Pharmacology of medicines for treatment of adults with generalized anxiety disorder (GAD)

Drug	Initial daily oral dose^*	Daily oral dose range^*	Primary metabolism^¶	Effect on metabolism of other drugs^¶	Selected characteristics relevant to treatment of adults with GAD
SSRI antidepressants Applies to all SSRIs: Onset of effect may be delayed 2 to 4 weeks or more. Adverse effects among the SSRIs include: Nausea, diarrhea, insomnia/agitation, somnolence, impaired sexual function, and hyponatremia. Adverse effects of individual agents are presented in a separate table in UpToDate.
Citalopram	10 mg	10 to 40 mg	CYP3A4, 2C19	None	Lower risk of insomnia/agitation Few drug interactions Can prolong QT interval with increasing blood levels
Escitalopram	5 to 10 mg	10 to 20 mg	CYP3A4, 2C19	None	Lower risk of insomnia/agitation Few drug interactions
Sertraline	25 to 50 mg	50 to 200 mg	Limited (minor CYP2C9, 2D6, and 3A4)	None	Greater risk of insomnia/agitation More frequent diarrhea and other gastrointestinal complaints
Paroxetine	10 to 20 mg	20 to 50 mg	CYP2D6	Inhibits 2D6	Mildly sedating Weakly anticholinergic Lower risk of insomnia/agitation Withdrawal symptoms if not tapered
Fluoxetine	10 to 20 mg	20 to 60 mg	CYP2D6, 2C9, and several minor	Inhibits CYP2D6, 2C19	Greater risk of insomnia/agitation No withdrawal symptoms if not tapered Takes weeks to reach steady blood levels due to long half-life
Fluvoxamine	50 mg	50 to 300 mg	CYP1A2, 2D6	Inhibits CYP1A2, 2C19	Lower risk of insomnia/agitation Withdrawal symptoms if not tapered Significant drug interactions
SNRI antidepressants Onset of effect and adverse effects of the SNRIs are similar to the SSRIs (refer to above). Adverse effects of individual agents are presented in a separate table in UpToDate.
Duloxetine	30 mg	60 to 120 mg	CYP1A2, 2D6	Inhibits CYP2D6	Greater risk of insomnia/agitation Useful for treatment of comorbid painful conditions Withdrawal symptoms if not tapered
Venlafaxine (extended-release)	75 mg	75 to 225 mg	CYP2D6, 3A4	None	Greater risk of insomnia/agitation Increased blood pressure (primarily diastolic) and heart rate with increasing doses Useful for treatment of comorbid painful conditions Few drug interactions Withdrawal symptoms if not tapered
Other
Buspirone	10 mg in divided doses	10 to 60 mg in divided doses	CYP3A4	None	A nonbenzodiazepine anxiolytic Augmentation choice for partial response to antidepressant Slow onset and modest efficacy Lacks tolerance, dependence, and withdrawal Ineffective for comorbid major depression
Gabapentin	300 mg	300 to 2400 mg in divided doses	Dependent on renal function for clearance	None	A GABA analog calcium-channel modulator antiseizure medication Onset within days of starting treatment Sedation and dizziness Tolerance, dependence, and withdrawal possible
Pregabalin	50 mg in divided doses	50 to 300 mg in divided doses	Dependent on renal function for clearance	None	A GABA analog calcium-channel modulator antiseizure medication Onset within days of starting treatment Approved for treatment of anxiety in some countries (not United States) Sedation and dizziness Tolerance, dependence, and withdrawal possible Schedule V controlled substance in United States Many patients require >150 mg/day, up to 300 mg/day
Mirtazapine	15 mg	15 to 60 mg	CYP1A2, 2D6, 3A4	None	An atypical antidepressant Alternate or augmentation choice for anxiety with insomnia Sedating; notably increases appetite
Quetiapine	25 to 50 mg	50 to 300 mg	CYP3A4	None	An SGA Potential augmentation choice for partial response to antidepressant or alternate as monotherapy Sedation, extrapyramidal effects, weight gain, and metabolic side effects (refer to separate table on SGA adverse effects) Rarely tardive dyskinesia
Hydroxyzine	50 mg at bedtime	25 to 50 mg three to four times per day as needed	None	None	A sedating antihistamine with anxiolytic properties Augmentation option for treatment of insomnia Anticholinergic side-effects with increasing doses
Imipramine	75 mg in divided doses	75 to 200 mg in divided doses	CYP2C19, 2D6	None	A tricyclic antidepressant Anticholinergic side effects Cardiotoxic in overdose May be poorly tolerated relative to SSRI and SNRI antidepressants

The pharmacology of benzodiazepines used for treatment of adults with generalized anxiety disorder is presented in a separate table in UpToDate.

CYP: cytochrome P450; GABA: gamma aminobutyric acid; GAD: generalized anxiety disorder; SGA: second-generation antipsychotic; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.

* A 50% dose reduction (round to pill strength) and gradual titration is suggested for older adults and individuals sensitive to adverse effects such as nausea, dizziness, headache, and initial insomnia/activation due to antidepressants.

¶ Data provided on drug metabolism are included to assess the potential for drug interactions. Only strong or moderate effects on other drugs are listed. These classifications are based upon US Food and Drug Administration guidance. Other sources may use a different classification system resulting in some agents being classified differently. Specific drug interactions and management suggestions may be determined by use of the drug interactions program included within UpToDate.

Data from:

Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision. World J Biol Psychiatry 2008; 9:248.
Bandelow B, Sher L, Bunevicius R, et al. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract 2012; 16:77.
UpToDate Lexidrug. More information available at https://online.lexi.com/.

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Pharmacology of medicines for treatment of adults with generalized anxiety disorder (GAD)