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Hydroxyzine (Vistaril, Atarax) For Anxiety Disorders

Hydroxyzine (brand names Vistaril, Atarax) is a first-generation antihistamine of the diphenylmethane and piperazine class.  It was initially synthesized in 1956 and thereafter marketed in the U.S. by the pharmaceutical juggernaut, Pfizer.  Although a relatively ancient medication by today’s standards, hydroxyzine is still commonly prescribed: as a preoperative anesthetic, analgesic, and anxiolytic adjunct; as an antiallergic agent for atopic dermatitis, chronic hives, and pruritus; and on occasion, as a neuropsychiatric intervention for generalized anxiety disorder, and alcohol withdrawal.

Upon administration, hydroxyzine functions principally as an inverse agonist of the H1 histamine receptor.  However, dissimilar to other first-generation antihistamine agents, it doesn’t significantly impact mACh (muscarinic acetylcholine receptors); this is favorable in reducing occurrence of anticholinergic side effects.  Hydroxyzine also elicits antiserotonergic effects, meaning it inhibits action at serotonin (5-HT) receptors, which in turn, yields a therapeutic anxiolytic response.

Research of hydroxyzine (Atarax, Vistaril) for the treatment of anxiety suggests that it is equally effective and tolerable to FDA approved anxiolytics such as Buspar and benzodiazepines.  In fact, some speculate that it may be a safer option than benzodiazepines due to its low propensity for abuse, dependence, and toxicity.  These findings have lead many individuals with severe anxiety disorders to actively pursue hydroxyzine as a pharmacological intervention.

How Hydroxyzine (Vistaril, Atarax) Treats Anxiety (Mechanism of Action)

Hydroxyzine exerts a bulk of its anxiolytic effect by acting as an H1 receptor inverse agonist.  However, H1 receptor inverse agonism alone may not fully alleviate one’s anxiety; hence the reason other first-generation antihistamines may be clinically ineffective anxiolytics.  What makes hydroxyzine unique distinct other first-generation antihistamines is its antiserotonergic properties which are thought to bolster its anxiolytic effect.

H1 inverse agonist: Hydroxyzine binds to H1 histamine receptors and inhibits activity of endogenous histamine at receptor sites.  This reduces histamine-mediated allergic reactions such as itchy skin, watery eyes, etc.  It is the H1 histamine receptor that facilitates the anti-allergy mechanisms of hydroxyzine.

Inhibition of endogenous histaminergic action upon the H1 receptors can also generate an anxiolytic response.  The mechanisms of this anxiolytic response isn’t fully understood, but several mechanisms have been proposed.  One hypothesis is that H1 receptor inhibition increases levels of serotonin (5-HT) and norepinephrine in certain regions of the brain, without affecting dopamine.

As most individuals are aware, increasing serotonin in certain regions can reduce anxiety – perhaps this is one mechanism by which hydroxyzine is anxiolytic.  H1 receptors are also known to interact with the sympathetic nervous system and it is possible that inverse agonism decreases sympathetic activation, leading to increased physical relaxation and a perceived anxiolytic response.  Moreover, it is likely that a complex reaction of altered neurotransmission of histamine (at H1 receptors), increased levels of serotonin, and decreased sympathetic activation – contribute to hydroxyzine’s anxiolytic effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25680462

5-HT2A antagonist: Though antihistaminergic effects stemming from hydroxyzine may reduce the majority of a user’s anxiety, its secondary antiserotonergic effects may bolster anxiolytic responses.  Hydroxyzine is believed to inhibit activity at 5-HT2A receptor sites, which often leads to an increase in drowsiness and somnolence.  This is similar to the mechanism employed by the pharmaceutical antidepressant and hypnotic, trazodone.

Ironically, a metabolite of hydroxyzine known as norchlorcyclizine of similar chemical structure to trazodone, possibly yielding analogous effects.  In any regard, it isn’t fully elucidated how 5-HT2A antagonism improves symptoms of anxiety, but some speculate that it decreases arousal and enhances slow-wave-sleep (SWS) – possibly increasing delta waves and theta waves.

It could be that part of the anxiolytic effect of hydroxyzine is associated with improved sleep quality.  There is some literature theorizing that individuals with anxiety and/or depression often exhibit deficiencies in slow-wave-sleep.  Perhaps ensuring sufficient slow wave sleep is enough to ameliorate symptoms of anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23616706

Subcortical suppression: Hydroxyzine and its primary metabolite (cetirizine) are thought to suppress activity in subcortical regions of the brain, contributing to an anxiolytic effect.  This subcortical suppression is thought to be facilitated by inverse agonism of the H1 receptor.  Since many subcortical regions are implicated in the pathophysiology of anxiety and fear, perhaps even partial suppression improves anxiety symptoms.

Dysfunction within subcortical regions such as excess activation may cause anxiety in certain individuals.  Via hydroxyzine-induced suppression of activity in these regions, an individual with subcortical dysfunction may no longer feel anxious (or as anxious) as pre-treatment.  Though the exact subcortical regions suppressed (and the degree of suppression) isn’t clear, this may be an important anxiolytic mechanism of hydroxyzine and other H1 inverse agonists.

Monoamine alterations: In addition to affecting the neurotransmission of histamine and serotonin, hydroxyzine is thought to alter catecholamine concentrations (norepinephrine and dopamine) to a small extent.  Particularly, hydroxyzine binds to alpha-1 adrenergic receptors and D2 dopamine receptors, acting as an antagonist.  Modest effects as an alpha-1 blocker and D2 antagonist may further decrease neurophysiologic stimulation and promote physical relaxation.

It is known that alpha-1 blockade decreases blood pressure and can be an effective treatment for hypertension.  Blockade of D2 receptors is known to prevent hyperdopaminergic reactions such as anxiety, paranoia, and agitation.  Research administering hydroxyzine to animals discovered that it increased monoamines (5-HT, DA, NE) in regions such as the hippocampus and cerebral cortex.

Benefits of Hydroxyzine for Anxiety Disorders (Possibilities)

There are numerous potential benefits associated with using hydroxyzine as an intervention for anxiety disorders.  Perhaps the most substantial benefits include: its unique mechanism of action (distinct from SSRIs and benzos), its fast-onset of effect (it doesn’t take weeks or months to “kick in”), and that it can be used as an adjunct with many other psychiatric medications (contraindications are minimal).

Adjunct: Hydroxyzine is an antihistaminergic anxiolytic that can be prescribed as an adjunct to many other psychiatric medications, including SSRIs.  Some may prefer hydroxyzine over other adjunct options due to: its distinct pharmacodynamics (from other agents), based on the fact that it doesn’t cancel out the therapeutic effects of other drugs, and its low propensity for abuse.  Furthermore, animal studies suggest that when a benzodiazepine is administered with an SSRI, learned helplessness increases.

On the other hand, when hydroxyzine is administered with an SSRI, a reversal of learned helplessness is maintained (as induced by the SSRI).  This suggests that hydroxyzine may be a superior complementary option to benzodiazepines for SSRI users.  Additionally, it may potentiate therapeutic alterations in monoamine levels throughout the brain to bolster anxiolytic effects.

When considering any agent as a potential adjunct for psychiatric conditions, a low propensity for abuse, addiction, dependence, and toxicity is necessary.  Most professionals consider hydroxyzine safer than benzodiazepines with fewer potential deleterious effects.  Therefore, it may be a favorable adjunct anxiolytic to many other medications.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9035982

Anxiety subtypes: Individuals with specific subtypes of anxiety may not respond to standard first-line neuropsychiatric interventions.  Many people test every SSRI and not only find that their anxiety doesn’t improve, but in some cases, it’s exacerbated.  Emerging evidence supports the idea that SSRIs may worsen some cases of anxiety due to the fact that certain anxious subtypes may manifest from too much serotonin (or high serotonin in specific neural regions).

If you’re an individual that doesn’t respond to standardized treatments (e.g. SSRIs), and have gone through the ringer of first-line medications only to feel miserable, you may derive benefit from hydroxyzine.  Although no anxiolytic medication can be considered a panacea intervention, for certain individuals, hydroxyzine may be their “magic bullet” or one of a few medications that actually works.  Others may find that hydroxyzine isn’t a perfect anxiolytic, but it works better than all other interventions that they’ve tried.

Research suggests that individuals with GAD (generalized anxiety disorder) and/or anxiety as induced by a medical condition may benefit from hydroxyzine.  Since hydroxyzine downregulates activity in subcortical regions of the brain, those with anxiety provoked by subcortical abnormalities may derive significant benefit from this medication.  Additionally, those with anxiety as a result of poor slow wave sleep may benefit significantly from hydroxyzine’s 5-HT2A antagonism.

Efficacy: Research suggests that between 60% and 90% of individuals with generalized anxiety disorder (GAD) derive significant therapeutic benefit from hydroxyzine.  Numerous comparison trials have demonstrated its superior anxiolytic efficacy over a placebo.  Although hydroxyzine is not considered a first-line intervention for the treatment of anxiety due to lack of large-scale studies and limitations associated with those studies (e.g. bias), evidence hints that it may be equally as efficacious.

For example, one study tested the anxiolytic efficacy of hydroxyzine over a 3-month term and results indicated that it was equal in efficacy to the benzodiazepine drug “bromazepam”; each of which were superior in efficacy to a placebo.  Another study discovered that hydroxyzine was equal in anxiolytic efficacy to the already-approved anxiolytic, Buspar (buspirone).  What’s more, it appears as though the anxiolytic effect as induced by hydroxyzine is maintained for a duration after discontinuation; this may be perceived as advantageous.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12444816
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9777055
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9809861

Fast-acting: Studies have shown that hydroxyzine is capable of significantly reducing anxiety scores within 1 week of administration when compared to a placebo.  This suggests that its anxiolytic benefits may be attained substantially quicker than other interventions such as SSRIs.  A major problem with most psychiatric medications is that they can take between 4 to 8 weeks to elicit anxiolytic effects; not everyone can afford to wait this duration.

The people that have anxiety so bad they can’t function want immediate relief or at least relief within a week.  Some anecdotal reports have noted that hydroxyzine’s anxiolytic effects can be attained immediately after administration of a single-dose, which makes sense when considering its H1 receptor inverse agonism.  Most individuals taking hydroxyzine experience an anxiety reduction within 7 days of consistent treatment.

Insomnia reduction: Many individuals with anxiety struggle from significant insomnia (and vice-versa).  Untreated anxiety often leads to insomnia, but the insomnia continues to fuel anxiety, and thereafter, the two conditions reinforce one another.  Hydroxyzine is believed to reduce insomnia via its antihistaminergic effect (from inverse agonism at the H1 receptor site).

Anyone that’s taken an antihistamine is familiar with the decrease in neurophysiologic arousal, drowsiness, and/or somnolence that ensues.  Decreased neurophysiologic arousal generally makes it easier for someone struggling with insomnia to fall asleep.  Therefore, hydroxyzine may be a good fit for those with anxiety disorders and comorbid insomnia.

Low cost: A prescription for hydroxyzine can be attained for an extremely low cost.  A user can get around 90 capsules of generic 25 mg hydroxyzine for around $9.  This means you’re paying around $0.10 per pill – this is far more affordable than newly patented anxiolytics.  Since not everyone with severe anxiety has a top-notch insurance plan, a medication that doesn’t put a dent in a user’s bank account may be preferred; hydroxyzine fits the bill.  Although brand name formulations such as Vistaril and Atarax are bound to carry a high price tag, most sensible people will go opt for standard hydroxyzine.

Mechanism of action: The pharmacodynamics of hydroxyzine are well-understood which may be perceived as favorable over anxiolytic agents with undeciphered mechanisms of action.  As already outlined and discussed above, hydroxyzine acts principally as a H1 receptor inverse agonist and secondarily as a 5-HT2A antagonist.  These two mechanisms are likely responsible for facilitating a majority of its anxiolytic effect.

Most present-day anxiolytics act as serotonin reuptake inhibitors or modulate the function of GABA (gamma-aminobutyric-acid).  Hydroxyzine isn’t known to affect GABA, and doesn’t directly inhibit the reuptake of serotonin.  For this reason, those who fail to respond to SSRIs or benzos may want to consider hydroxyzine – it exerts completely different neurochemical effects.

Refractory cases: Many individuals struggle with refractory anxiety or anxiety that doesn’t respond to standard, recommended anxiolytic interventions.  In cases of refractory anxiety, it may be necessary to prescribe an agent that isn’t FDA approved to treat anxiety, yet may provide benefit as an “off-label” intervention.  Although hydroxyzine isn’t clinically approved to treat anxiety, there is evidence to suggest that it is likely effective.

Since hydroxyzine exhibits a unique mechanism of action, it may prove efficacious in the attenuation of anxious symptoms among a subset of individuals with refractory cases.  Though not all refractory cases will benefit from hydroxyzine, compared to other off-label agents, there is ample evidence to support its hypothesized efficacy.  Among those with refractory anxiety that derive slight relief from a first or second-line intervention, hydroxyzine (as an adjunct) may potentiate anxiolytic effects, thereby bolstering overall relief.

Safer than benzos: It is thought that hydroxyzine may be safer than benzodiazepines for several reasons.  Benzodiazepines are known to induce tolerance rapidly, are addictive, have a high potential for abuse, interact with many other drugs, and have serious withdrawal symptoms.  Hydroxyzine isn’t associated with rapid tolerance induction, addiction, or abuse.

It is also known that benzodiazepines impair driving, cognitive performance (e.g. ability to encode memories), and are linked to dementia; they are dangerous psychiatric drugs.  Although hydroxyzine shouldn’t be considered completely safe nor devoid of risk, evidence suggests it may be holistically safer than benzodiazepines.  Furthermore, long-term effects of hydroxyzine are hypothesized to be less deleterious than those of benzodiazepines.

Individuals looking for a (possibly) safer alternative to Xanax (and related chemicals) may want to pursue hydroxyzine.  The fact that hydroxyzine acts upon the H1 and 5-HT2A receptors as opposed to GABA receptors likely makes it safer with less potential for addiction.

Sleep enhancement: An added benefit of using hydroxyzine for anxiety is that it could enhance your quality of sleep, specifically by increasing slow-wave-sleep.  A mechanism by which hydroxyzine may bolster slow-wave-sleep is via 5-HT2A antagonism.  Antagonism of the 5-HT2A receptor is thought to ameliorate depressive symptoms principally by optimizing sleep.

Since many individuals with anxiety disorders may be unable to attain the deepest, most restorative sleep – enhancement of sleep quality may have numerous therapeutic implications.  Therefore, hydroxyzine may be an appealing option for cases of anxiety in which individuals report comorbid sleep disturbances.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23616706
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17222324

Side effects: Like any drug, hydroxyzine can cause side effects – some of which may be perceived as problematic.  However, when compared to many other anxiolytic drugs, its side effect profile may be considered favorable.  Users taking serotonergic anxiolytics often complain of severe sexual dysfunction and weight gain, whereas those taking benzodiazepines may report severe cognitive deficits and/or impaired motor skills.

When compared to those taking serotonergic anxiolytics, users of hydroxyzine may be less likely to report sexual dysfunction and weight gain.  Compared to benzodiazepines, hydroxyzine may be less likely to cause cognitive impairment.  Additionally, if compared to related H1 receptor inverse agonists, hydroxyzine isn’t associated with significant anticholinergic side effects (due to its low affinity for mAChRs).

Withdrawal: A potentially significant advantage associated with hydroxyzine over other medications is that it isn’t associated with a severe discontinuation syndrome.  In other words, users are unlikely to report debilitating withdrawal symptoms.  Most anxiolytics are associated with protracted or post-acute withdrawal syndromes, especially benzodiazepines.

Studies have documented that abrupt discontinuation of hydroxyzine after 4 weeks of daily administration (50 mg), users experienced no withdrawal symptoms.  What’s more is that there was no rebound anxiety after cessation of treatment (as is commonly experienced with other medications) and anxiolytic effects appeared to linger after discontinuation.  The favorable withdrawal profile may be a significant advantage of hydroxyzine.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7875114

Disadvantages of Hydroxyzine for Anxiety Disorders (Possibilities)

In no way should hydroxyzine be considered a utopian anxiolytic.  Many users find that the efficacy of hydroxyzine is subpar compared to other medications, while others note that hydroxyzine doesn’t provide any anxiolytic benefit.  Potential disadvantages of hydroxyzine are rampant and should always be considered prior to its usage.

Brain fog: Anytime you’re taking an antihistaminergic drug, you may experience brain fog characterized by feeling spaced out and have difficulty performing cognitively-demanding tasks.  Hydroxyzine functions primarily by acting as an inverse agonist of your H1 receptors, thereby preventing stimulation of histamine.  This may lead to clouded-thinking, drowsiness, depersonalization, and as if your brain is stuck in some sort of a half-baked twilight zone.

Cognitive impairment: Although cognitive deficits associated with hydroxyzine may be less significant than those associated with benzodiazepines, hydroxyzine users may struggle with learning and memory tasks.  Studies that initially linked just benzos to memory impairment have now discovered that antihistamines can also interfere with memory processes (encoding and retrieval).  A subset of individuals may be unable to use hydroxyzine because their school or occupational work is cognitively-demanding.

Impaired cognitive function as a result of hydroxyzine may lead to decreased motivation and productivity, compromised problem solving, and poorer decision making – any of which could get a person fired from his/her job.  Since many drugs that enhance histamine function (e.g. modafinil) improve cognitive performance, hydroxyzine could be thought to do the opposite.

Fatigue: A detrimental, yet common side effect of hydroxyzine is excessive fatigue and/or drowsiness.  Some individuals may experience anxiety relief, but are also unable to function in society because they feel extremely tired with low energy.  This effect is chiefly a result of hydroxyzine’s inverse agonism of the H1 receptor.

Daytime fatigue and drowsiness should be considered highly problematic for those operating heavy machinery and/or driving a motor vehicle.  Additionally, the overwhelming fatigue may impair an individual’s ability to exercise, engage in social interactions, or simply get out of bed.  Although dosages can be lowered to minimize fatigue, anxiolytic relief may be insignificant at lower doses.

Ineffective: While hydroxyzine (Vistaril, Atarax) may provide an optimal neurochemical tweak for certain individuals, others may derive zero anxiolytic benefit from its usage.  Just like any other pharmaceutical drug, a subset of users will find hydroxyzine useless as an anxiolytic intervention.  Furthermore, it is important to recognize the fact that hydroxyzine is not FDA approved to treat anxiety disorders.

Although some studies suggest hydroxyzine’s anxiolytic efficacy, particularly among those with generalized anxiety disorders, a review of evidence notes that these studies may have had biases.  Since hydroxyzine has not been subject to robust (placebo-controlled, double-blinded, randomized) clinical testing, it cannot be assumed to be an effective anxiolytic.  Therefore, it is important to know that the anxiolytic efficacy of this drug is questionable.

Long-term effects: The effects of long-term hydroxyzine administration aren’t well-known, therefore, it is necessary to speculate that some could be deleterious.  Long-term administration of other antihistamines has been linked to memory impairment, difficulty learning, and/or other cognitive deficits.  Although hydroxyzine is an older medication, it hasn’t been studied extensively in long-term trials among those with anxiety.

Some users may experience adverse effects as a result of neurophysiologic adaptations that occur over a long-term of treatment.  It is also necessary to consider that when administered over a long-term, the anxiolytic efficacy of hydroxyzine may dwindle.  Compared to other drugs that have been well-researched over the long-term (e.g. SSRIs), long-term effects of hydroxyzine may be less favorable.

Side effects: The antihistaminergic properties of hydroxyzine often trigger unwanted side effects such as: blurred vision, dizziness, drowsiness, dry mouth, and skin reddening.  While some may prefer this set of side effects over those associated with another drug (e.g. an SSRI), others may find that the drowsiness alone is so severe that they cannot function.  Medical professionals advise users of hydroxyzine to refrain from operating motor vehicles and/or heavy machinery due to the fact that it can impair coordination and promote somnolence.

If you need to drive a vehicle or are responsible for machine operations, you may need to pursue a different medication.  The combination of antihistaminergic side effects such as brain fog, cognitive impairment, and fatigue – may outweigh any anxiolytic benefit attained by the user.

Tolerance: A major drawback associated with hydroxyzine is that some individuals may develop tolerance to its effects.  Although tolerance to hydroxyzine isn’t considered “rapid onset” such as that developed on benzodiazepines, it may occur after several weeks or months of treatment.  This means that users who were formerly taking a low dose of hydroxyzine for anxiolytic benefit will likely need to increase their dosage to maintain efficacy.

As a result of tolerance onset, anxiolytic benefit may be unsustainable over the long-term.  Once an individual becomes tolerant to the highest hydroxyzine dose, he/she will have reached a peak and may eventually find that even the highest dose “stops working” (due to tolerance).  Furthermore, high doses (as a result of tolerance) are more likely to prompt unwanted side effects and adverse reactions.  Tolerance may be a significant, underreported drawback of hydroxyzine treatment.

Withdrawal: Of the available scientific literature, no studies document significant discontinuation effects associated with hydroxyzine.  However, just because there are no scientifically documented withdrawal symptoms doesn’t mean that users won’t experience discontinuation effects.  Many drugs are touted as being devoid of withdrawal symptoms, yet personal accounts of debilitating withdrawals are summarized online by long-term users.

Scientists often scoff at these anecdotal accounts, but years later, discover more significant withdrawal symptoms than originally summarized.  It is very likely that long-term, regular hydroxyzine users will experience withdrawal symptoms.  Although the withdrawal may not be as severe as benzodiazepines, it may take weeks and/or months after discontinuation to attain neurochemical homeostasis.

Hydroxyzine for Anxiety Disorders (Review of Evidence)

Many studies (1994 to present) have been conducted to investigate the therapeutic potential of hydroxyzine for anxiety disorders.  Although some may question the quality and duration of these studies, nearly all results highlight the anxiolytic efficacy of hydroxyzine when compared to a placebo and/or FDA-approved anxiolytics.  That said, it may be helpful to read and understand the results of each study for yourself, especially if you are considering hydroxyzine as an anxiolytic intervention.

2011: Successful treatment with hydroxyzine of acute exacerbation of panic disorder in a healthy man: a case report.

A case study published by Iskandar, Griffeth, and Rubio-Cespedes C. (2011) documented a patient with panic disorder who utilized hydroxyzine to attenuate his panic attack.  A 25-year old referred to as “Mr. A” with a history of panic disorder appeared in the emergency department, noting symptoms such as: derealization, shortness of breath, sweating, nausea, vomiting, and fear of another panic attack.  Medical professionals ruled out myocardial infarction and a blood sample was tested to rule out other conditions.

It should be noted that Mr. A had been taking Effexor (Venlafaxine) 75 mg per day for 6+ months prior to his appearance in the emergency room and was also a regular smoker.  The patient was referred to receive psychiatric care and was prescribed hydroxyzine 25 mg and instructed to take three time per day (t.i.d.).  Nearly immediate relief was noted in regards to his symptoms and Mr. A experienced no additional panic attacks between the emergency visit and his follow-up appointment (1 month later).

Authors of this report note that there is no prior documentation reporting or investigating efficacy of hydroxyzine for the treatment of panic disorder.  Due to the fact that previous studies document anxiolytic benefits of hydroxyzine, it should be hypothesized that hydroxyzine is a viable antipanic agent.  Since over 6 million Americans experience panic disorder, and it poses fewer risks than benzodiazepines, it may be a favorable intervention.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21977373

2004: Hydroxyzine prevents isolation-induced vocalization in guinea pig pups: comparison with chlorpheniramine and immepip.

A study published by Lamberty and Gower (2004) investigated the histaminergic system in guinea pigs.  Specifically, they sought to determine how the histaminergic system affected vocalizations emitted by guinea pig pups when separated from their mothers and isolated in unfamiliar environments.  To accomplish this, researchers administered intraperitoneal injections of hydroxyzine and chlorpheniramine – each of which function as inverse agonists at the H1 receptor.

They also investigated the effects immepip, a H3 receptor agonist.  Results indicated that when separated from mothers in unfamiliar environments, hydroxyzine was the only drug that suppressed vocalization in a dose-dependent manner.  This suggests that histaminergic and non-histaminergic effects of hydroxyzine may alleviate anxiety in nonhumans, and potentially among humans.

It should be speculated that hydroxyzine’s secondary mechanism as a 5-HT2A antagonist and corresponding antiserotonergic effects may effectively reduce anxiety.  To a lesser extent, mechanisms such as alpha-1 and D2 antagonism may also contribute to anxiolytic effects.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/15388291

2002: Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study.

A study published by Llorca et al. (2002) investigated the efficacy and safety of hydroxyzine for the treatment of generalized anxiety over a period of 3 months.  Authors noted that evidence from previous short-term trials documented the efficacy of hydroxyzine, but longer term trials were lacking.  Researchers designed a multi-center, parallel, randomized, double-blind, placebo-controlled trial.

This trial involved administering a placebo-only for the first 2 weeks, a randomized treatment for 12 weeks (placebo, hydroxyzine 50 mg/day, bromazepam 6 mg/day), and 4 more weeks of placebo-only.  Of the 369 participants, a total of 334 were formally diagnosed with generalized anxiety disorder (GAD) in accordance with the DSM-IV.  From baseline to 12 weeks, researchers documented changes in anxiety levels as measured by the HAM-A (Hamilton Rating Scale for Anxiety).

Results indicated that anxiety scores significantly dropped as a result of hydroxyzine administration compared to the placebo.  The CGI-S (Clinical Global Impressions-Severity) scale confirmed the safety and efficacy of hydroxyzine.  Although there was no significant difference in therapeutic efficacy between hydroxyzine and bromazepam, bromazepam was associated with greater drowsiness (an unwanted side effect).

Authors note that hydroxyzine was both safe and effective for the treatment of generalized anxiety disorder.  This trial supports the idea that hydroxyzine is an effective alternative to benzodiazepines and may carry fewer side effects.  Moreover, this trial highlights the sustained efficacy and safety of long-term hydroxyzine administration for the management of generalized anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12444816

1998: Recent clinical trials of hydroxyzine in generalized anxiety disorder.

A report published by Ferreri and Hantouche (1998) discussed all investigatory trials of hydroxyzine as an intervention for generalized anxiety disorder.  Authors reported that as early as the 1960s and 1970s, hydroxyzine administration was discovered to decrease stress and anxiety as a result of coronary disease, as well as improve sleep.  They also highlight the safety of hydroxyzine compared to other anxiolytics, suggesting that is isn’t known to cause organ toxicity and doesn’t appear to cause dependency.

Authors discuss one trial in particular in which a 50 mg fixed-dose of hydroxyzine proved superior to a placebo in reducing all measures of anxiety within just one week of administration.  They noted that its efficacy was maintained for the full 4-week study period and even after discontinuation.  Another study was also mentioned in which hydroxyzine was compared to (Ativan) lorazepam and was found to improve cognitive symptoms faster and to a more significant extent.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9777055

1998: A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder.

A study published by Lader and Scotto (1998) compared the efficacy of hydroxyzine and buspar (buspirone) to that of a placebo.  They set up a double-blind, parallel group, multi-center study at sites in France and the UK.  A total of 244 individuals diagnosed with generalized anxiety disorder (GAD) via primary care physicians were assigned randomly to receive one of three treatments.

Treatments included either: hydroxyzine (12.5 mg morning and afternoon / 25 mg night), buspar (5 mg morning and afternoon / 10 mg night), or placebo (morning, afternoon, night).  All participants received a placebo for 1 week, then their assigned treatment (hydroxyzine, buspar, or placebo) for 4 weeks, followed by an additional week of placebo.  Anxiety levels were measured with the Hamilton Rating Scale for Anxiety (HAM-A).

Measurements were collected 7 days prior to the study, immediately before the study, and after: 1 week, 2 weeks, 12 days, 4 weeks, and 5 weeks.  Results from the study indicated that hydroxyzine and buspar were significantly more effective than the placebo in reducing anxiety.  Authors concluded that hydroxyzine is a therapeutic intervention for generalized anxiety disorder.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9809861

1995: A multicentre double-blind placebo-controlled study investigating the anxiolytic efficacy of hydroxyzine in patients with generalized anxiety.

A study published by Darcis et al. (1995) investigated the efficacy of hydroxyzine among 110 individuals with generalized anxiety disorder.  They organized a multicenter study that incorporated a double-blind, randomized design.  Participants were set to receive either hydroxyzine 50 mg per day or a placebo for a period of 4 weeks.

Severity of participant anxiety was measured with the Hamilton Rating Scale for Anxiety (HAM-A).  Results suggested that hydroxyzine administration (50 mg per day) for 4 weeks significantly reduced anxiety scores (by 50% or more) compared to a placebo.  It was noted that 41% of the hydroxyzine group experienced anxiolytic relief, whereas only 18% in the placebo group experienced anxiolytic relief.

Authors noted that significant improvements in anxiety were noted within the first week of hydroxyzine administration and were maintained throughout the 4-week study period.  The most common adverse effect was increased sleepiness.  That said, it was concluded that hydroxyzine was effective and well-tolerated as a treatment for generalized anxiety disorders.

  • Source: http://onlinelibrary.wiley.com/doi/10.1002/hup.470100303/abstract

1994: Value of hydroxyzine in generalized anxiety disorder: controlled double-blind study versus placebo.

A French study by Ferreri, Hantouche, and Billardon (1994) was among the first to report the anxiolytic efficacy of hydroxyzine for the treatment of anxiety disorders.  This study was considered placebo-controlled, double-blinded, and multi-center.  It incorporated a total of 133 patients, each of which was formally diagnosed with generalized anxiety disorder in accordance with DSM III-R criteria.

Participants were assigned to receive either hydroxyzine (50 mg/day) or a placebo (daily) for 4 weeks.  Anxiety severity was measured prior to the study, during the course of treatment, and after the study ended.  Results noted that those receiving hydroxyzine (50 mg per day) experienced significant decreases in anxiety scores as compared to those receiving the placebo.

Decreases in anxiety were noted as being of significance within the first week of treatment.  Statistical superiority of hydroxyzine (over the placebo) as an anxiolytic was maintained throughout the duration of the 4-week study.  Side effects were more common in the hydroxyzine group (e.g. sleepiness, dry mouth, etc.).  That said, this study provides evidence that hydroxyzine is efficacious for the management of generalized anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7875114

Verdict: Hydroxyzine likely effective for anxiety disorders

Based on studies investigating the efficacy of hydroxyzine for the treatment of anxiety, we can conclude that hydroxyzine is likely an effective pharmacological anxiolytic intervention.  In every published study, hydroxyzine was noted as exhibiting superior anxiolytic efficacy over a placebo (as evidenced by reductions in anxiety scores).  Since most of the studies investigated hydroxyzine for the treatment of generalized anxiety disorder, it may be ideally suited for that particular diagnosis.

However, due to the fact that it remains uninvestigated as an intervention for other anxiety subtypes, it is unclear as to whether it would provide therapeutic benefit.  There is some evidence from a case study to suggest that hydroxyzine may be an effective treatment for acute panic associated with panic disorder.  Further investigation of its potential as an anti-panic agent may be warranted.

Side effects from hydroxyzine appear to be minimal outside of transient sleepiness and dry mouth.  It appears to be well-tolerated, safe, and isn’t associated with abuse or dependence.  Upon reading the literature, it is relatively clear that hydroxyzine effectively reduces anxious symptoms among those with generalized anxiety disorder.

Its efficacy is noted as being comparable to benzodiazepines (bromazepam) and atypical anxiolytics (buspar).  Therefore, it is necessary to conclude that hydroxyzine may be an overlooked, underutilized second-line intervention for those with generalized anxiety disorder.  As a result of its unique pharmacodynamics, individuals that fail to derive satisfactory therapeutic benefit from standard first-line anxiolytics may want to consider hydroxyzine as an alternative.

Have you tried hydroxyzine for anxiety?

If you’ve tried hydroxyzine (Vistaril, Atarax) for an anxiety disorder, feel free to share your experience in the comments section below.  Mention the specific type of anxiety you were treating and discuss the perceived efficacy of hydroxyzine (such as by rating it on a scale from 1 to 10).  Note how long it took for hydroxyzine to “kick in” and provide anxiolytic benefit, your dosage, any unwanted side effects, and whether you’ve continued using it.

If you happen to be a long-term hydroxyzine user, have you noticed any diminishing efficacy or tolerance onset?  Discuss whether you are taking hydroxyzine as part of a pharmacological cocktail or whether you use it as a standalone anxiolytic.  Are there any medications that you’ve found similar in mechanism to hydroxyzine with superior anxiolytic efficacy?

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{ 3 comments… add one }
  • Josee January 31, 2016, 2:59 pm

    Thank you for this article. I love your blog!!

  • Claire May 6, 2016, 9:21 pm

    I’ve been taking Hydroxyzine for anxiety and sleep for about a year and a half now. I started off with just 10mg at night and another 10mg if I wasn’t asleep after 45min. Later on in order to combat anxiety more than just sleep, I started taking 20mg 3x per day. I am very sensitive to medication, hence the lower dose.

    I have noticed a tolerance, but mostly in helping with sleep, not so much anxiety. The sedating/really sleepy effect has become less prevalent for me over time, but the calming effect where my thoughts stop rushing and calm down my physical body has not really decreased. I have Generalized Anxiety Disorder. It has been really effective, I would say for GAD probably a 9 and for sleep more like a 7.

    I have taken it both as a stand-alone for about 6 months, and in combination with some anti-depressants and birth control. Hydroxyzine was really similar to Trazodone for me. Unfortunately, because of some side effects with Trazodone, I had to stop taking it – but Hydroxyzine honestly feels very similar.

    Trazodone, in my experience, had a higher sedative effect for helping with sleep- but hydroxyzine’s anxiolytic (anti-anxiety) effect has been greater. I think Hydroxyzine and Trazodone are both really good alternatives to more addictive, dangerous anxiolytics. Personally my bet is on Hydroxyzine, which I’ve had less side effects and a little (but not a huge) difference in how helpful it is, but they are both useful.

  • James Synegal June 9, 2016, 4:16 am

    Hi. I first took atarax aka “hydroxyzine” after deciding that I did not want to be on benzodiazepines any longer. I was on Ativan and struggling with severe withdrawals. One day I ran out and could not see my psychiatrist until the next day. I went to the ER and they did give me my Ativan a RX for it but gave me atarax while in the ER to calm me down.

    They also suggested I use it while weaning off the Ativan. I was in severe withdrawal and one 25mg tablet was enough to calm me down until I got my script several hours later. I was in withdrawal about six hours. Anyone who has been in benzo withdrawal will attest to the fact that it is no prize! You feel as if death is imminent.

    Hydroxyzine calmed me even at that small dose and I felt almost a euphoric high like feeling even tho I was in withdrawal. When I ran out of my benzos (which was all the time) I used 75mg of atarax and would feel almost fine. One doc hipped me to the use of Metoprolol to calm heart and stabilize blood pressure while in withdrawal.

    With the combo of the two I could wait almost a day to get my benzos and felt almost fine. All in all being on benzos was a two year struggle I would never recommend. I would not wish benzo withdrawal on Hitler! It was terrible. Benzos are the devil. Hydroxyzine at the right doses pretty much does the same thing.

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