ANXIETY DISORDERS

Definition Anxiety is an unpleasant feeling of apprehension or fearful concern.

It can be : -Normal, reasonable and expected response to a stressful situation or perceived danger (adaptive purposes)

or

It may be: -An excessive, irrational state that signifies a mental disorder (maladaptive)

Clinical subtypes of anxiety include:

•Generalized anxiety disorder (GAD)

•Panic disorder (PD)

•Obsessive-compulsive disorder (OCD)

• Posttraumatic stress disorder (PTSD)

•Social phobia (SP)

Epidemiology

The prevalence of anxiety disorders in the general population is about 10-20%

There is a high rate of co-morbidity with depressive disorders.

The overall female to male ratio is nearly 2:1.

The age of onset of most anxiety disorders is in young adulthood (twenties and thirties)

The maximum prevalence of generalized anxiety and agoraphobia-panic in the general population is in the 50-64 year age group.

Pathophysiology Neurotransmitter systems involved in anxiety generation include:

1) The GABAA-benzodiazepine receptor complex

2) The serotonin (5HT1A/5HT2C) receptor group

3) The noradrenergic system

These brain receptor systems mediate the effects of the three main classes of drugs used for treating neurotic disorders

Patients with anxiety disorders, particularly PD, exhibit symptoms of peripheral autonomic hyperactivity including: Tremulousness, palpitations, and hyperventilation

According to the noradrenergic model:

The autonomic nervous system of patients with anxiety disorders becomes oversensitive to various stimuli, responding with:

excess amount of noradrenaline.

GABA (Gamma-aminobutyric acid) is the major inhibitory neurotransmitter

Attenuation of the effects of GABA causes:

Increased arousal

Enhanced memory

Anxiety

Restlessness

Insomnia

Exaggerated reactivity (startle)

Convulsions

The indolamine neurotransmitter serotonin (5HT) has been proposed to play a role in anxiety disorders

The hypothalamic-pituitary-adrenal axis (HPA) also plays a role in anxiety disorders

Perceived threat or stress activates the HPA axis and one of its components, corticotrophin-releasing factor (CRF)

Evidence suggests that CRF is responsible for integrating the endocrine, autonomic, and behavioral responses of an organism to stress

Clinical presentation and diagnosis

It is important to exclude organic causes such as:

•Thyrotoxicosis

•Excessive use of stimulant drugs such as caffeine

•The possibility of alcoholism or withdrawal effects from benzodiazepines

Unnecessary investigations should be avoided if possible

It is also important to determine whether the anxiety is situational anxiety (usually last 2-3 weeks) or an anxiety disorder

A variety of medical conditions may cause anxiety symptoms

In this case the anxiety may be labeled as anxiety disorder due to a general medical condition

Anxiety symptoms may be associated with almost all major psychiatric illnesses such as:

•Schizophrenia•Major depression•Dysthymia•Mania•Delirium•Dementia•Substance-related disorders

Medical disorders associated with anxiety

Cardiovascular Arrhythmias, Angina MI, HTN, CHF Mitral valve prolapse Respiratory COPD, PE, Pneumonia Hyperventilation

Endocrine Hyperthyroidism Hypothyrodisim Hypoglycemia Pheochrmocytoma Metabolic B12 deficiency, Porphyria

Gastrointestinal Ulcerative colitis Peptic ulcer disease Irritable bowel syndrome Inflammatory Rheumatoid arthritis Lupus erythematosus

Neurologic Neoplasms Encephalitis Miscellaneous Chronic infections Malignancies

CNS stimulants Albuterol, Amphetamines, Cocaine, Fenfluramine, Isoproterenol, M ethylphenidate

CNS depressants Alcohol, Narcotic analgesics Barbiturates, Meprobamate, BZDs

Nonprescription drugs Caffeine, Nicotine, Decongestants: (ephedrine, pseudo ephedrine, oxymetazoline, naphzoline.....)

Several pharmacologic agents are known to produce anxious symptoms

Anxiety associated with the use of these agents is seen when they are abruptly discontinued after chronic use

Some pharmacologic agents known to produce anxious symptoms

Generalized Anxiety DisorderThe essential feature of GAD is excessive and unrealistic worry about several life situations that has been present for 6 months or longer

The anxiety must be accompanied by at least three of the following six symptoms: •Restlessness•Fatigability•Difficulty concentrating•Irritability•Muscle tension•Disturbed sleep

Many patients with GAD also experience somatic symptoms (e.g., headache, irritable bowel syndrome) and depressive symptoms

Panic Disorder: A Panic attack is a discrete period of intense fear or discomfort that is accompanied by at least four somatic or cognitive symptoms

Palpitations or tachycardia Sweating Trembling or shaking Sensations of shortness of breath or smothering Feeling of choking

Chest pain Nausea or abdominal distress Feelings of dizziness, light- headedness, or fainting Feelings of unreality, or feelings of being detached from oneself

Fear of losing control or going crazy Fear of dying Numbness or tingling sensations Chills or hot flashes

Panic attacks occur in the context of several different anxiety disorders and it is separate from the disorder

The essential criterion of Panic Disorder (PD)is

•Recurrent, unexpected panic attacks (without specific stimulus)

•Followed by at least one month of persistent concern with the possibility of experiencing further attacks,

•Worry about the possible implications or consequences of the episodes, or

•A significant change in the patient’s behavior secondary to the attacks

Obsessive-Compulsive Disorder:

The essential feature of OCD is recurrent obsessions or compulsions

•That cause marked distress,

•Are time consuming, or

•Interfere significantly, with normal occupational functioning, social activities, or relationships

Posttraumatic Stress Disorder:

PTSD may develop when a person experiences or witnesses an event that involves actual or threatened death or serious injury, or a threat to the physical integrity of self or others

As a response to the event, the person reacts with intense fear, helplessness, or horror

Social Phobia:

SP is characterized by a persistent fear of social or performance situations in which embarrassment may occur

TREATMENT

•Drugs provide only symptomatic treatment of anxiety and do not cure the underlying disorder

•They may temporarily help patients to cope with stress and provide a short-term cover

•This will allows time for more specific treatments to take effect

•Effective treatment in the long term is by non-pharmacological interventions including: -Counseling-Psychotherapy-Behavioral and cognitive methods-Relaxation and anxiety management training

Pharmacotherapy

Commonly used antianxiety medications include:

BZDs

Buspirone

β-blockers

TCAs

MAOIs,

SSRIs

BenzodiazepinesCurrently available BZD antianxiety agents areAlprazolam (Xanax®)Chlordiazepoxide (Librium®)Clonazepam (Rivotril®)Diazepam (Valium®)Lorazepam (Ativan®) Oxazepam (Serax®)

•Still the most commonly prescribed drugs for anxiety

•Have potent anxiolytic effects which are exerted at low doses that produce minimal sedation

•In subjects with low trait anxiety and in non-stressful conditions BZDs may paradoxically increase anxiety and impair psychomotor performance

The major site of anxiolytic action is the limbic system

The effect is mediated by a primary action at GABAA

receptors, resulting in enhancement of inhibitory GABA activity

Secondary suppression of noradrenergic and/or serotonergic pathways may be of particular importance in relation to anxiolytic effects

The most common indication for BZD therapy is GAD

Alprazolam has the efficacy of as an antipanic agent

2 to 6 mg/day usually is sufficient for most patients with PD taking alprazolam

The total daily BZD dosages in PD tend to be much higher than those in GAD

Patients experiencing interdose symptom breakthrough:

switch from alprazolam to clonazepam (anticonvulsant)

Clonazepam has longer half life

Patients who do not respond to one BZD may respond to another

The high-potency BZD are effective for SP, with onset of response occurring within 2 weeks.

Clonazepam was reported to significantly improve patients with long-term treatment in dose of 1.5 to 2 mg/day

Alprazolam is another BZD considered effective for SP at 3 mg/day.

Choice of BZD in anxietyBZD can be valuable in the short term management of anxiety because of their anxiolytic efficacy and rapid onset of action.

Pharmacokinetic characteristics affect the choice of an appropriate BZD

Potent BZDs such as lorazepam have been widely used for anxiety disorders but are probably inappropriate.

Lorazepam is moderately rapidly eliminated and needs to be taken several times daily.

Declining blood concentrations may lead to inter-dose anxiety as the anxiolytic effect of each tablet wears off.

A slowly eliminated BZD such as diazepam is more appropriate in most cases.

Diazepam has a rapid onset of action, and its slow elimination ensures a steady blood concentration.

It should be prescribed in the minimal effective dosage to avoid cumulative effects

It can also be used as a hypnotic, thus avoiding the need for a separate hypnotic drug.

Patients with hypoalbuminemia may have greater free fraction of BZDs that are highly protein bound.

For these patients, lorazepam or alprazolam would be a rational choice because of its lower percentage of protein binding.

Patients should be started on low dosages and titrated upward to the lowest effective dosage.

The anxiolytic use of BZDs should generally be limited to short-term (2 weeks) or intermittent use.

Parenteral administration of lorazepam or diazepam may occasionally be indicated for severely agitated psychiatric patients.

Drug Elimination half-life (h) Anxiolytic dosage Maximum dosage Benzodiazepines Alprazolam Chlordiazepoxide Clonazepam Diazepam Lorazepam Oxazepam

12-15 5-30 20-50

20-100 10-18 4-15

0.25-0.5 mg TID

15-30 mg TID 0.5 mg BID 2-5 mg TID 1 mg TID

10-30 mg TID

1 mg QID

100 mg QHS 3 mg BID

40 mg QHS 5 mg BID 30 mg TID

Buspirone 2-11 5-10 mg TID 20 mg TID β adrenoceptor antagonist Atenolol Propranolol

6-7 2-4

25 mg QAM 40 mg BID

100 mg QAM 120 mg TID

Tricyclic antidepressants Amitriptyline Clomipramine Imipramine

10-25 16-20 4-18

25-50 mg QHS

25 mg QHS 25-50 mg QHS

300 mg QHS 250 mg QHS 300 mg QHS

SSRIs Fluoxetine Fluvoxamine Paroxetine Sertraline Citalopram

2-3 days

15 20 26 33

20 mg QAM 100 mg QHS 20 mg QAM 50 mg QAM

10-20 mg QAM

80 mg QAM 150 mg BID 50 mg QAM 200 mg QAM 40 mg QAM

MAOIs Moclobemide Phenelzine

1-4 1

300 mg daily 15 mg TID

300 mg BID 30 mg TID

Profile of some drugs used in anxiety disorders

Adverse effect of anxiolytic use

Tolerance

Tolerance to the anxiolytic effects of BZDs seems to develop more slowly than to the hypnotic effects.

Most patients reporting initial drowsiness find that it wears off in a few days while the anxiolytic effects remains for some weeks.

BZDs are usually no longer effective in the treatment of anxiety after 1-4 months of regular use.

Psychomotor impairment

Long-term use of BZDs results in psychomotor impairment and has adverse effects on memory

Many patients on long-term BZDs complain of poor memory, and incidents of shoplifting have been attributed to memory lapses caused by BZDs use.

Additive effects with other CNS depressants including alcohol occur, and may contribute to traffic and other accidents

Disinhibition, paradoxical effects

Occasionally, BZDs produce paradoxical stimulant effects.

These effects are most marked in anxious subjects and include: Excitement Increased anxiety Irritability Outbursts of rage

Increased daytime anxiety can occur with rapidly eliminated BZDs, such as lorazepam, and is probably a withdrawal effect.

Affective reactions

Chronic use of BZDs:

•Can aggravate depression and provoke suicide in depressed patients

•Can cause depression in patients with no previous history of depressive disorder.

•Some patients on long-term BZDs complain of ‘emotional anesthesia’ with inability to experience either pleasure or distress.

•In some patients, BZDs induce euphoria, and they are increasingly used as drug of abuse when taken in high doses or self administered intravenously

Dependence

The greatest drawback of chronic BZD use is the development of drug dependence.

The regular use of therapeutic doses of BZDs for more than a few weeks can give rise to dependence

Withdrawal symptoms on cessation of drug use occur in over 40% of patients.

Abuse Patients with a history of alcohol or other drug abuse are at greatest risk of becoming BZD abusers.

Diazepam, followed by alprazolam and lorazepam, has been judged to have the greatest potential for abuse among the BZDs.

BZD withdrawal

Abrupt withdrawal in dependent subjects is dangerous, and can induce acute anxiety, psychosis or convulsion.

BZDs should be discontinued gradually, by one-eighth to one-fourth of the total dosage every few weeks to allow careful monitoring and to reduce the risk of withdrawal or rebound.

Substituting a long-half-life BZD for a short to intermediate-half-life drug before downward tapering may reduce the severity of withdrawal symptoms

Drug Effect Drug Effect Antacids Decreased rate of diazepam and

chlordiazepoxide absorption Isoniazid Decreased oxidative metabolism

of diazepam β-blockers Propranolol cause a small reduction

in oxidative metabolism of diazepam Levodopa Worsening of parkinsonian

symptoms Cimetidine Decreased oxidative metabolism of

most BZDs Probenecid May increase lorazepam level by

decreasing clearance Digoxin ↑digoxin serum concentrations

with reported toxicity with addition of alprazolam or diazepam

Rifampin Increased oxidative metabolism of diazepam

Disulfiram Decreased oxidative metabolism of BZDs

Theophylline Antagonism of CNS depressant effects of BZDs

Ethanol Inhibition of BZD metabolism; additive or synergistic CNS depression

Valproic acid Decreased oxidative metabolism of diazepam, protein binding of diazepam may also be altered.

Hydantoins ↑&↓ phenytoin serum concent. reported with diazepam & chlordiazepoxide; Increased oxazepam eelimination

Oral contraceptives

↓ clearance of chlordiazepoxide, diazepam and alprazolam; ↑ metabolism of lorazepam and oxazepam

Drug interactions with the BZD antianxiety agents

Buspirone

Buspirone has a structure and mode of action completely different from that of BZDs

It has mixed agonist/antagonist action at serotonergic receptors that are thought to be involved in anxiety

It has anxiolytic effects comparable with those of BZDs, but it is without sedative/hypnotic, anticonvulsant or muscle relaxant effects

A major disadvantage is that anxiolytic effects are delayed for up to 3 weeks, and in some patients buspirone produces dysphoria and may actually increase anxiety

Concurrent use of buspirone and MAOIs is not recommended because blood pressure may increase

Buspirone may displace digoxin from plasma proteins.

Serum haloperidol may be increased by buspirone.

Unlike BZDs, buspirone does not produce

-Physical dependence

-Withdrawal symptoms

-Abuse

-Lacks interaction with alcohol

Buspirone does not usually alleviate anxiety associated with BZD withdrawal.

Buspirone is recommended for short term use only and its place in the treatment of anxiety is doubtful at present.

Antidepressant drugs

A number of tricyclic (TCAs) and other antidepressants have additional sedative or anxiolytic effects

They appear to be as effective as BZDs in GAD and superior in agoraphobia.

The efficacy of imipramine in treating PD is now well established, and recently clomipramine has been reported to be superior to imipramine in PD treatment.

Also, clomipramine is well-documented to be effective in treating OCD.

The TCAs have the most solidly established efficacy in treating core intrusive PTSD symptoms.

Imipramine and amitriptyline have produced positive results in treating veterans with PTSD.

TCAs are also of value in depressive states associated with anxiety and in anxiety/depression associated with BZD withdrawal

Selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are also effective in phobic states and panic disorders.

A disadvantage of all these drugs is:

•Their slow onset of action which may be delayed for 2-4 weeks

•They may initially exacerbate anxiety symptoms.

For this reason it is advisable to start with small doses.

The mode of action of these drugs is thought to be:

•An initial increase in central serotonergic and noradrenergic activity

•This may cause further anxiety

•Followed by a down-regulation of adrenergic and serotonergic receptors, accounting for the delayed anxiolytic effect.

Another disadvantage of antidepressants is that:

•Some are toxic in overdose

•Have many adverse effects including anticholinergic actions, cardiovascular actions, especially in the elderly

•Drug interactions, and interaction with certain foods.

Antidepressants more suitable for long term use than BZDs, and can be continued for several months.

They are often effective in low to moderate doses and do not cause cognitive impairment.

Some patients have difficulty in stopping these drugs because of withdrawal symptoms, which include:

•Rebound excessive cholinergic activity •Increased anxiety or depression.

Withdrawal should therefore be carried out gradually.

β adrenoceptor blockers

Some somatic symptoms of anxiety such as palpitations and tremor are due to excessive sympathetic activity acting on peripheral β adrenoceptors

These symptoms can be alleviated by β adrenoceptor blockers such as propranolol

These drugs, when used in small doses which do not induce hypotension, can be of value in acutely stressful situations or panic attacks where physical symptoms dominate the picture

They have little effect on subjective symptoms

If used regularly, withdrawal should be gradual to prevent rebound tachycardia and return of palpitations.

Antipsychotic drugs Some antipsychotic drugs such as chlorpromazine and haloperidol have sedative and anxiolytic effects

They may, on occasion, be of short term use in severe anxiety disorders associated with panic.

They have a rapid onset of action (within 1 hr) but should be used in minimal dosage and only short-term since they carry a risk of dyskinesias and other adverse effects.

Anxious patients may have withdrawal problems after regular use.

The growing tendency to prescribe these drugs as alternatives to BZDs is to be deprecated.

Rational use of drugs in anxiety It is clear that drugs do not provide a long-term solution for anxiety.

In acute anxiety states, often precipitated by stress, short-term BZDs may help to cop with the immediate situation as they have high efficacy and a rapid onset of action.

Diazepam is probably the drug of choice.

A single dose may be sufficient, and it should not be continued regularly for more than 1 or 2 weeks

It can be given intermittently and intermittent courses can be repeated if necessary

Potent, short acting BZDs such as alprazolam and lorazepam should be avoided

BZDs are not recommended in bereavement because their amnesic actions may interfere with subsequent adjustment

If longer-term treatment is required in GAD, anxiety/depression or phobic states, sedative TCAs or SSRIs are preferred

These drugs are efficacious, can be used for several months and do not interfere with non-pharmacological treatment

MAOIs are effective in panic and phobic disorders

β adrenoceptor blockers are effective in controlling somatic symptoms such as palpitations and tremor

The most effective long-term treatment of anxiety is by psychological methods, which can include:

•Self-help groups

•Counseling

•Behavioral and cognitive techniques

•Anxiety management training

•Psychotherapy

Problem Contributing factors Management BZD overdose BZD often taken with other

drugs including antidepressants, paracetamol, alcohol and opiates

Flumazenil (a competitive antagonist at BZD receptors) may be administered cautiously. It may precipitate withdrawal reactions in BZD-dependent patients. Flumazenil is short-acting, repeated administration may be required if long-acting BZD has been taken in overdose.

Patients wishing to withdraw from lorazepam or other potent, relatively short-acting BZDs

Lorazepam is 10 times potent than diazepam.

If BZD withdrawal is indicated, it is usually advisable to switch to the equivalent diazepam dose then withdrawal can be carried out gradually at the rate of 1-2 mg diazepam every 2-4 weeks

Patients taking a combination of a BZD and an antidepressant drug

An antidepressant may have been prescribed for depression caused by chronic BZD use, or for patients with anxiety/depr-ession, although this is not recommended.

Gradual withdrawal from BZD may be indicated. In this case, the patient should continue on the antidepressant drug until BZD withdrawal is complete. The advisability of continuing or slowly withdrawing the antidepressant can then be considered

Patients attending pharmacies for several months to obtain repeat prescriptions for BZDs

A considerable proportion of these patients are likely to be dependent and to be at risk of adverse effects, especially if elderly

The pharmacist may approach the prescriber and suggest methods of withdrawal and help in supervision of withdrawal.

BZD abuse Illicit BZD abuse is common among polydrug users, alcoholic, and psychiatric patients.

The source of most illicitly obtained BZDs is stolen prescriptions. Reduction in BZD prescribing would help to alleviate this problem.

Common therapeutic problems in the management of anxiety