety disorder is also called as Social phobia which is observed when people become overwhelmingly anxious about everyday social situations. People with social phobia have an intense, persistent, and chronic fear.^(1-4). Physical symptoms that often accompany social phobia include blushing, profuse sweating, trembling, nausea, and difficulty talking.⁽⁴⁾

 

Phobia:

Phobia is a strong fear about specific things or situations while specific phobia is an intense, irrational fear of something that actually poses little or no threat. Some of the common specific phobias are heights, escalators, tunnels, highway driving etc⁽¹⁾ Physical symptoms that often accompany specific phobias include blushing, profuse sweating, trembling, nausea, and difficulty talking.⁽⁴⁾

 

Obsessive- Compulsive Disorder:

Obsessive-compulsive disorder (OCD) is a condition of repetitive thoughts and behaviors, i.e. recurrent obsessions or compulsions that cause marked distress or interfere significantly with normal activities.^(1-4)

NEUROMODULATORS OF ANXIETY:

Neuromodulators are simply neurotransmitters. These are the chemicals that are released from the brain and allows the impulses to transfer from one nerve cell to another nerve cell. These neurotransmitters affects the pathophysiology of anxiety in many ways.⁽⁵⁾ Some of the main biomodulators of anxiety are serotonin, dopamine, GABA, glutamate etc.

 

Seratonin:

Serotonergic pathways originate in the raphe nuclei and travels to forebrain. These circuits play a fundamental role in regulating brain states including anxiety, mood, energy and modulate the dopaminergic and noradrenergic pathways.^(5-6)

 

GABA (Gamma-amino butyric Acid):

GABA is the main inhibitory neurotransmitter in the central nervous system (CNS). Increases in GABA neurotransmission mediate the anxiolytic effect of barbiturates and benzodiazepines by opening chloride channels. Increased GABA level leads to increased neuronal firing and lowers its activity. ^(5-6)

 

Dopamine:

Dopaminergic pathways originate from the midbrain in the ventral tegmental area and substantia nigra travels to the cortex, striatum, limbic nuclei, and infundibulum. Dopamine blockade is the mechanism of antipsychotic medications which act as an anxiolytic. The upregulation of dopamine with norepinephrine in anxiety states, increases the dopaminergic signaling and reduce anxiety^(5-6)

 

Glutamate:

Glutamate is the excitatory neurotransmitter in the CNS. Glutamatergic pathways are probably involved in both conditioning and extinction helps in the development and treatment of anxiety disorders^(5-6)

 

Other neurotransmitters are substance P, neurosteroids, norepinephrine, melatonin, cholecystokinin etc. ^(5-6)

 

PATHOPHYSIOLOGY OF ANXIETY DISODERS:

Our human body tries to maintain homeostasis. Substances that disturb homeostasis is referred to as stressors. Homeostatic balance can be re-established by physiologic adaptations that are made to stress response.⁽⁶⁾ The pathophysiology of anxiety disorders are depicted in fig 1

 

 

Fig:1 Pathophysiology of anxiety disorders

 

The stress response in humans involves the cascade of release of Corticotropin Releasing Factor (CRF) which stimulates the release of corticotropin leading to release of stress hormones (glucocorticoids and epinephrine) from the adrenal cortex. The glucocorticoids exerts negative feedback to the hypothalamus, decreasing the release of CRF. This stress response can be often triggered by physical and homeostatic challenge.^(5,7,8)

 

The amygdala is the primary modulator of stress response inducing stimuli. This may receives input from neurons in the cortex and trigger the anxiety response. The amygdala also receives sensory input that bypasses the cortex. At the time of activation, amygdala stimulates the regions of the mid brain and brain stem causing autonomic hyperactivity. Thus the stress response involves the activation of hypothalamic pituitary adrenal axis (HPA). This axis will be hyperactive in anxiety and depression.^(7-8)

 

PHARMACOTHERAPY FOR ANXIETY DISORDERS:

People with anxiety disorders can benefit from a variety of treatments and services. Following an accurate diagnosis, possible treatments includes psychological treatments and medication therapy.⁽⁹⁾

 

Anti anxiety medications:

Psychological treatments:

·        Cognitive behavioural therapy (CBT)

·        Behavioral therapy

·        Psychotherapy

·        Psychodynamic therapy

·        Family therapy and parent training

 

 

Antianxiety drugs:

Benzodiazepines:

Diazepam, Lorazepam, Alprazolam, Oxazepam

 

Azapirones:

Buspirone, Ispapirone,Gepirone

 

Sedative antihistaminic:

Hydroxyzine

 

β blocker:

Propranolol

In addition to the above drugs, antidepressants, especially the selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors are effective in OCD, phobias, panic and many types of  severe generalized anxiety disorders.⁽⁸⁾List of anti anxiety drugs, their mechanism of action and their adverse effects are summarized in table 1

 

Psychological Treatments:

Psychotherapy is one of the choice of treatment in certain cases where anxiety is so severe that immediate relief is necessary to restore functioning and to prevent immediate and severe consequences.⁽⁸⁾

 

Behavioral Therapies:

These techniques mainly involves guided imagery, relaxation training, biofeedback (to control stress and muscle tension); progressive desensitization, flooding as means to reduce anxiety responses or eliminate specific phobias.⁽⁸⁾

 

Cognitive-behavioral therapy (CBT):

In this therapy, people learn to deal with fears by modifying the ways they think and behave. A major aim of CBT and behavioral therapy is to reduce anxiety by eliminating beliefs or behaviors that help to maintain the anxiety disorder. It has two components. The cognitive component helps people change thinking patterns that keep them from overcoming their fears. The behavioral component of CBT seeks to change people's reactions to anxiety-provoking situations.⁽⁷⁾

 

Psychotherapy:

Psychotherapy involves talking with a trained mental health professional, such as a psychiatrist, psychologist, social worker, or counselor to learn how to deal with problems like anxiety disorders^(7-8)

 

Psychodynamic therapy:

This therapy is based on primary sources of abnormal behavior and the possibility of unacceptable unconscious impulses will enter consciousness.^(7-8)

 

 

 

Family therapy and parent training:

This is based on the assumption that the individuals of a family cannot improve without understanding the conflicts that are found in the interactions of the family members.^(7-8)

 

TRADITIONAL MEDICINAL PLANTS WITH ANXIOLYTIC POTENTIAL:

Herbal medicines are one of the popular remedies for treating various ailments and very often these drugs are unscientifically exploited or improperly used. The traditional medicine refers to a broad range of ancient natural health care practices. Therefore, these plant traditions are dynamic entities of unchanging knowledge. Traditional medicine is an evolutionary process as communities and individuals continue to discover new techniques that can transform practices.^(9-10) Some of the medicinal plants that have anxiolytic potential are summarized in table 2.

Table: 1 Mechanism of action and adverse effects of anti anxiety drugs

Drugs	Mechanism of action	Adverse effects
Benzodiazepines (Diazepam, Lorazepam, Alprazolam)	Potentiates GABAergic transmission by influx of chloride ions and causes hyperpolarization effect	Sedation, light-headedness, psychomotor and cognitive impairment, confusional state, increased appetite and weight gain, alterations in sexual function.
Buspirones	Selective partial agonistic action on serotonin receptors. By stimulating presynaptic  serotonin autoreceptors, it reduces the activity of dorsal raphe seratonergic neurons.	Dizziness, head ache, rise in BP, nausea and light –headedness.
Selective serotonin reuptake inhibitors (Fluoxetine, Fluvoxamine, Paroxetine, citalopram , Dapoxetine)	Inhibit the serotonin transporter and appear to cause desensitization of postsynaptic serotonin receptors, thus normalizing the activity of serotonergic pathways	Nervousness, insomnia, anorexia, head ache, restlessness, dyskinesia, bowel upset
Seratonin , Noradrenaline reuptake inhibitors (Venlafaxine, Duloxetine)	Inhibit the serotonin and norepinephrine transporters	Nausea, sweating, anxiety, dizziness, impotence, increased appetite

 

Table :2 Anxiolytic potential of medicinal plants

Plant name	Chemical constituents	Uses
Hypericum perforatum	Hypericin, hyperforin	Anti‑depressent, anti anxiety, sedative, insomnia
Gastro diaelata  Blume	Phenolic compounds like vanillin, gastrodin	Neuroprotective activity, smooth muscle relaxant
Galphimia glauca Cav	Nor‑seco triterpene	Cytotoxic, sedative ,anti‑protozoal,anti‑anxiety
Citrus sineis Linn	Essential oils	Uterotonic, antifertility, anti‑diarrhoel activity
Euphorbia hirta Linn	Euphorbone	Anti‑diabetic, anti‑oxidant activity, hepatoprotective activity
Cecropia glazioui Sneth	Flavanoids like orientin, Terpene	Antihypertensive, cardiotonic, anti‑convulsants, anti‑nociceptive, anti‑inflammatory
Passiflora incarnata	Schaftoside orientins	Tranquillising effect on nervous system, anxiety, insomnia
Panax ginseng	Panaxidin	Anxiolytic
Centella  asiatica Linn	Asiaticoside	Anti‑stress, anti‑depressant

 

 

CONCLUSION:

Anxiety disorders are associated with cognitive impairments. An acute stress is the common outcome of exaggerated fear. Various allopathic medicines like benzodiazepines and selective serotonin inhibitors are available in the market. Due to their adverse effects and dependence potential they prove to be a challenge in the clinical practice.  A systematic approach of treatment should include patient education, examination of potential co morbidities empirically proven psychological and pharmacologic treatments with adequate monitoring and duration. Nowadays herbal medicines are preferred over the allopathic medications for treating anxiety disorders. Effective screening of herbal medicines will help to unveil newer anxiolytic drugs of plant origin.

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7.     Alexander B, Sahib SK, Michael E. Current Diagnosis and Treatment of Anxiety Disorders. Pharmacy and Therapeutics.  2013; 38 (1): 30-44.

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Received on 19.06.2017       Accepted on 10.08.2017     

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