Anxiety Treatment

When deciding which medications for anxiety disorders to offer, take into account:

• Age of patient
• Treatment response
  • When a member of a certain drug class has been proven effective, it must not be assumed that the other members of that class will be similarly effective

• Risks for accidental overdose and deliberate self-harm
• Tolerability
• Patient’s previous experience of treatment with individual drugs (eg adherence, effectiveness, side effects, experience of withdrawal syndrome)
• Patient’s preference
  • Discuss patient’s reason for this intervention and other concerns

• Cost of therapy

Benzodiazepines

• Act through enhancement of gamma-aminobutyric acid (GABA) which is a major inhibitory neurotransmitter in the brain
  • Reduced neural transmission throughout the central nervous system
    

• Recommended for short-term treatment with regular use
• Physical dependence and tolerance may develop
• Use with caution in patients with history of substance or drug abuse

• Generalized anxiety disorder (GAD)
  • Widely used
  • Both short- and long-acting benzodiazepines have been proven to have a rapid onset of anxiolytic action
  • Effectively decrease somatic symptoms
  • Do not reduce depressive symptoms
  • Limited effect on reducing worry
  • Recommend to limit use to acute treatment
    • May be used as an adjunct for long-term treatment if there is no occurrence of serious side effects, misuse or abuse
  • Should not be used beyond 2-4 weeks

• Panic disorder
  • May be added to antidepressants up to 4 weeks (short-term) for rapid response then tapered down and withdrawn by 4 weeks
  • May be used as second line or alternative agent
  • Alprazolam, Clonazepam, Lorazepam and Diazepam have demonstrated efficacy
  • Studies have shown that addition of Clonazepam to selective serotonin reuptake inhibitor at start of treatment can lead to rapid response
  • Reduce frequency and intensity of panic attacks, reduce anticipatory anxiety
  • May also lead to decreased avoidance of phobias
  • Rapid onset of action
  • Associated with less good long-term outcome than antidepressants

• Social anxiety disorder (SAD)
  • May be used with selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor; however, available literature is not available to support this
  • Not recommended as mono-therapy for patients with concomitant depression
  • Rapid onset of action
  • Relapse upon withdrawal is common

Azaspirodecanedione

Buspirone

• Has dopaminergic, noradrenergic and serotonin-modulating properties
  • Anxiolytic effects seem to be due to its action on serotonin

• Generalized anxiety disorder
  • May be used as 2nd-line agent
  • Useful in patients with history of substance abuse
  • Has shown to be as effective as benzodiazepines
    • More effective in treating cognitive rather than somatic symptoms
    • Does not cause physical dependence or tolerance
    • Takes 2-3 weeks to see effect, average of 4 weeks
    • Effects may be reduced in patients who have recently taken benzodiazepines
  • Not suitable for patients with comorbid depression

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Selective serotonin reuptake inhibitors are recommended as 1st-line drug treatment for anxiety disorders
• All selective serotonin reuptake inhibitors are thought to be equally effective; however, they differ in their side-effect profiles
• Generalized anxiety disorder
  • Not all selective serotonin reuptake inhibitors have been studied or approved for use in generalized anxiety disorder
  • Consider giving Sertraline as the 1st drug because it is the most cost-effective among the selective serotonin reuptake inhibitors
  • Other selective serotonin reuptake inhibitors recommended are Escitalopram and Paroxetine
  • May be more effective than benzodiazepines
    • Provide greater benefit than benzodiazepines for decreasing cognitive issues
    • Do not cause physical dependence or tolerance
    • Slower onset of action than benzodiazepines
    • Suitable for patients with comorbid depression

• Panic disorder
  • Not all selective serotonin reuptake inhibitors have been approved for use in panic disorder but studies have shown all are helpful in panic disorder
  • Eg Citalopram, Escitalopram, Fluoxetine, Paroxetine, Sertraline
  • Better tolerated and with better adverse effect profile compared to older antidepressants
  • Reduce frequency and intensity of panic attacks, reduce anticipatory anxiety and associated depression

• Social anxiety disorder
  • Many studies of certain selective serotonin reuptake inhibitors have shown efficacy
    • Consider Citalopram, Escitalopram, Fluvoxamine, Paroxetine or Sertraline
  • Suitable for patients with comorbid depression

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

Venlafaxine

• Considered as 1st-line agent for generalized anxiety disorder, panic disorder and social anxiety disorder
• Requires initial electrocardiogram (ECG) and blood pressure (BP) reading prior to treatment
• Generalized anxiety disorder
  • Studies have shown therapeutic benefit in both long- and short-term use
  • Onset of action: Improvement has been observed after 1 week of treatment
  • Suitable for patients with comorbid depression
  • Reported to improve social functioning and to reduce ruminative worry

• Panic disorder
  • Studies have shown that Venlafaxine reduces severity of symptoms

• Social anxiety disorder
  • Efficacy established in four 12-weeks randomized controlled trials (RCTs)
  • Significantly reduced patient’s social anxiety depression symptoms within 4-6 weeks

Duloxetine

• Considered as 1st line agent for generalized anxiety disorder

Tricyclic Antidepressants (TCAs)

• Generalized anxiety disorder
  • Imipramine is the only agent that has consistently shown benefit in generalized anxiety disorder
  • Imipramine may be used as an alternative treatment for generalized anxiety disorder
  • Slower onset of action than benzodiazepines but shown to be as effective
  • More effective in treating psychic rather than somatic symptoms
  • Suitable for patients with comorbid depression
  • Adverse effects are usually the limiting factor

• Panic disorder
  • Eg Clomipramine, Imipramine
  • May be used as an alternative treatment for panic disorder
  • Imipramine is the most extensively studied tricyclic antidepressant
  • Reduce frequency and intensity of panic attacks, reduce anticipatory anxiety and associated depression
  • May also lead to decreased avoidance of phobias
  • Adverse effects are usually the limiting factor

Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)

• Generalized anxiety disorder
  • Mirtazapine may be considered as a second-line treatment for generalized anxiety disorder for its anxiolytic effects for refractory anxiety with insomnia
  • Adverse effects of weight gain and sedation are the usual limiting factor for use

• Panic disorder
  • Mirtazapine may be used as an alternative treatment for panic disorder

Anxiolytics

Hydroxyzine

• It blocks H₁ and muscarinic receptors
• Generalized anxiety disorder
  • Considered as a weak anxiolytic 
  • Has been shown to be more sedative than benzodiazepines and Buspirone that can be useful for treatment of insomnia associated with generalized anxiety disorder

Monoamine Oxidase Inhibitors (MAOIs)

• Panic disorder
  • Phenelzine is the most extensively studied monoamine oxidase inhibitor
  • Reduce frequency and intensity of panic attacks, reduce anticipatory anxiety and associated depression
  • May also lead to decreased avoidance of phobias
  • Adverse effects, drug interactions and dietary tyramine restrictions cause this group to be reserved for patients who fail selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants  (TCAs) or benzodiazepines

• Social anxiety disorder
  • Given to patients unresponsive to an alternative selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor
  • Phenelzine and Moclobemide has been shown to be the most effective of this group
  • Studies have shown they are effective in patients with social anxiety disorder
  • Adverse effects, drug interactions and dietary tyramine restrictions limit its usage

Anticonvulsants

• Generalized anxiety disorder
  • Pregabalin has been shown to improve somatic and psychic symptoms in patients with generalized anxiety disorder
  • Pregabalin has proven efficacy for acute treatment and prevention of relapse
• Panic disorder
  • Studies demonstrated a significant benefit for patients with severe panic disorder
• Social anxiety disorder
  • Gabapentin and Pregabalin have been demonstrated to decrease social anxiety disorder symptoms
  • More studies are needed

Antipsychotics

• Generalized anxiety disorder
  • There are good evidences that Quetiapine extended-release formulation is effective for the management of generalized anxiety disorder and can be considered as adjunctive drug to a selective serotonin reuptake inhibitor or a serotonin and norepinephrine reuptake inhibitor for treatment of resistant generalized anxiety disorder
  • Due to likelihood of adverse effects like sedation, extrapyramidal symptoms and tardive dyskinesia, use is recommended only after safer alternatives have been exhausted

Beta-Blockers

• Social anxiety disorder (Non-generalized Subtype)
  • Relieve autonomic symptoms (eg sweating, tremor) only
  • Use should be intermittent and only administered until individual’s performance confidence has returned
  • Atenolol is not recommended

• Generalized anxiety disorder
  • Agomelatine was found to be as effective as Escitalopram for the treatment of generalized anxiety disorder

• For patients with generalized anxiety disorder and other comorbid conditions (eg depressive or other anxiety disorders), it is recommended to treat the disorder that is more severe and in which it is more likely that treatment will improve overall functioning

Cognitive-Behavioral Therapy (CBT)

• A process that focuses on intervening in the thoughts and behaviors that have strong influence on the experience of emotion
• The most effective form of psychotherapy for most anxiety disorders
• Psychoeducation - Identify patient’s symptoms, explain basis of symptom and outline techniques for dealing with symptoms
  • May include workbooks and/or self-help materials

• Problem solving - Done in collaboration between the patient and the physician
  • Deals with identifying the problem, generating alternative solutions, selecting and implementing initial approach, and monitoring of implementation and results

• Continuous panic monitoring
• Cognitive restructuring
  • Investigate and reverse fears that arise from misinterpretation of body sensations
  • Teach patient how to think about different outcomes of situations other than the negative ones

• In vivo exposure
  • Involves the actual exposure of the patient to their fear cues

• Relapse prevention - Develops a strategy in coping with problems that may arise in the future
• Booster sessions can be used to control or lessen the symptoms especially in patients where cognitive-behavioral therapy has been effective
• Combination of cognitive-behavioral therapy and pharmacological intervention shows some effectiveness; however, further studies on benefit and cost of combined over single treatments are still lacking
• Generalized Anxiety Disorder
  • Relapse rates after discontinuing cognitive-behavioral therapy are low compared to pharmacological therapy

• Panic Disorder
  • There is insufficient evidence to support whether cognitive-behavioral therapy is superior to pharmacological therapy; therefore, either therapy may be used as 1st-line treatment
  • Cognitive-behavioral therapy is psychotherapy of choice for panic disorder
  • Particularly useful during withdrawal of anxiolytics

• Social Anxiety Disorder
  • As an initial treatment option, individual cognitive-behavioral therapy, especially in vivo exposure, has been shown to be superior to other forms of psychotherapy interventions
  • Cognitive techniques include restructuring and challenging of maladaptive thoughts, while the behavioral component is typically in the form of exposure therapy
  • Cognitive-behavioral therapy treatment gains may be maintained longer than pharmacological therapy
    • Treatment gains tend to remain over no-treatment follow-up periods
  • If with only partial response to individual cognitive-behavioral therapy, consider pharmacological therapy
  • May be given together with an selective serotonin reuptake inhibitor if patient had partial response with 10-12 weeks selective serotonin reuptake inhibitor therapy
  • May use a cognitive behavioral therapy-based self-help book for support

Distraction Techniques

• Listening to soothing music or thinking about pleasurable memory to replace anxiety-provoking thoughts

Lifestyle Changes

• Stress reduction
• Reduction of alcohol and caffeine consumption
• Avoidance of nicotine and drug use
• Regular exercise
• Sleep hygiene

Psychodynamic Psychotherapy

• Involves exploring patient’s biopsychosocial development and the events before the onset of symptoms
• Goal is to understand the reason of the anxiety based on patient’s personality and development
• An option for patients with social anxiety disorder who refused cognitive-behavioral therapy and pharmacological approaches
• Less evidence showing its efficacy for the treatment of anxiety disorders

Relaxation Techniques and Biofeedback

• May be used to treat mild generalized anxiety disorder
• Used to decrease arousal and control somatic manifestations
• Studies have found these techniques are more effective if combined with cognitive therapy
• May be combined with cognitive-behavioral therapy (CBT) in generalized anxiety disorder treatment
• Relaxation breathing, eg abdominal breathing, helps to control physiologic overactivity