HANDBOOK OF PSYCHIATRIC DRUGS - PART 6 potx

4 ANXIOLYTIC DRUGSINTRODUCTION There has been an exponential increase in the number ofmedications demonstrated to be effective for the treatment ofanxiety and anxiety disorders.. The int

of their need for specific agents and likelihood and speed ofrelapse off of medication This must be done in a very open andcomprehensive fashion, fully involving the patient and otherimportant individuals, and emphasizing a thorough discussion

of both the known risks and the limits of our knowledge.Ideally, options for pharmacologic intervention, if either eleva-tion or depression intercedes, should be thoroughly discussed,

in order to allow for the most efficient and informed tion, should one be needed

interven-Another critical feature to consider is that the window

of opportunity for medication discontinuation is very narrowwith respect to the congenital abnormalities of concern withmood stabilizers Cardiac development and neural tube closureoccur relatively early, in the first trimester Therefore, a patientpresenting with one or two missed periods is likely already to

be beyond the stage where medication discontinuation will beable to prevent increased risk This argues for having a fulldiscussion of risks with reproductive age women and a discus-sion about contraceptive methods being employed Keep inmind, as well, that low potency oral contraceptives may berendered ineffective by enzyme inducing medications such ascarbamazepine

Evidence from retrospective studies suggests that there is

no protective effect of pregnancy on mood stability In theimmediate post-partum period, bipolar women are at markedlyelevated risk of relapse The most thorough study to date found

a 90% relapse rate for unmedicated bipolar women in the firsttwo months post-partum Therefore, regardless of the decisionsmade during pregnancy, aggressive pharmacotherapy should

be initiated in the immediate post-partum period

SUMMARY

Recent years have seen a remarkable increase in our standing of bipolar disorder and the range of pharmacologicagents with which it can be treated Lithium and valproateremain the core treatment options for bipolar disorder butare increasingly being supported by additional anticonvulsantand atypical antipsychotic agents Although not definitivelydemonstrated yet, two relatively new medications, lamotrigine

and quetiapine, hold significant promise as mood stabilizerswith more robust antidepressant efficacy, helping to address

an area of critical need The increase in treatment options

is simultaneously promising and challenging It requires thatclinicians learn to employ newer and older agents in the mostrational manner, with decisions soundly based upon evidence

of efficacy in clinical trials, as well as upon the individualclinical characteristics of each patient with whom we work.Carefully reviewing and documenting treatment response andtolerability is especially important in the unstable setting ofbipolar illness, and can be aided by the use of clinical ratingscales and daily prospective mood charting

Even the best medication selection is of limited value

by itself A close, collaborative, and honest working alliancebetween the psychiatrist, the patient and family members, aswell as a commitment to psychoeducation, is important forfostering trust, treatment adherence, and insight Supportivepsychotherapy techniques employed by a therapist knowledge-able about bipolar illness can also be extremely useful, helpingpatients to learn to properly differentiate normal emotions orreactions from affective symptoms, and promoting a healthylifestyle with good sleep hygiene, reduction of stress, and avoid-ance of drugs and alcohol

Associa-diabetes J Clin Psychiatry 2004 Feb; 65(2):267–72.

4 ANXIOLYTIC DRUGS

INTRODUCTION

There has been an exponential increase in the number ofmedications demonstrated to be effective for the treatment ofanxiety and anxiety disorders

Barbiturates and meprobamate were some of the firstagents shown to be effective in decreasing anxiety, but wereaddictive and often lethal in overdose In the early 1960s,Klein demonstrated that the tricyclic antidepressant (TCA)imipramine was useful in the treatment of panic disorder Inthe 1970s, studies showed that monoamine oxidase inhibitors(MAOIs) were also effective in the treatment of certain anxietydisorders, such as social anxiety and anxiety with coexistingdepression

The introduction of benzodiazepines in the early 1960swas a major advance; they were much safer than the barbi-turates and meprobamate, had a rapid onset of action, and abroad spectrum of efficacy extending from situational anxiety

to pathological anxiety disorders Many different azepines, with different absorption times and half-lives, weredeveloped and have been valuable not only for treating anxietysymptoms and anxiety disorders but for treating seizure disor-ders and alcohol withdrawal Unfortunately, with wide-scaleusage, problems with craving, dependence, and withdrawalwith abrupt discontinuation were noted The next major class

benzodi-Handbook of Psychiatric Drugs Jeffrey A Lieberman and Allan Tasman

2006 John Wiley & Sons, Ltd ISBN: 0-470-02821-1

of agents approved was the azopyrones, of which buspirone isthe most well known This agent was effective in generalizedanxiety disorder (GAD) but not for other anxiety disorders.The selective serotonin reuptake inhibitors (SSRIs) as

a class have demonstrated effficacy for most anxiety ders Although these agents have a delayed onset whencontrasted with the benzodiazepines, they have a broader spec-trum of action, no problems with dependence, and much less

disor-of a problem with withdrawal syndromes Controlled trialshave demonstrated the efficacy and safety of the selectiveserotonin-norepinephrine reuptake inhibitor (SNRI) medica-tion venlafaxine in the treatment of anxiety disorders includingsocial anxiety disorder, generalized anxiety disorder, posttrau-matic stress disorder, panic disorder, and obsessive–compulsivedisorder Other classes of medications used in the treatment ofanxiety disorders (either as primary treatments or as adjuvants)include anticonvulsants, beta-blockers, and atypical antipsy-chotics

A GENERAL APPROACH TO USING MEDICATION WITH ANXIOUS PATIENTS

Patients may present to physicians with many differentconcerns related to anxiety Such patients commonly havethe need for reassurance that their disorder is treatable,and that their physicians truly hear their concerns and willattempt to help them Taking a complete history is essentialnot only for making an appropriate diagnostic formulationbut for developing a therapeutic alliance Medical evaluation,including laboratory testing, and assessment of current andpast substance abuse or dependence, are particularly impor-tant in the evaluation of patients presenting with symptoms ofanxiety The differential diagnosis for such patients includes:

• Adjustment disorders secondary to life stressors

• Anxiety symptoms or anxiety disorders secondary to amedical condition

• Anxiety secondary to alcohol or substance abuse, dence, or withdrawal

depen-• Generalized anxiety disorder (GAD)

• Panic disorder (PD), with or without agoraphobia

• Social anxiety disorder (e.g., social phobia)

• Specific phobia

• Posttraumatic stress disorder (PTSD)

• Obsessive–compulsive disorder (OCD)

Sharing the diagnostic formulation with the patient is

an important intervention that often facilitates the patient’scommitment to the treatment plan This is crucial since anxiouspatients may be reluctant to take medication When they dotake medications, they commonly ruminate about medicationside effects Patients with anxiety symptoms or anxiety disor-ders are likely to have somatic preoccupations and heightenedsomatic sensitivity A collaborative approach where physiciansand patients form a “team” to monitor both the potentialbenefits and risks of any medication intervention frequentlyenhances adherence An important rule when initiating phar-macological treatment for patients with anxiety disorders is

“to start low and go slow” Interestingly, although patientswith anxiety disorders frequently require more gradual initialtitration schedules, they often attain maintenance dosages ofantidepressant medications that are greater than the doses used

to treat major depressive disorder

Along with medication interventions, psychoeducationabout anxiety disorders is often a key part of treatment Inaddition, psychotherapeutic interventions have been demon-strated to be effective in anxiety disorders, particularlycognitive-behavioral therapy, which may include cognitiverestructuring, relaxation and breathing exercises, and gradedexposure to anxiety-provoking stimuli

PHARMACOLOGY

Antidepressants

It has long been known that antidepressants are also frequentlyeffective treatments for anxiety disorders The basic action ofthe majority of the antidepressants is to increase the avail-ability of neurotransmitters in the synaptic cleft The chemistryand pharmacokinetics of these agents are reviewed fully inChapter 2

Other antidepressants with anxiolytic effects have differentmechanisms of action These include the inhibition of bothserotonin and norepinephrine transporter sites (as seenwith venlafaxine dosed above 150 mg/d, and with duloxetineand clomipramine); antagonism of the presynaptic alpha-2-adrenergic receptors (mirtazepine); and antagonism of postsy-naptic serotonin type-2 receptors (nefazodone).

The relative differences in terms of major pharmacokineticand pharmacodynamic properties are outlined in Table 4-1

Benzodiazepines

The benzodiazepines as a class work by increasing the relativeefficiency of the gamma-aminobutyric acid (GABA) receptorwhen stimulated by GABA They bind to a site located adja-cent to the GABA receptor and cause an allosteric change

to the receptor that facilitates the increased passage of thechloride ions intracellularly when GABA interacts with thereceptor complex This leads to a relative hyperpolarization

of the neuronal membrane and inhibition of activity in thebrain

The benzodiazepines as a group have different affinities forGABA receptors; some agents bind to only one of the twotypes of GABA receptors Both clonezapam and alprazolamwork only on the central GABAA receptor, while diazepambinds to both GABAA and GABAB receptors The pharma-cokinetic properties of the benzodiazepines are outlined inTable 4-1 The half life of clonazepam is significantly longerthan alprazolam (30–40 hours vs 6–27 hours respectively); this

is reflected in the longer time to steady-state plasma levels forclonazepam (up to 1 week) The relative pharmacodynamic

and pharmacokinetic properties of the benzodiazepines arefurther outlined in comparison to the other medications inTable 4-2

Buspirone

Buspirone is believed to exert its anxiolytic effect by acting as

a partial agonist at the 5-HT1A autoreceptor Stimulation ofthe 5-HT1Aautoreceptor causes decreased release of serotonininto the synaptic cleft However, buspirone also exerts anothereffect through its active metabolite 1-phenyl-piperazine (1-PP), which acts on alpha-2-adrenergic receptors to increase

the firing rate of the locus coeruleus Some not yet

well-characterized combination of these effects may be responsible

for the anxiolytic effect of buspirone

It usually takes approximately four weeks for the benefit

of buspirone therapy to be detected in patients with GAD Amajor advantage of buspirone is that it does not cross-reactwith benzodiazepines The most common side effects associ-ated with buspirone include dizziness, gastrointestinal distress,headache, numbness, and tingling The pharmacokinetics andaverage daily dosage are described in Table 4-1 The mostcommon pharmacokinetic and pharmacodynamic actions ofbuspirone are described in Table 4-2

Beta-Blocker Medications

Beta-adrenergic blockers competitively antagonize pinephrine and epinephrine at the beta-adrenergic receptor(Table 4-2) It is thought that the majority of positive effects ofbeta-blockers are due to their peripheral (rather than central)actions Beta-blockers can decrease many of the peripheralmanifestations of anxiety such as tachycardia, diaphoresis,trembling, and blushing The advent of more selective beta-blockers that only block the beta-2-adrenergic receptor hasbeen beneficial since blockade of beta-1-adrenergic receptorscan be associated with bronchospasm

The precise mechanism of action of many mood stabilizers arenot yet fully understood Gabapentin, pregabalin, and viga-batrin increase brain GABA levels or neurotransmission atleast in part by targeting the metabolic pathways of GABA.Tiagabine selectively increases synaptic GABA availability byblocking the reuptake of GABA via transporter inhibition.Evidence exists, to a greater or lesser extent, that all of theseagents possess anxiolytic properties See Tables 4-1 and 4-2 for

a review of some of the more salient pharmacological ties of these agents

proper-Antipsychotics

Conventional or typical antipsychotics are rarely used as vant medication for anxiety disorders due to problems withextrapyramidal side effects and the risk of developing tardivedyskinesia The newer class of atypical antipsychotic medica-tions appear to have a decreased risk of these side effects andare beginning to be used as adjuvants in patients with treat-ment resistant anxiety disorders

adju-Although the different atypical antipsychotic medicationshave varying affinities for dopamine Type-2 and serotoninType-2receptors, this is the common mechanism of action ofthese agents The atypical antipsychotic medications also differdramatically in terms of their pharmacodynamic properties; afull review of these can be found in Chapter 1 and in Tables 4-1and 4-2

INDICATIONS FOR USE

The efficacy of various psychotropic drugs for the treatment

of anxiety disorders is summarized in Table 4-3

Antidepressants

The SSRIs are considered the first-line treatment option formost of the anxiety disorders, including generalized anxietydisorder (GAD), social anxiety disorder (SAD), panic disorder

Mirtazepine Nefazodone Clonazepam

Gabapentin Tiagabine Pagoclone

Venlafaxine Lamotrigine Valproate Nefazodone Mirtazapine Clonidine

effi-to be effective and well effi-tolerated Escitalopram has also beendemonstrated to be effective in GAD.

SSRIs have emerged as first-line treatment for socialanxiety disorder (SAD), also known as social phobia Most

of the efficacy data are derived from multicenter, blind trials of paroxetine, sertraline, and fluvoxamine The use

double-of sertraline for the longer-term treatment double-of social anxietydisorder has been investigated and shown efficacy in alleviatingsymptoms and prevention of relapse Other SSRIs includingfluoxetine, citalopram, and escitalopram also seem to be effec-tive in the treatment of this disorder

SSRIs are generally accepted as a first-line treatment forpanic disorder (PD) The major advantage of these agents istheir tolerability and thus longer-term acceptance by patients

At present there is evidence that fluoxetine, sertraline, etine, fluvoxamine, and citalopram are effective in the acutetreatment of panic disorder Fluoxetine and sertraline havebeen shown to reduce panic attack frequency, global distress,and agoraphobic distress Maintenance treatment with sertra-line in one study was associated with continued improvementand protected patients from recurrence Paroxetine has beenreported to have a more rapid onset of action than otherSSRIs in PD, and to show continued improvement over time.Citalopram and escitalopram are effective treatments of panicdisorder, decreasing both panic attacks and phobic symptoms.Fluvoxamine has also shown efficacy for the treatment of panicdisorder with or without agoraphobia

parox-SSRIs are effective for the treatment of PTSD, decreasingmany of the core symptoms of this disorder Fluoxetine wasthe first SSRI to be studied in randomized clinical trials, andshowed significant improvement in both civilian and veteranpopulations Two SSRIs have been approved by the FDAfor the treatment of PTSD, sertraline and paroxetine In onestudy, doses of sertraline of 50 and 200 mg/day gave sustained