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PHARMACOLOGICAL MANAGEMENT OF ANXIETY DISORDERS

PRESENTED BY : DR. NARESH SOLANKI

GUIDED BY : DR. U. SARDESAI

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INTRODUCTION

Anxiety symptoms are common in the community, and anxiety disorders are common in primary and secondary medical care settings (King et al., 2008).

Pharmacological treatments for anxiety disorders have become more tolerable, available,and numerous over the past half century.

At the same time, research has yielded a vastly improved understanding of the neurobiological and physiological mechanisms involved in chronic anxiety and stress responses, suggesting new approaches to the treatment of anxiety disorders.

Despite these impressive changes, however, between one-third and one-half of patients on a modern antidepressant do not achieve sustained remission from anxiety

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TREATMENT OPTIONS AVAILABLE ARE:

I. Pharmacological – antidepressants , anxiolytics, anticonvulsants, antipsychotics .

II. Non pharmacological

- psychotherapy

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GENERALISED ANXIETY DISORDER Once a residual category in the DSM, GAD did not achieve the status of

a full disorder until the publication of DSM-III-R in 1987.

As it is currently defined, GAD is associated with high rates of comorbidity and substantial overlap with depression and other anxiety disorders.

The most common pharmacological treatments for GAD include SSRIs , SNRIs and TCA.

Other compounds used in acute treatment include pregabalin (Wensel et al., 2012), some benzodiazepines (alprazolam, diazepam, lorazepam : Martin et al., 2007), buspirone (Chessick et al., 2006), some antipsychotic drugs (quetiapine, trifluoperazine :Lalonde and Van Lieshout, 2011) and the antihistamine hydroxyzine (Guaiana et al., 2010).

Beta-blockers are often used in primary medical management of physical symptoms of anxiety .

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the use of fast-acting drugs such as benzodiazepines and azapirones may be contraindicated by cognitive-behavioral approaches to GAD, which emphasize the importance of tolerating rather than avoiding the experience of anxiety.

SSRIs and serotonin and norepinephrine-reuptake inhibitors (SNRIs), have produced most promising findings.

Venlafaxine, an SNRI, was the first antidepressant approved by the FDA for the treatment of GAD.

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Most studies reveal no significant differences in overall efficacy between active compounds.

Combining drug and psychological treatments have not shown greater overall efficacy than either treatment given alone (Bandelow et al., 2007a) .

The addition of pregabalin to SSRI or SNRI antidepressant drugs is superior to continued treatment with antidepressants alone (Rickels et al., 2012).

There is evidence of a dose-response relationship for pregabalin in some trials (Lydiard et al., 2010), but studies with antidepressant drugs provide no consistent evidence for a dose-relationship (Baldwin et al., 2011a).

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response is likely only if there is an onset of effect within four weeks of treatment.

CONTINUATION TREATMENT There is significant advantage for staying on active

medication , when compared with switching to placebo, for periods of between 6–18 months (Baldwin et al., 2012).

DISCONTINUATION When stopping treatment, reduce the dose

gradually over an extended period of three months to avoid discontinuation and rebound symptoms.

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POST TRAUMATIC STRESS DISORDER

there is evidence for the efficacy of a range of antidepressants including fluoxetine, paroxetine, sertraline, amitriptyline, imipramine, mirtazapine, nefazodone, phenelzine and venlafaxine (Ipser and Stein, 2011), antipsychotics risperidone (Padala et al., 2006), olanzapine (Carey et al., 2012) , and the anticonvulsant topiramate; (Yeh et al., 2011).

the selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRI) have now considered as first-line agents (Davidson 2006 ).

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SSRIs and SNRIs has broad-spectrum properties across the full symptom range of the disorder, as well as improving function and, perhaps, resilience, or stress coping ( Davidson 2006 ).

They also support the benefit of SSRI drugs in those with and without comorbid major depression (Brady et al. 2000 , Davidson et al. 2001).

The appropriate role for the use of benzodiazepines is not well defined.

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augmentation studies of either olanzapine or risperidone have shown positive benefits for the drug, in combat veterans and noncombat veterans, with PTSD.

Almost all patients were already taking an SSRI, to which they had shown partial response (Bartzokis et al. 2005) .

Antipsychotic medications appear to be useful in enhancing sleep, reducing aggression, and otherwise treating different aspects of PTSD.

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We do not have adequate data to suggest in what ways, if any, anticonvulsants, mood stabilizers, or other drugs are helpful.

One exception may be prazosin , for which there is some evidence that, in augmentation to an antidepressant, it leads to improvement in nightmares (Raskind et al. 2003 ).

Advise the patient that treatment periods of up to 12 weeks may be needed to assess efficacy .

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approaches is not recommended for initial treatment in the absence of consistent evidence for enhanced efficacy over each treatment when given alone .

but, paroxetine may enhance the effectiveness of exposure therapy .

CONTINUATION TREATMENT Because PTSD is a chronic disorder, there is a

significant risk of relapse, especially if treatment is discontinued prematurely.

So, It is recommended to continue drug treatment for at least 12 months in patients who have responded to treatment (Davidson et al. 2005 ). Then taper off over 3 months period.

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PHOBIA

The most studied and most effective treatment for phobias is probably behavior therapy.

A variety of behavioral treatment techniques have

been used, the most common being systematic desensitization.

In this method, the patient is exposed serially to a

predetermined list of anxiety-provoking stimuli graded in a hierarchy from the least to the most frightening.

techniques that have been used more recently involve

intensive exposure to the phobic stimulus through either imagery or desensitization in vivo.

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SPECIFIC PHOBIA

pharmacotherapy is generally thought to be ineffective for specific phobias (Antony and Barlow 2002 ).

exposure-based therapies (particularly those involving in vivo exposure) are more effective than other psychological interventions.

effectiveness being seen regardless of the nature of the specific phobia, and being somewhat greater with multiple rather than single sessions (Wolitzky-Taylor et al., 2008).

However, claustrophobia and other phobias of the situational type appear to share more features with panic disorder than with the other specific phobia types.

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Therefore, medications that are effective for panic disorder (e.g., SSRIs , SNRIs) may prove to be effective for situational phobias. These may also useful for patients who have not responded to psychological interventions .

it is also common for phobic patients occasionally to be prescribed low dosages of benzodiazepines to be taken in the phobic situation (e.g., while flying).

So , benzodiazepines may be helpful in the short-term. but BZDs lead to greater relapse in the long-term . And , possibly interfere with the therapeutic effects of exposure

across sessions (Wilhelm and Roth 1996 ).

Some studies findings suggest that the efficacy of exposure therapy can be enhanced through prior administration of d-cycloserine (Nave et al., 2012).

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SOCIAL PHOBIA

In contrast to specific phobias, social phobia has been treated successfully with a variety of pharmacological interventions including SSRIs ,SNRIs,BZDs , traditional monoamine oxidase inhibitors (MAOIs) such as phenelzine and reversible inhibitors of monoamine oxidase A (RIMA) such as moclobemide.

Due to their tolerability and broad spectrum efficacy , the SSRIs have been referred to as “the gold standard” in pharmacological treatment for social phobia (Van Ameringen et al. , 2000 ).

Routine prescription of higher doses of SSRIs is not recommended, but individual patients may benefit from higher doses .

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Some benzodiazepines (bromazepam and clonazepam) and anticonvulsants (gabapentin and pregabalin), and the antipsychotic olanzapine also appear efficacious in acute treatment (Blanco et al., 2013).

Several studies have examined the utility of

clonazepam for treating social phobia. Davidson et al. ( 1993 ) found that 78% of patients responded to clonazepam (mean dosage, 2.4 mg/day), whereas only 20% responded to placebo.

However , given risk:benefit considerations, benzodiazepines are not usually recommended as first-line agents for SAD.

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Due to the potentially severe side effects , the necessity for certain dietary restrictions and a greater tendency to relapse after discontinuation , MAOIs are not considered as first line treatment .

RIMAs such as moclobemide and brofaromine, do not require such dietary restrictions and are well tolerated. However, they have not proved consistently efficacious in SAD and are not typically considered first-line agents.

Neither buspirone, nor the beta-blocker atenolol are efficacious in generalised social anxiety disorder (Blanco et al., 2013)

although, beta-blockers are often prescribed for discrete performance-related social phobias but their efficacy for treating individuals with clinically diagnosed discrete social phobia has not been established.

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Advise the patient that treatment periods of up to 12 weeks may be needed to assess efficacy in acute phase.

Pharmacological and psychological treatments, when delivered singly, have broadly similar efficacy in acute treatment (Canton et al., 2012).

However, acute treatment with cognitive therapy (group or individual) is associated with a reduced risk of symptomatic relapse at follow-up (Canton et al., 2012).

It is unlikely that the combination of pharmacological with psychological treatments is associated with greater overall efficacy than with either treatment, when given alone. (Blanco et al., 2010).

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CONTINUATION TREATMENT There is a significant advantage for

staying on active medication (clonazepam, escitalopram, paroxetine, pregabalin, sertraline) for up to six months (Blanco et al., 2013).

DISCONTINUATION To discontinue the treatment , tapering

off the drug over 3 month period is advised .

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PANIC DISORDER : with and without agorophobia

effective anti-panic medications include tricyclic antidepressants (e.g., imipramine),MAOIs (e.g., phenelzine), high-potency benzodiazepines (e.g., alprazolam), the selective noradrenaline reuptake inhibitor(NARI; reboxetine) , SSRIs (e.g., fluvoxamine), and SNRIs (e.g., venlafaxine) and some anticonvulsants (gabapentin, sodium valproate) in acute treatment (Batelaan et al., 2012) .

When efficacy and side effects are considered together, SSRIs (and possibly SNRIs) emerge as the most promising drug treatments for panic disorder.

The relative efficacy and tolerability of differing pharmacological treatments is uncertain, but there may be efficacy advantages for venlafaxine, and tolerability disadvantages for fluvoxamine and reboxetine (Andrisano et al., 2013) .

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findings from a randomised placebo-controlled trial suggests that escitalopram is superior to citalopram (Bandelow et al., 2007b).

Some trials suggest that SSRIs (fluvoxamine, paroxetine)

are more effective than some noradrenaline reuptake inhibitors (maprotiline, reboxetine) (Bertani et al., 2004).

Little is known about the efficacy of pharmacological or psychological treatment in patients with agoraphobia but without panic attacks (Perna et al., 2011).

In panic disorder with agorophobia , After panic attacks have been reduced, treat residual problems, such as agoraphobic avoidance.

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both the American Psychiatric Association (APA 1998) and the British Association for Psychopharmacology (BAP) (Baldwin et al 2005) recommend use of either pharmacotherapy or CBT because –

“drug and psychological treatments, delivered singly, have broadly similar efficacy in acute treatment” (BAP 2005; Bandelow et al., 2007b; McHugh et al., 2009).

Exploratory placebo-controlled studies suggest that the addition of d-cycloserine may hasten the onset of effect (Siegmund et al., 2011) or increase overall effectiveness (Otto et al., 2010) of CBT in the acute treatment of patients with panic disorder.

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The course of PD is variable: approximately one third of patients achieve remission, whereas one out of five follows an unremitting and chronic course ( Katschnig and Amering 1998).

Therefore, most of PD patients require long-term treatments ( Doyle and Pollack 2004).

International Consensus Group on Depression and Anxiety (ICGDA) (Ballenger et al 1998) suggests that the outcome of treatment should be evaluated in five domains:

panic attacks (including limited-symptom attacks), anticipatory anxiety, panic-related phobias, overall illness severity and disabilities.

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The ICGDA defines: (1) “response” as a stable clinically significant improvement of the full range of symptoms, but more than minimal symptoms continue to be present; and (2) “full remission” as the resolution of all five domains of symptoms, maintained for a period of three months.

CONTINUATION TREATMENT significant advantage for staying on active medication ,

compared to switching to placebo, for periods of up to six months has found .

but the optimal duration of continuation treatment is uncertain (Donovan et al., 2010).

DISCONTINUATION When stopping treatment, reduce the dose gradually over an

extended period to avoid discontinuation and rebound symptoms : in the absence of evidence a minimum of three months is recommended for this taper period .

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ILLNESS ANXIETY DISORDER

The DSM-5 ((American Psychiatric Association, 2013) includes ‘illness anxiety disorder’ within the group of ‘somatic symptom and related disorders’.

The condition is characterised by excessive concern over health, constant fear of undiagnosed disease that physicians may have missed, and the characteristic behaviours of repeated checking and need for medical reassurance.

Pharmacological treatment is not normally acceptable to patients, as those with marked health anxiety are typically very sensitive to adverse effects of medication.

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but , fluoxetine showed some benefit over placebo, though this was not pronounced and occurred late in treatment (8–12 weeks) (Fallon et al., 2008).

Psychological treatments have been found beneficial (Thomson and Page, 2007), and include behavioural stress management , cognitive behaviour therapy, in both face-to-face and internet format (Hedman et al., 2011b; Sørensen et al., 2011), and mindfulness –based CBT (McManus et al., 2012) .

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SEPARATION ANXIETY DISORDER

Though traditionally regarded as having an onset in childhood, separation anxiety disorder is now recognised as both continuing into and having an onset during adult life,

and as such is grouped with other anxiety disorders within the DSM-5 (American Psychiatric Association, 2013).

The efficacy of psychological or pharmacological treatment in adults with separation anxiety disorder has not been studied extensively .

The findings of randomised placebo-controlled trials of pharmacological treatment in children with separation anxiety disorder provide no convincing evidence of benefit for any medication.

Although, fluvoxamine (Walkup et al., 2001) and sertraline have been found efficacious among the separation anxiety disorder sub-group within mixed diagnostic samples (Walkup et al., 2008)

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TREATMENT RESISTANCE

The common strategy to deal with treatment resistance in anxiety disorders :

● Consider raising the dosage if the current dosage is well tolerated .● Consider switching to another evidence-based treatment .● Consider combining evidence-based treatments only when there are no contraindications.● Consider augmentation with other drug class. ● Consider combining evidence-based pharmacological and psychological treatments .

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CONCLUSION

Although there are different diagnostic criteria for different anxiety disorders , they can all be considered to have overlapping symptoms of anxiety/fear coupled with worry .

Amygdala and hippocampus have central role in regulating anxiety .

there is high prevalence of Anxiety disorders in society and this translates into significant mortality, morbidity and decrease in quality of life.

There also significant cost to society associated with high disability and high health care utilization. 

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Although many medications currently available offer anxiolytic benefits , antidepressants ( SSRIs and SNRIs mainly) are more effective than others.

Benzodiazepines can used for short term but can cause greater relapses in long term.

Psychotherapy has prominent role in anxiety disorders , especially in phobias where it is more efficacious than pharmacotherapy.

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combining drug and psychological treatments have not shown greater overall efficacy than either treatment given alone in various anxiety disorders.

A minimum of 4-12 week period is needed to assess efficacy in acute phase in various anxiety disorders.

There is a significant advantage for staying on active medication for 6-18 months period in continuation phase in various anxiety disorders.

A period of 3 month is required for discontinuation of the medication.

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THANK YOU