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Seroquel (Quetiapine) For Anxiety Disorders: An “Atypical” Treatment

Seroquel (Quetiapine) is an atypical antipsychotic engineered in the early 1990s by the pharmaceutical company AstraZeneca.  It was first approved by the FDA in 1997 for the treatment of schizophrenia, and was sequentially approved by the FDA in 2004 for the management of bipolar mania.  Seroquel would also receive subsequent FDA approval in 2009 as an antidepressant adjunct for the treatment of major depressive disorder.

Although Seroquel is medically indicated to treat schizophrenia, bipolar mania, and major depression (as an adjunct), it is occasionally prescribed off-label for other neuropsychiatric conditions, including anxiety disorders.  Individuals who receive Seroquel for anxiety are usually patients who’ve tried all FDA approved anxiolytics (e.g. serotonergic antidepressants, benzodiazepines, etc.), yet failed to derive adequate symptomatic relief.  Among non-responders to conventional anxiolytics, administering a potent antipsychotic like Seroquel is often extremely effective for anxiety reduction.

The ability of Seroquel to reduce anxiety stems from its sedative hypnotic effect elicited through blockade of central catecholaminergic and histaminergic receptors.  In fact, a subset of users claim that Seroquel induces such profound tranquility, that it’s nearly impossible to remain anxious throughout the duration of its effect.  That said, anyone using Seroquel for anxiety should be informed of its: anxiolytic mechanisms, benefit/risk profile, and relevant research examining its therapeutic efficacy.

How Seroquel (Quetiapine) May Treat Anxiety (Mechanisms of Action)

There are many mechanisms of quetiapine’s action that may contribute to the generation of an anxiolytic effect.  Upon analysis of it’s pharmacodynamics, it’s apparent that quetiapine modulates a variety of neurotransmitter systems including: histamine, norepinephrine, dopamine, and serotonin.  That said, analogous to most neuropsychiatric medications, it exhibits greater affinity for certain neurochemical targets compared to others.

For this reason, it is logical to surmise that certain mechanisms of quetiapine’s action are more culpable for its anxiolytic properties.  Research suggests that Seroquel exhibits respective binding affinity of the following receptors: H1, alpha-1B, alpha-1A, alpha-2C, and H2.  At each of the aforementioned receptors, quetiapine functions as an antagonist, indicating that the bulk of its anxiolytic effect is generated through the blockage of histamine and catecholamines (e.g. norepinephrine).

H1 antagonist: Among those who claim it’s effective, quetiapine treats anxiety partly through its antagonism of the H1 histamine receptor.  Quetiapine has a higher affinity for the H1 receptors than any other targets, meaning at the lowest doses, H1 receptors are most noticeably impacted.  There’s significant evidence to suggest that activation of the H1 receptor is associated with anxiety, and that by blocking stimulation of this receptor, anxiety decreases.

A study by Malmberg-Aiello, Ipponi, Bartolini, and Schunack (2002) reported that stimulation of H1 receptors causes anxiety in animal models.  In their study, researchers administered the drug FMPH (a selective agonist of H1 receptors) to mice.  The performance of mice on a light/dark box test was recorded after the FMPH, and results demonstrated that FMPH provoked anxiety through H1 receptor stimulation.

Results also suggested that administration of pyrilamine, a selective H1 receptor antagonist, protected against anxiety induced by FMPH.  The team of researchers concluded that H1 receptor activation induces anxiety and H1 inactivation facilitates anxiolytic effects.  Other research by Kumar, Krishna, and Palit (2007) reported similar relationships between activity of the H1 receptor and anxiety.  In their study, administration of L-histidine was discovered to induce anxiety-like behaviors among mice in an elevated plus maze (EPM) through activation of H1 receptors.

Following the administration of L-histidine, mice explored for less time in open arms and made fewer entries into open arms of the maze, indicating anxiety-like behavior.  That said, when an H1 receptor antagonist was administered to the mice prior to L-histidine, they exhibited reduced anxiety.  Evidence that H1 receptor antagonism can facilitate anxiolytic effects is also derived from a study by Hasenöhrl, Weth, Huston (1999).

In this particular study, infusions of chlorpheniramine, an H1 receptor antagonist, reduced fear-related behaviors in an open field and black-and-white box among rats.  This supports the idea that H1 receptor antagonism can induce anxiolytic effects, and that hyperactivation of H1 receptors may be implicated as a direct cause of anxiety.  Since Seroquel acts as a highly-potent H1 receptor antagonist, and H1 receptor activation can cause anxiety, it’s logical to speculate H1 antagonism could generate an anxiolytic effect in a subset of users.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11812538
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Alpha-1B antagonist: Another target that may be implicated an anxiolytic effect of quetiapine is the alpha-1B receptor.  It is understood that quetiapine binds with high affinity to alpha-1B receptor sites whereby it acts as an antagonist.  In other words, quetiapine blocks alpha-1B stimulation from catecholamines such as norepinephrine, epinephrine, and dopamine – all of which increase arousal and might induce anxiety in a subset of persons through alpha-1B receptor overstimulation.

Since the alpha-1B receptors are not activated by catecholaminergic stimulation after administration of quetiapine, arousal and corresponding anxiety are likely to decrease.  Research suggests that administration of alpha-1B blockers is associated with reduced blood pressure and decreased sympathetic nervous system activity, possibly alleviating symptoms of anxiety.  A study by Spreng, Cotecchia, and Schenk (2001) assessed the effect of mice lacking alpha-1B adrenergic receptors with behavioral experiments.

The results indicated that alpha-1B knockout mice were quicker to enter novel environments, covered longer paths in an open field, and spent more time exploring new objects.  Based on these findings, we might surmise that modulation of noradrenergic pathways via the alpha-1B receptor reduced anxiety, which in turn, lead to increased exploratory behavior.  Moreover, it’s possible that quetiapine’s inhibition of this specific receptor in humans might induce an anxiolytic effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11222061

Alpha-1A antagonist: To a slightly lesser extent than its antagonism of alpha-1B receptors, quetiapine antagonizes alpha-1A receptors.  It is understood that alpha-1A receptors are stimulated by catecholamines such as norepinephrine, epinephrine, and dopamine – and may be implicated in a stress response.  For this reason, blockade of alpha-1A receptors via administration of quetiapine should be suspected as a possible target for anxiety reduction.

Zimnik, Treadway, Smith, and Araneda (2013) investigated the role of alpha-1A receptors within the olfactory bulb of animals and discovered that alpha-1A receptors upregulated inhibition at dendrodendritic synapses (connections between the dendrites of 2 neurons).  This suggests that alpha-1A receptors reduce intrasynaptic signaling of norepinephrine.  What’s more, there’s some evidence to suggest that blockers of alpha-1A receptors can reduce blood pressure, usually a sign of lower anxiety.

More research is necessary to determine whether alpha-1A receptors are overactive among persons with anxiety disorders and/or whether antagonizing alpha-1A receptors might generate anxiolytic effects.  As of current, alpha-1A receptor antagonism warrants consideration as a possible target for anxiety reduction.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/23266935

Alpha-2C antagonist: The alpha-2C receptor is associated with an inhibitory presynaptic feedback loop that modulates neurotransmitter release from adrenergic nerves.  Stimulation of alpha-2C receptors may upregulate activation of the sympathetic nervous system and/or CNS arousal to induce states of psychological anxiety.  In animal models, alpha-2C receptors are localized within regions of the brain such as the striatum, cerebral cortex, hippocampus, basal ganglia, and olfactory tubercle.

A paper by Fagerholm, Rokka, Nyman, et al. (2008) reports that the alpha-2C receptor may be an important target for the treatment of neuropsychiatric disorders, one of which could be anxiety.  It was noted that within the human brain, alpha-2C-adrenoreceptors are positioned within the striatum, whereas other alpha-2C receptors are found within the cortex and cerebellum.  Given the speculation that targeting the alpha-2C receptors could improve symptoms of neuropsychiatric disorders, it’s reasonable to think that antagonism of alpha-2C receptors with quetiapine may attenuate symptoms of anxiety.

Bücheler, Hadamek, and Hein (2002) documented that alpha-2C receptors regulate the presynaptic release of stimulatory neurotransmitters from adrenergic neurons in the CNS.  Since quetiapine binds to the alpha-2C receptor sites to prevent activation, it’s possible that lower quantities of stimulatory neurotransmitters (e.g. catecholamines) are released in the human brain.  Reducing catecholaminergic transmission is generally considered therapeutic for a subset of individuals with anxiety disorders.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18435421
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H2 antagonist: It’s also possible that the anxiolytic effect of quetiapine is mediated partly through its antagonism of the H2 histamine receptor.  A study by Provou, Knoche, Hasenöhrl, and Huston (1998) discovered that administration of the drug ranitidine, an H2 receptor antagonist, reduced anxiety-like behaviors among mice.  Lower anxiety among mice following the administration of ranitidine was evidenced by increased time spent in open arm portions of an elevated plus maze (EPM), as well as increased scanning over the edge of the open arm.

It was concluded that the H2 receptors modulate fear-related processes within the brain, and that administration of H2 antagonists could attenuate them.  Levine and Napoliello (1998) conducted a study in which buspirone (an FDA-approved anxiolytic) was co-prescribed along with H2 receptor antagonists in anxious outpatients.  The fact that such a study was conducted indicates suspicion that H2 receptor antagonists could promote anxiolytic effects.

What’s more, Robins, Lucke, McFadyen, and Wright (1984) tested the efficacy of the H2 receptor antagonist ranitidine on anxiety levels among patients with duodenal ulcer.  Administration of ranitidine at a dosage of 150 mg (b.i.d.) significantly improved ratings of anxiety at 2 and 4 weeks compared to pre-treatment ratings.  That said, due to equally significant anxiety reductions following administration of a placebo control, it it’s difficult to know whether H2 receptor antagonism was culpable for a clinically relevant anxiolytic response.

It should also be mentioned that blocking the H2 receptor will have downstream effects on cyclic AMP (cAMP) and corresponding protein kinase A (PKA), possibly an indirect means by which the specific H2 receptor target reduces anxiety.  When H2 receptors are activated, production of cyclic AMP (cAMP) increases, which in turn enhances the expression of protein kinase A.  Work by Keil, Briassoulis, Gokarn, et al. (2012) indicates that certain types of anxiety may be caused by overexpression of protein kinase A.

Other studies indicate that irregularities within cyclic AMP (cAMP) and protein kinase A (PKA) systems could cause anxiety in humans.  The blockade of H2 receptors by quetiapine could directly and indirectly reduce anxiety symptoms in humans through H2-mediated cyclic AMP and PKA concentrations.  Moreover, it’s possible that simultaneous antagonism of the H2 and H1 receptors yields a synergistic anxiolytic effect via widespread histaminergic modulation.

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5-HT2A antagonist: Although antagonism of histamine (H1 & H2) and alpha (1B, 1A, 2C) receptors may generate sufficient anxiety reduction, it’s possible that 5-HT2A antagonism adds to quetiapine’s anxiolytic effect.  Research suggests that activation 5-HT2A receptors can play a role in the pathogenesis of anxiety disorders, particularly those positioned within the ventromedial prefrontal cortex (vmPFC).  When ventromedial prefrontal 5-HT2A receptors are overexpressed, excitatory signaling may increase to the brainstem and amygdala whereby a fear or anxiety-response occurs.

Animal model studies using show that expression of 5-HT2A receptors correlates directly with anxiety-like behavior.  For example, a study by Weisstaub, Zhou, Lira, et al. (2006) demonstrates that global disruption of 5-HT2A receptor signaling reduces inhibition in conflict anxiety paradigms.  Specifically, genetically modified mice with 5-HT2A receptor knockout (KO) exhibit reductions in anxiety-like behaviors on open field tests, forced-swim tests, elevated plus mazes, novelty suppressed feeding tests, and dark/light choice tests.

Preece, Dalley, Theobald, et al. (2004) discovered that rats reared in isolation exhibited increases in 5-HT2A binding density throughout regions such as the prelimbic cortex, rostral motor cortex, and cingulate cortex.  Furthermore, it was noted that there was a correlation between 5-HT2A expression levels and anxiety-like behaviors among the rats reared in isolation.  This suggests that activation of 5-HT2A receptors in humans, particularly within the ventromedial prefrontal cortex, might induce anxiety, whereas blocking 5-HT2A receptors in this region with an antagonist such as quetiapine could induce anxiolytic effects.

Another means by which 5-HT2A receptor antagonism may promote an anxiolytic effect is through enhancement of sleep quality and/or reduction of insomnia.  A study by Vanover and Davis (2010) reported that 5-HT2A receptor antagonists increase slow-wave sleep – as is evidenced by polysomnography data.  Since many individuals with anxiety exhibit deficits in slow-wave sleep, an enhancement of slow wave sleep via 5-HT2A antagonism provided by quetiapine may ameliorate symptoms of anxiety.

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Other Possible Anxiolytic Mechanisms of Seroquel (Quetiapine)

Though quetiapine may alleviate symptoms of anxiety primarily by antagonizing histamine (H1 & H2), alpha (1B, 1A, 2C), and serotonin (5-HT2A) receptors – other targets could synergistically enhance an anxiolytic effect.  It is understood that quetiapine also exerts effects upon other serotonergic, dopaminergic, and muscarinic receptors – mostly as an antagonist.  For this reason, the potential role of each of these receptors should be explored as potentially involved in the overall anxiolytic response among higher-dose users.

5-HT7 antagonist: The antagonism of quetiapine at 5-HT7 receptors may yield anxiety reductions for a subset of persons.  A report by Hedlund (2009) highlighted a complex relationship between 5-HT7 receptor activation and anxiety-like behavior in animal models.  Although mice of multiple genotypes lacking 5-HT7 receptors as a result of knockout (KO) don’t exhibit less anxiety than mice with normative 5-HT7 receptor expression, administration of the substance SB-269970, a 5-HT7 receptor antagonist, exerts a significant anxiolytic effect.

Specifically, animal models of anxiety that receive SB-269970 (systemically or intra-hippocampally) exhibit less anxiety on Vogel conflict drinking tests and elevated plus mazes (EPM) than others.  Research by Wesołowska, Nikiforuk, Stachowicz, et al. (2006) reveals that SB-269970 reduces anxiety in mice as evidenced by a greater number of “punished crossings” on a conflict-based four-plate test.  Additionally, this study discovered that there was an inverted U-shaped dose-response curve associated with the anxiolytic effect of SB-269970.

In comparison to diazepam, the anxiolytic effect derived from SB-269970 was less substantial.  It is unknown how quetiapine’s effect upon 5-HT7 receptors compares to that of SB-269970 and whether 5-HT7 receptors can affect human levels of anxiety similar to animal models.  Additionally, Naumenko, Popova, Lacivita, et al. (2014) theorize that 5-HT7 receptors engage in crosstalk with 5-HT1A receptors, a common target of anxiolytic medications (e.g. buspirone).

They propose that an interaction between 5-HT7 and 5-HT1A sites may be clinically relevant because both receptors may be useful for the treatment of anxiety.  It’s possible that quetiapine’s antagonism at 5-HT7 receptors is sufficient enough to facilitate a marginal degree of anxiety reduction.  Moreover, since quetiapine affects both 5-HT7 and 5-HT1A receptors, perhaps it’s the crosstalk between these sites that synergistically facilitates a stronger anxiolytic effect than expected.

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D3 receptor antagonist: Another neurobiological target of quetiapine that may facilitate an anxiolytic effect is the D3 dopamine receptor.  Quetiapine is understood to function as a D3 receptor antagonist, whereby it binds to this receptor and inhibits activation.  A study by Diaz, Chappell, Christian, et al. (2011) provides evidence to suggest that D3-like receptors modulate anxiety-like behavior and the neurotransmission of GABA (gamma-aminobutyric-acid) within the lateral/basolateral amygdala of rats.

In this study, researchers reported that activation of D3 receptors (by way of dopamine release) inhibits GABAergic synapses without affecting glutamatergic ones, which substantially modifies signaling to projection neurons within the basolateral amygdala, thereby possibly causing anxiety.  Microinjection administration of selective D3 antagonists (U99194 or GR103691) within the basolateral amygdala of mice significantly reduces anxiety-like behaviors, as is evidenced by performances on light/dark transition tests and in elevated plus mazes.  Researchers concluded that D3 receptors located in the basolateral amygdala can influence anxiety-like behavior.

Findings from an earlier study by Steiner, Fuchs, and Accili (1997) support the idea that the D3 receptor is implicated in regulation of anxiety-like behavior.  Steiner, Fuchs, and Accili compared the behaviors of D3 receptor knockout mice to those of a control group with normative D3 receptor expression in open field tests and elevated plus mazes.  Results indicated that knocking out the D3 receptor generated an anxiolytic-like effect as was evidenced by significant reductions in anxiety-like behaviors in open-field tests and elevated plus mazes – compared to a control group.

Other research by Xing, Liu, Jiang, et al. (2013) discovered that D3R knockout mice were more resistant to stressful procedures than wild-type mice, suggesting that activation of D3 receptors might induce anxiety.  A study by Seo and Kuzhikandathil (2015) indicates that D3 receptor activation during preadolescence of mice can induce adult-onset anxiety, whereas D3 receptor antagonism OR knockout of the D3 receptor protects against adult-onset anxiety.

Rogóz, Kłodzińska, and Maj (2000) also report that administration of D3 receptor antagonists nafadotride and PNU 99194A induces an anxiolytic effect in animals.  Considering the data compiled from numerous animal studies, we might theorize that antagonism of D3 receptors, especially those positioned in the basolateral amygdala, effectively reduces anxiety in humans.  Since quetiapine exerts moderate antagonism upon D3 receptors, and D3 antagonism seems to decrease anxiety, this may be a mechanism contributing to its overall anxiolytic effect.

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D2 antagonist: Although it’s unlikely that quetiapine’s action as a D2 receptor antagonist generates a robust anxiolytic effect, it’s possible that this mechanism facilitates a modest reduction in anxious symptoms for a subset of persons.  Evidence that D2 receptor antagonism is unlikely effective as an anxiolytic is derived from a study by Bell, Bhikha, Colhoun, et al. (2013) in which researchers administered sulpiride (a selective D2 receptor antagonist) to participants with and without social anxiety disorder.  Results of the study indicated that sulpiride had no effect on social anxiety scores of participants compared to pre-treatment baseline, indicating that D2 receptor abnormalities may not be implicated in social anxiety.

It’s possible that the results of this study are relevant to all types of anxiety disorders, such that antagonism of D2 receptors would be predictably ineffective as an anxiolytic, however, there appears to be conflicting evidence.  A study by Mizuki, Suetsugi, Ushijima, and Yamada (1997) discovered that administration of sulpiride, a D2 receptor antagonist, significantly reduced STAI (State-Trait Anxiety Inventory) scores of healthy university students.  From this study, it was concluded that D2 antagonism is most likely to facilitate anxiolytic effects among persons with high anxiety [likely caused by excessive dopaminergic transmission].

Additionally, data from preliminary animal model studies suggests that D2 receptor antagonism can reduce anxiety.  For example, a study by Rodgers, Nikulina, and Cole (1994) administered sulpiride (a D2 receptor antagonist) to mice and discovered that it decreased anxiety-like behavior in an elevated plus maze.  Another study by Ponnusamy, Nissim, and Barad (2005) documented that systemic blockade of D2 receptors by sulpiride facilitated extinction of conditioned fear in mice.

Researchers concluded that modulation of D2 receptor signaling through administration of D2 antagonists could prove useful for the treatment of anxiety disorders in humans.  Regarding quetiapine, it is understood to occupy approximately 30% of D2 receptors, but exhibits a “kiss and run” effect of brief D2 receptor antagonism (i.e. “kissing”) followed by dislodging itself (i.e. “running”) from the D2 receptors.  Whether transient antagonism of D2 receptors yields an anxiolytic effect remains unknown, however, it should be considered as a possibility.

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5-HT1A partial agonist: It is understood that activation of 5-HT1A receptors is often abnormal among those with anxiety disorders.  Lesch, Wiesmann, Hoh, et al. (1992) documented that presynaptic and postsynaptic 5-HT1A receptors appear subsensitive among persons with panic disorder.  They mention that abnormal sensitivities of 5-HT1A receptors might lead to dysfunctional serotonin signaling, ultimately contributing to anxiety.

Research by Neumeister, Bain, Nugent, et al. (2004) reported a decrease in 5-HT1A binding among humans with panic disorder compared to healthy controls, as evidenced by PET neuroimaging scans.  This suggests that the 5-HT1A receptor is likely implicated in the pathogenesis of certain anxiety disorders.  Studies by Nash, Sargent, Rabiner, et al. (2008) discovered similar presynaptic and postsynaptic 5-HT1A receptor binding reductions in patients with panic disorder.

The most significant binding reductions were observed within the raphe, orbitofrontal cortex, temporal cortex, and amygdala.  Considering the aforementioned findings of 5-HT1A irregularities among persons with panic disorder, most would speculate that modulation of 5-HT1A receptor activation could effectively treat certain types of anxiety.  Drugs like buspirone that primarily target the 5-HT1A receptor via partial agonism are understood to effectively attenuate symptoms of anxiety.  Though the 5-HT1A partial agonism exerted by quetiapine isn’t the same as buspirone, it’s possible that it generates a modest anxiolytic effect, thereby contributing to the overall anxiolytic response reported by users.

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M1 antagonist: Antagonism of the M1 muscarinic receptor is another mechanism of quetiapine’s action which may contribute modestly to its total anxiolytic effect.  Evidence from animal models suggests that M1 receptors can influence anxiety-related behaviors.  For example, a study by Wall, Flinn, and Messier (2001) discovered that blocking M1 receptors within the ventromedial prefrontal cortex (vmPFC) reduced anxiety-related information, possibly resulting in an anxiolytic effect.

It also appears as though M1 antagonists can effectively reduce anxiety and depression in a subset of humans.  Research by Furey, Khanna, Hoffman, and Drevets (2010) assessed the therapeutic effect of scopolamine, an M1 antagonist, among persons diagnosed with major depression or bipolar disorder.  Results suggested that scopolamine significantly reduced symptoms of anxiety among female users.

This supports the idea that M1 receptor antagonism may reduce anxiety in a subset of humans, particularly females.  Since quetiapine has a relatively low affinity for the M1 receptors compared to others, substantial reductions in anxiety as a result of M1 receptor antagonism should not be expected.  Nonetheless, it’s possible that quetiapine antagonizes M1 receptors just enough for a subtle anxiolytic effect.

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Antioxidant effect: Another mechanism by which quetiapine might reduce symptoms of anxiety is through facilitation of an antioxidant effect.  Mounting evidence suggests a relationship between excessive oxidative stress in the brain and pathological anxiety.  A study by Hovatta, Tennant, Helton, et al. (2005) established links between enzymatic expressions of glyoxalase 1 and glutathione reductase 1 – and anxiety-like behavior in various strains of mice.

Both glyoxalase 1 and glutathione reductase 1 are involved in antioxidant metabolism, and when overexpressed in certain strains of mice, anxiety-like behavior increases.  When glyoxalase 1 and glutathione reductase 1 are inhibited locally with RNA interference, anxiety-like behavior subsides.  Other research by Krömer, Kessler, Milfay, et al. (2005) suggested that glyoxalase 1 was a biomarker for trait anxiety in mouse models, indicative of the fact that glyoxalase 1 affects antioxidant status and corresponding anxiety.

Another study by Desrumaux, Risold, Schroeder, et al. (2005) discovered that a deficiency of vitamin E leads to high oxidative stress capable of damaging the brain, and as a result of the oxidative stress-mediated damage, anxiety-like symptoms can emerge.  Subsequent research by Ditzen, Jastorff, Kessler, et al. (2006) documented that glyoxalase 1 expression in specific brain areas was associated with lower anxiety, and that inhibition of its expression increased anxiety.  The principal takeaway from the aforestated studies is that glyoxalase 1 expression modulates anxiety-like behavior, likely through antioxidant status.

Work by Bouayed, Rammal, Younos, and Soulimani (2007) revealed that peripheral markers of oxidative stress correlate linearly with anxiety-like behaviors in mice.  In other words, the greater the concentrations of reactive oxygen species measured on a blood test, the more likely mice were to exhibit anxiety-like behavior on a light/dark choice test.  A paper by Bouayed, Rammal, and Soulimani (2009) reemphasizes overlap between cellular pathways of oxidative stress and pathways implicated in anxiety disorders.

Hassan, Silva, Mohammadzai, and da Rocha (2014) suggest that generalized anxiety disorder, panic disorder, phobias, OCD, and PTSD are all associated with increased oxidative stress.  They believe that interventions aiming to increase antioxidant status could prove effective as treatments.  Though it is important to avoid assuming that oxidative stress is a direct cause of anxiety disorders, it’s possible that in some individuals, it may be causally implicated.

Even if oxidative stress isn’t a direct cause of anxiety, any increase in oxidative stress could exacerbate preexisting symptoms of anxiety, making it more severe over time.  Therefore, it’s reasonable to suspect that agents with antioxidant properties may reduce symptoms of anxiety.  Evidence from a study by Xu, Wang, Zhuang, et al. (2008) suggests that quetiapine functions as an antioxidant.

In this study, quetiapine administration protected against cytotoxicity induced by amyloid beta within cultured cells.  It appeared as though quetiapine blocked damage from a hydroxyl radical and scavenged free radicals.  Assuming quetiapine noticeably upregulates the antioxidant status of patients with anxiety, this may contribute to its effectiveness as an anxiolytic.

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Note: Quetiapine is recorded as exhibiting a low affinity for additional targets, including: 5-HT6, D1, NET, 5-HT2C, M3, D4, and alpha-2A.  It is unlikely that these contribute to any noticeable anxiolytic effect, especially at low doses.  Nonetheless, the cumulative impact of its action at these receptors and transporters at high doses may contribute (ever-so-slightly) to is net anxiolytic effect.

Benefits of Seroquel (Quetiapine) For Anxiety (Possibilities)

There are potential benefits associated with utilizing quetiapine for the treatment of anxiety to consider.  Arguably the most significant benefit is that quetiapine can be an effective anxiolytic for a subset of persons with refractory or treatment-resistant anxiety disorders.  Another substantial benefit is that quetiapine monotherapy can treat anxiety, plus neuropsychiatric comorbidities such as: schizophrenia, bipolar disorder, and major depression.  Moreover, the fact that quetiapine is manufactured in multiple formats (XR and IR), has a unique mechanism of anxiolytic action, and is substantiated by RCTs as an acute and long-term intervention for anxiety, might make it appealing to some.

  • Adjunctive option: In many cases, quetiapine can be safely administered as an anxiolytic adjunct with a variety of other medications, including certain serotonergic antidepressants. Individuals who derive only partial anxiolytic benefit from first-line interventions such as SSRIs may find that “adding-on” low-dose quetiapine leads to complete symptomatic remission.  Some speculate that quetiapine acts synergistically with serotonergic antidepressants to generate a more robust anxiolytic effect than would be attained with each agent administered as a standalone.  In other words, when combining serotonin reuptake inhibition with antagonism of histaminergic and adrenergic receptors, users often experience a more potent anxiolytic effect.
  • “As-needed” usage: Although not commonly administered on an “as-needed” basis for anxiety, quetiapine could be effective [for a subset of persons] when utilized in this manner. Many individuals with anxiety disorders use benzodiazepines “as-needed” to attenuate anxious symptoms, yet benzos are problematic due to: abuse potential, rapid tolerance onset, discontinuation symptoms, cognitive impairment, and links to neurodegeneration.  Given the fact that quetiapine is manufactured in an instant-release format, many successfully administer low-doses “as-needed” to rapidly alleviate unexpected anxiety and/or panic via histaminergic and adrenergic blockade.  Moreover, while long-term risks may be equally as severe as benzodiazepines, quetiapine is not associated with rapid tolerance onset or abuse, possibly making it a favorable “as-needed” anxiolytic.
  • Comorbid conditions: Research suggests that nearly 4 of 5 individuals diagnosed with anxiety disorders exhibit comorbid neuropsychiatric conditions.  It is known that quetiapine is FDA approved for the treatment of schizophrenia, bipolar disorder, and major depression (as an adjunct).  Other comorbidities for which quetiapine often proves efficacious as a treatment include: insomnia, PTSD, and OCD.  For this reason, persons with an anxiety disorder or anxious symptoms that co-occur with any of the aforestated conditions (schizophrenia, bipolar disorder, major depression), may find that standalone quetiapine effectively reduces all unwanted neuropsychiatric symptoms.  Administration of quetiapine as a monotherapy for the management of multiple conditions may be advantageous because individuals will only need to administer a single tablet per day and multi-drug interactions won’t occur.
  • Comparative efficacy: Studies analyzing the efficacy of quetiapine as a treatment for anxiety suggest that it’s significantly more effective than a placebo. Additionally, a large-scale randomized controlled trial (with hundreds of participants) compared the efficacy of quetiapine XR (150 mg/day and 300 mg/day) to that of escitalopram (10 mg/day) for the treatment of generalized anxiety disorder.  Upon comparison, it was revealed that quetiapine XR was equally as effective as escitalopram (Lexapro), an FDA approved anxiolytic.  Based on this finding, it’s possible that quetiapine is as effective as all serotonergic antidepressants for the treatment of anxiety.
  • Evidence-based: Although quetiapine is regarded as an off-label anxiolytic due to its lack of FDA approval specifically for the treatment of anxiety, it is an evidence-based option. A systematic review and meta-analysis by Maneeton, Maneeton, Woottiluk, et al. (2016) analyzed data from 3 RCTs with 2,248 participants and concluded that quetiapine was effective for the treatment of generalized anxiety disorder.  Kreys and Phan (2015) conducted an earlier systematic review, suggesting that quetiapine was effective as an anxiolytic.  Multiple systematic reviews from several large-scale trials provide strong evidence to support the anxiolytic efficacy of quetiapine – over a short-term and long-term, and as a monotherapy and adjunct.
  • Fast-acting: When taking Seroquel for insomnia, many report getting knocked “out cold” into a deep slumber quicker than expected. This suggests that, unlike serotonergic antidepressants which can take long “kick in” (4 to 8 weeks) and exert an anxiolytic effect, quetiapine might alleviate anxiety on the first day of its administration.  The rapid anxiolytic action of quetiapine is likely due to its potent histamine and alpha receptor antagonism, whereby sedation is induced and it becomes difficult to remain anxious.  While not everyone will experience drastic anxiety reduction on the first day of quetiapine administration, RCTs support the idea that its anxiolytic effect is often statistically significant (compared to a placebo) within 1-week.
  • Generalized anxiety disorder: Each year, approximately 6.8 million adults (3.1% of the U.S. population) are affected by generalized anxiety disorder, a condition characterized by frequent, persistent, excessive, and/or unrealistic worry.  Although quetiapine is considered useful as an intervention for many specific types of anxiety, strongest evidence supports its efficacy for the treatment of generalized anxiety disorder.  As was mentioned, multiple systematic reviews conclude that quetiapine is effective as a monotherapy for persons with generalized anxiety disorder.
  • Long-term efficacy: Not only does evidence support the efficacy of quetiapine when administered acutely for anxiety, but there’s solid data suggesting quetiapine maintains anxiolytic efficacy over a long-term. One large-scale randomized controlled trial discovered that quetiapine XR was effective for the long-term maintenance of anxiety remission.  Another trial in which quetiapine was administered to patients with schizophrenia discovered that its initial anxiolytic efficacy was maintained for up to 3-years.  In fact, data from the aforementioned trial indicated that average anxiety scores among patients were lower after long-term quetiapine administration (several years) compared to over a short-term (several months).  Since certain medications for anxiety tend to stop working over time, quetiapine may be advantageous in that it appears to maintain its anxiolytic efficacy over an extended duration.
  • Low cost: The patent for immediate-release quetiapine has expired and its cost is affordable for most individuals. Estimates suggest that at a low dose of 25 mg, 60 tablets of quetiapine can be purchased for $10 to $15.  At a higher dose of 50 mg, 60 tablets can be purchased for $15 to $20.  Overall, the cost per tablet is relatively cheap compared to newer antipsychotics and antidepressants.  Persons that have tried conventional anxiolytics without benefit, but cannot afford to use the newer drugs may opt to utilize quetiapine based on its reasonable price.
  • Mechanism of action: The mechanism of quetiapine’s action is regarded as unique, making it an appealing alternative for those who respond inadequately to conventional anxiolytics. Quetiapine functions primarily via antagonism of histamine and alpha receptors, but also modifies activation of serotonin and dopamine receptors, ultimately affecting a myriad of neurotransmitter systems and signaling cascades.  In contrast, most FDA approved anxiolytics function predominantly by increasing extracellular concentrations of serotonin (e.g. SSRIs, TCAs, MAOIs) OR through modulation of GABA (e.g. benzodiazepines).  Some patients will likely derive greater anxiety reduction through quetiapine’s antihistaminergic and anticatecholaminergic effect.
  • Monotherapeutic intervention: Although many psychiatrists and/or patients may be wary of using quetiapine as a standalone treatment for anxiety, there’s significant evidence indicating that it can be an effective monotherapy. In fact, stronger data supports quetiapine’s efficacy as a monotherapy than as an adjunct, perhaps indicating that it is more effective as a standalone than when combined with another drug.  Monotherapeutic doses of 50 mg/day and 150 mg/day of quetiapine XR have been documented in multiple systematic reviews as effective for the treatment of anxiety.  Knowing that quetiapine as a monotherapy is efficacious as an anxiolytic is useful because certain patients may tolerate standalone quetiapine better than multi-drug anxiolytic protocols.
  • Multiple formats: Another benefit of using quetiapine for anxiety is that there are multiple formats to choose from, including an immediate-release (IR) and extended-release (XR). The duration of effect is thought to be 12 hours for the IR version and 24 hours for the XR version.  Based on these differences, some persons may prefer to use quetiapine IR due to the fact that they’re only dealing with unexpected flare-ups of anxious symptoms.  Others may prefer quetiapine XR due to the fact that they experience 24/7 anxiety and need a full day’s worth of anxiety relief.
  • Refractory anxiety: A subset of individuals diagnosed with anxiety have tried all conventional FDA approved anxiolytics without therapeutic benefit. They may have also tested various psychotropic medication cocktails (e.g. SSRIs plus benzodiazepines) and ongoing cognitive behavioral therapy (CBT) without any significant anxiety relief.  These individuals are diagnosed with refractory anxiety and often require atypical pharmaceutical interventions.  Among those with refractory anxiety disorders, quetiapine may be effective simply due to its unique pharmacodynamics.

Drawbacks of Seroquel (Quetiapine) For Anxiety (Possibilities)

While there are some benefits associated with using quetiapine for anxiety, there are some serious drawbacks to contemplate.  Sure it’s great that quetiapine is an evidence-based treatment for certain types of anxiety, and is highly effective as an anxiolytic, but the risks may not be worth it.  Perhaps the most prominent drawback is that, during treatment, users can develop permanent life-altering medical complications (e.g. tardive dyskinesia).  Other drawbacks to consider include: adverse reactions, brain shrinkage, cognitive deficits, and emergence of withdrawal symptoms upon discontinuation.

  • Adverse reactions: Incidence of adverse reactions associated with quetiapine is generally greater compared to most conventional and off-label non-antipsychotic anxiolytics. Examples of some relatively common adverse reactions that may occur while taking quetiapine include: elevated pulse rate, gastrointestinal distress, hypercholesterolemia, hypertension, hypothyroidism, increased liver enzymes, neuroleptic malignant syndrome, orthostatic hypotension, and vomiting.  Many individuals wouldn’t consider the reduction of anxiety to outweigh the risk of these adverse reactions.  Hypothetically, if you’re vomiting on a daily basis from quetiapine and develop high blood pressure during treatment, the anxiety relief provided by quetiapine probably won’t trump its emetic and cardiac toll.
  • Age-restricted: Another drawback of quetiapine is that it has not been confirmed for safety, efficacy, and/or tolerability among children and adolescents with anxiety disorders, meaning its usage is restricted to adults.  Children and adolescents with should be encouraged to pursue non-pharmacological treatments (e.g. cognitive behavioral therapy) and/or low-dose pharmaceuticals (approved for usage in pediatrics) for anxiety.  Although antipsychotics like quetiapine are a potent last-resort option for the treatment of refractory anxiety, they may impair brain development if administered frequently during critical developmental years.  For this reason, they should only be administered by adults and/or persons with neuropsychiatric conditions for which they are approved (e.g. schizophrenia, bipolar disorder).
  • Brain damage or volume loss: There’s mounting evidence from neuroimaging studies to suggest that ongoing administration of antipsychotics can cause brain damage, volume loss, and/or shrinkage. Since most people would rather deal with anxiety than risk brain shrinkage, quetiapine quickly becomes an unappealing anxiolytic intervention.  As of current, it’s unclear as to why brain volume is lost with antipsychotic treatment and there aren’t any reliable strategies to prevent its occurrence.  Obviously in extreme cases, some individuals may opt to risk the brain volume loss for symptomatic relief, however, most will not.  Furthermore, there aren’t known risks of brain volume loss associated with conventional anxiolytics (e.g. serotonergic antidepressants).
  • Cognitive deficits: A well-known side effect of quetiapine and other antipsychotics is cognitive dysfunction plus “brain fog” (fuzzy thinking). While taking quetiapine, aspects of cognition such as: abstract thinking, attention, memorization, memory retrieval, organization of thoughts, etc. – might be impaired.  The impaired cognitive function generally occurs because quetiapine inhibits histaminergic and catecholaminergic stimulation at various receptors to decrease arousal.  Although quetiapine may prove remarkably effective as an anxiolytic, it may impair your ability to perform cognitively-demanding tasks in an occupational or academic setting.  As a result, you may find yourself out of a job and/or dropping out of school due to the drug-induced cognitive impairment.
  • Contraindications: Although quetiapine is effective for the treatment of anxiety, not every person can safely tolerate its administration. Upon evaluation of your current medical status and/or medical history, a professional may determine that you cannot safely use quetiapine due to a contraindication.  Examples of some contraindications with quetiapine include: cancer, cardiac abnormalities, cholesterol problems, dementia, hepatic impairment, and thyroid problems.  Despite the fact that all medications are contraindicated with certain conditions, quetiapine may have more contraindications than others.
  • High-cost: An advantage of quetiapine is that the immediate-release version can be purchased for a low-cost. That said, anyone who wants the extended-release (XR) may find it downright unaffordable.  Currently, 30 tablets of quetiapine XR at the 50 mg dosage sells for $250 to $270, whereas 30 tablets of quetiapine XR at the 150 mg dosage will cost $450 to $490.  This means that you might be paying nearly $500 per month for your medication if you have a minimalist insurance policy.  Compared to other anxiolytics that can be attained in extended-release form as generics at a low cost (e.g. under $10 for a 30-day supply), quetiapine XR is expensive.
  • Interactions: If administering quetiapine along with other pharmaceutical drugs and/or supplements, it’s possible that unwanted or dangerous interaction effects could occur. The risks of administering quetiapine along with other medications hasn’t been extensively evaluated in large-scale trials.  Given the fact that quetiapine is associated with depression of the CNS, it should not be combined with other CNS depressants such as alcohol.  Additionally, since quetiapine is hepatically metabolized principally by CYP3A4 enzymes, any drugs that induce or inhibit this enzyme may lead to an unwanted interaction effect.  In most cases, when prescribed with a strong CYP3A4 inducer, quetiapine necessitates a dosage increase, whereas when prescribed with a CYP3A4 inhibitor, a dosage reduction is necessary.
  • Lower-risk medications: There are many FDA approved medications that are less risky than quetiapine for the treatment of anxiety, especially when administered over a long-term. Just a few examples of risks associated with using quetiapine include brain volume loss, diabetes, and tardive dyskinesia.  The aforestated risks can be avoided with traditional anxiolytics and many other off-label [non-antipsychotic] anxiolytics.  While quetiapine may be equally as effective (or even more effective) than other anxiolytics, the fact that it is an antipsychotic makes it (by default) among the most dangerous psychiatric drugs.  Hence, most will want to avoid it if possible for a lower-risk intervention.
  • Motor impairment: Like other antipsychotics, quetiapine may impair motor function in a subset of users. Antipsychotic-induced motor impairment can significantly interfere with a person’s ability to safely operate a motor vehicle and heavy machinery.  For this reason, quetiapine may be a poor treatment choice for individuals regularly operating motor vehicles and/or heavy machinery as part of lifestyle and/or occupational necessities.  Operating motor vehicles and/or heavy machinery with quetiapine-induced motor impairment will increase risk of accidents and the corresponding possibilities of injury/death.
  • Neurodegeneration: An emergence of correlational research indicates that long-term administration of benzodiazepines, anticholinergics, and antihistamines significantly increase risk of dementia. Although quetiapine does not function like a benzodiazepine via allosteric modulation of GABA receptors, nor does it exert a strong anticholinergic effect, it is a very potent antihistamine.  In fact, it has a higher affinity for the H1 histamine receptor (as an antagonist) than any other receptor sites.  It’s possible that long-term administration of quetiapine might, through antihistaminergic mechanisms, increase risk of dementia.
  • Off-label: Another drawback of using quetiapine as an anxiolytic is that it is not approved by the FDA for the treatment of anxiety disorders. Due to lack of approval, quetiapine can only be prescribed “off-label” for anxiety, or outside of the FDA-recommended indications.  The off-label status of quetiapine for anxiety makes it difficult for some individuals to attain.  In order to get a prescription for quetiapine as an anxiolytic, you’ll likely need to have pursued all standard treatments without adequate symptomatic reduction.
  • Permanent medical complications: Though risk of permanent medical complications is said to be lower with atypical antipsychotics like quetiapine compared to older neuroleptics, its usage may induce permanent, life-altering medical conditions. A few irreversible complications that patients might endure as a result of their quetiapine usage include: tardive dyskinesia, diabetes (type 2), and cataracts.  While many professionals will take precaution to prevent and/or reverse the onset of the aforestated conditions during treatment, they are not always successful.  Risk-averse individuals may be unwilling to use quetiapine after being informed of these potential complications.
  • Sedation: Quetiapine is known to be a very sedating medication for most users, especially during the early stages of treatment. If you’re taking quetiapine on a daily basis for several months, the sedation may subside, but there’s no guarantee.  Any drug that exerts a potent antihistaminergic and anticatecholaminergic effect is likely going to induce some degree of sedation and drowsiness.  Though you may choose to deal with sedation over anxiety, if the sedation impairs your cognitive and motor function, you may struggle to complete tasks at work or home.
  • Side effects: Even if you never experience an adverse reaction or develop a permanent medical complication while taking quetiapine, you may find yourself struggling to cope with some of its general side effects. Examples of Seroquel side effects include:  appetite increase, confusion, dizziness, dry mouth, gynecomastia, headaches, lightheadedness, somnolence, upset stomach, and weight gain.  Those that end up with severe headaches, somnolence, and/or stomach aches during treatment may have a difficult time justifying continued quetiapine usage.
  • Untargeted mechanism: At low doses, we know that quetiapine will exert mostly an antihistaminergic and anticatecholaminergic effect, however, at higher doses, many other receptor sites of serotonin and dopamine are affected.  The sheer number of different receptors that are affected by quetiapine at higher doses makes it difficult to know what’s contributing to the overall anxiolytic effect.  For some patients that respond well to quetiapine, there may be drugs that work better on a specific mechanism and are more targeted with less side effects.
  • Unknown long-term efficacy: There’s evidence indicating that quetiapine is effective for the treatment of anxiety among patients with schizophrenia over the long-term. As was mentioned, one study showed that quetiapine’s anxiolytic effect remained significant for up to a 3-year duration.  That said, it was unreported as to whether the dosage was modified along the way.  It is likely that if quetiapine XR is administered on a daily basis over an extended duration for the treatment of anxiety, users will become tolerant via changes in receptor density.  Though increasing the dosage is a reasonable option, it increases risk of serious adverse reactions and permanent medical complications.  For this reason, it’s possible that daily quetiapine administration to those with anxiety is a poorer long-term option than others.
  • Weight gain: A side effect that may be a deal-breaker among persons taking quetiapine for anxiety is weight gain. Many people notice that quetiapine causes brain fog, lethargy, increases appetite and/or food cravings, plus modifies hormones – all of which may lead to the gaining of bodyweight.  Pharmacological researchers believe that quetiapine’s action at the H1 receptor and 5-HT2C receptor are critical mechanisms that provoke weight gain.  Although the literature suggests that quetiapine users will only gain around 1 lb. during treatment, most consider this to be an intentionally misleading approximation.  In any regard, while most people would gladly trade in their severe anxiety for modest weight gain on Seroquel, if the weight gain becomes significant, the gain itself may cause body-image anxiety.
  • Withdrawal: Some would argue that quetiapine is among the most difficult of medications to discontinue due to the onslaught of deleterious effects that emerge. Withdrawing from quetiapine is tough because, during treatment, it will have modified many neurotransmitter systems (e.g. histamine, norepinephrine, dopamine, serotonin, etc.).  When you cease usage of the drug, multiple neurotransmitter systems will remain in disarray, expecting to receive the drug – hence an onslaught of Seroquel withdrawal symptoms, including: agitation, anxiety, brain fog, cognitive deficits, depression, sleep problems, suicidal thoughts, etc.  Moreover, these withdrawal symptoms can persist for months (sometimes longer) even after Seroquel is fully out of your system.
  • Worsening of anxiety: While quetiapine may effectively reduce anxiety in many users, others may experience a worsening of anxious symptoms. Worsening of anxiety generally occurs as a result of quetiapine inducing changes to a persons’ neurochemistry that potentiate preexisting neurochemical abnormalities causally implicated in their particular neurobiological anxiety signature.  In many cases, exacerbation of anxiety yields disastrous consequences for those with already-severe symptoms.  Although anxiety doesn’t commonly worsen from quetiapine, it is an experience that some have reported.

Seroquel (Quetiapine) for Anxiety (Review of Research)

To determine whether Seroquel (Quetiapine) is an effective medication for the treatment of anxiety, it’s necessary to examine the available published research.  Included below are summaries of trials and reports (published from 2003 to 2016) that have analyzed or discussed the effect of Seroquel (Quetiapine) symptoms of anxiety.  Trials that implement quality designs (randomized, controlled, double-blinded) and enroll large numbers of human participants should give us the most accurate understanding of Seroquel’s anxiolytic efficacy.  As you’ll see, most data suggest that quetiapine is an effective anxiolytic intervention.

2016: Quetiapine monotherapy in acute treatment of generalized anxiety disorder: a systematic review and meta-analysis of randomized controlled trials.

A systematic review and meta-analysis was conducted by Maneeton, Maneeton, Woottiluk, et al. (2016) to assess the effectiveness of quetiapine for the treatment of generalized anxiety disorder (GAD).  It should be noted that, when properly conducted, systematic reviews provide robust data regarding the significance of a medication’s therapeutic effect.  The goal of this particular review was to determine the acceptability, efficacy, and tolerability of quetiapine in adult populations diagnosed with generalized anxiety disorder.

Researchers analyzed scientific and medical databases for randomized controlled trials that tested quetiapine for the treatment of generalized anxiety disorder.  A total of 3 RCTs, encompassing 2,248 participants, met inclusion criteria for this systematic review.  The efficacy of quetiapine as an anxiolytic intervention among patients with generalized anxiety disorder was determined based on average-change on anxiety rating scales (from pre-treatment baseline to post-treatment) and response rates.

Pooled results indicated that average-change in anxiety scores among persons receiving quetiapine was significantly greater than recipients of a placebo control.  It was noted that the response and remission rates from treatment with quetiapine XR at 50 mg/day and 150 mg/day dosages were superior to those of a placebo.  The anxiolytic effect of quetiapine XR at the aforestated dosages was analogous to the anxiolytic effect of SSRIs, and discontinuation rates were similar to those of SSRIs.

The reviewers concluded that quetiapine XR is an effective intervention for the treatment of generalized anxiety disorder in adults.  That said, it was mentioned that patients often struggle to tolerate and/or accept treatment with quetiapine XR for anxiety.  Although more research would be useful, this review provides strong evidence to support the usage of quetiapine XR (50 mg/day or 150 mg/day) in adults with generalized anxiety disorders.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26834458

2015: A literature review of quetiapine for generalized anxiety disorder.

Kreys and Phan (2015) conducted a literature review to assess the effectiveness of Seroquel as a treatment for generalized anxiety disorder.  Researchers utilized the Medline database to collect data from randomized controlled trials (RCTs) in which quetiapine was administered as either a standalone or adjunct anxiolytic – to adult patients with generalized anxiety disorder.  A total of 9 studies were uncovered via the literature search: 3 studies testing quetiapine XR monotherapy for acute generalized anxiety; 1 study testing quetiapine XR monotherapy as a maintenance therapy for generalized anxiety disorder; and 5 studies testing quetiapine (3 IR / 2 XR) as an adjunct for acute generalized anxiety.

Data from trials in which quetiapine was administered as a monotherapy indicated that it was effective and well-tolerated for the acute or long-term treatment of generalized anxiety disorder.  A total of 3 of the 5 trials in which quetiapine was administered as an adjunct indicated that it was effective for the treatment of generalized anxiety disorder.  In the 3 adjunct studies that reported quetiapine as effective for anxiety, its efficacy was based upon significant symptomatic improvement on the Hamilton Anxiety Rating Scale (HAM-A) and the Clinical Global Impressions Scale (CGI-S) from pre-treatment baseline to post-treatment.

Although there were some limitations associated with trials in which quetiapine was administered as an adjunct (e.g. lack of heterogeneity), most data support the idea that quetiapine is an effective (acute or long-term) intervention for generalized anxiety disorder, regardless of whether used as a standalone or adjuvant.  Authors of the review noted that longer-term trials with less restrictive inclusion criteria would prove useful in understanding whether the anxiolytic benefits derived from quetiapine outweigh its risks.  Moreover, authors suggest that quetiapine may be a viable pharmacological anxiolytic for patients with refractory generalized anxiety disorder, however, these patients will require frequent monitoring for adverse effects.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25689246

2014: Extended release quetiapine fumarate as adjunct to antidepressant therapy in patients with major depressive disorder: pooled analyses of data in patients with anxious depression versus low levels of anxiety at baseline.

Bandelow, Bauer, Vieta, et al. (2014) sought to determine the efficacy of quetiapine XR among patients diagnosed with “anxious depression” (i.e. major depression with comorbid anxiety) compared to patients with non-anxious depression.  For this study, data were compiled from 2 randomized, double-blinded, placebo-controlled, 6-week trials that tested the adjunct efficacy of quetiapine XR (150 mg/day OR 300 mg/day) among patients exhibiting insufficient therapeutic responses to conventional antidepressants.  Patients with “anxious depression” were distinguished from those with non-anxious depression through analysis of baseline anxiety scores.

Any participants exhibiting either: HAM-A (Hamilton Anxiety Rating Scale) scores exceeding 20 at baseline or HAM-D (Hamilton Depression Rating Scale) scores exceeding 7 [on the anxiety/somatization section] at baseline – met criteria for “anxious depression.”  All other participants were regarded as exhibiting non-anxious depression.  After the participants with anxious depression were isolated from those with non-anxious depression, researchers gauged the therapeutic efficacy of quetiapine XR in each diagnostic subtype.

Efficacy of adjunct quetiapine XR was based upon change in total score on the MADRS (Montgomery-Asberg Depression Rating Scale) from baseline (pre-treatment) through the 6-week trial duration.  Results indicated that patients with anxious depression exhibited reductions on MADRS total scores of ~15.20 and ~15.92 after receiving adjunct quetiapine XR at 150 mg/day and 300 mg/day, respectively.  Among those with non-anxious depression, adjunct quetiapine XR (150 mg/day and 300 mg/day) significantly reduced MADRS total scores.

Researchers concluded that adjunct quetiapine XR is appears effective for the treatment of anxious and non-anxious depression.  What’s more, secondary analyses revealed that adjunct quetiapine XR significantly improved HAM-A scores and anxiety/somatization scores (on the HAM-D).  This suggests that quetiapine XR facilitates an antidepressant plus anxiolytic effect among patients with “anxious depression,” and indicates that quetiapine XR could prove useful as an intervention for anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24506289

2012: Efficacy and tolerability of extended release quetiapine fumarate monotherapy in the acute treatment of generalized anxiety disorder: a randomized, placebo controlled and active-controlled study.

Merideth, Cutler, She, and Eriksson (2012) organized a randomized, placebo-controlled, and active-controlled trial to gauge the efficacy and tolerability of quetiapine XR as a monotherapeutic intervention for generalized anxiety disorder (GAD).  Researchers recruited a total of 854 individuals, each of whom met diagnostic criteria for generalized anxiety disorder, to participate in the 8-week trial with a 2-week follow-up period.  The participants were assigned at random to receive one of the following: quetiapine XR at 150 mg/day (219 participants) or 300 mg/day (207 participants); escitalopram 10 mg/day (213 participants); or a placebo (215 participants).

Prior to the trial (at baseline), the severity of participants’ anxiety was assessed with the Hamilton Anxiety Rating Scale (HAM-A).  The anxiolytic efficacy of each intervention was determined based on change of HAM-A score from baseline to through Week 8.  Results indicated significant average reductions in HAM-A scores among recipients of quetiapine XR and escitalopram compared to the placebo.

Specifically, recipients of quetiapine XR exhibited average HAM-A score reductions of 13.9 and 12.3 at the 150 mg/day and 300 mg/day dosages, respectively.  Recipients of escitalopram 10 mg/day exhibited an average HAM-A score reduction of 12.3, whereas those taking the placebo exhibited an average an average HAM-A score reduction of 10.7.  Additionally, quetiapine XR (150 mg/day and 300 mg/day) appeared to have the quickest onset of anxiolytic action, as evidenced by significant HAM-A score reductions within just 4 days of treatment.

A few unwanted side effects were reported among quetiapine XR users including dry mouth, somnolence, and sedation.  Nonetheless, researchers concluded that quetiapine XR appears safe, tolerable, and effective for the treatment of generalized anxiety disorder, at both 150 mg/day and 300 mg/day dosages, over an 8-week duration.  Moreover, when considering that the 150 mg/day quetiapine XR dose appeared more effective than the 300 mg/day in terms of somatic symptoms, cluster scores, HAM-A responses, and remission rates – it makes logical sense to utilize this lower dose for the treatment of generalized anxiety disorder.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22045039

2012: Quetiapine fumarate augmentation for patients with a primary anxiety disorder or a mood disorder: a pilot study.

Chen, Chen, and Wang (2012) noted that untreated anxiety among persons with neuropsychiatric disorders leads to poorer long-term health outcomes and is of detriment to the healthcare system.  Since patients with an anxiety disorder or a mood disorder plus comorbid anxiety may not respond to conventional anxiolytics, it’s necessary to test the efficacy of alternative options.  One such alternative intervention that warrants testing is quetiapine, an atypical antipsychotic.

For this reason, researchers organized a pilot study to evaluate the practicality of using quetiapine XR (extended-release) as a treatment for anxiety.  This pilot study recruited 35 patients that had been diagnosed with either a standalone anxiety disorder or mood disorder plus comorbid anxiety.  It was noted that all patients were taking stable doses of an antidepressant monotherapy prior to their involvement with this trial.

All participants were assigned at random to receive adjuvant: quetiapine XR or a placebo – for an 8-week duration.  Anxiolytic efficacy of quetiapine XR was determined based upon changes in HAM-A (Hamilton Anxiety Rating Scale) and CGI-S (Clinical Global Impression Scale) scores from pre-treatment baseline to Week 1, Week 4, and Week 8.  Results indicated that by Week 4, quetiapine XR recipients exhibited significant reductions on the HAM-A and CGI-S (~13 points) compared to those receiving the placebo (~6.63 points).

Despite the noticeable reduction in anxiety among quetiapine XR recipients compared to placebo recipients at Week 4, there were no significant differences in anxiety levels between quetiapine and placebo recipients at Week 8.  Researchers concluded that adjuvant quetiapine XR failed to attenuate anxious symptoms among those with a standalone anxiety disorders or mood disorders plus comorbid anxiety.  Clearly the results of this study do not support the adjunct usage of quetiapine XR for the treatment of anxiety over a 2-month duration.

Nonetheless, since quetiapine XR significantly reduced anxious symptoms at Week 4, it should be considered that quetiapine XR may facilitate a short-term anxiolytic effect.  Perhaps those with severe refractory anxiety would benefit from short-term (or possibly “as-needed”) adjunct administration of quetiapine XR.  It should be restated that this was a pilot study limited by its small sample size, design, and dosage of quetiapine.  Overall, it’s impossible to know whether quetiapine XR is effective for the treatment of anxiety based on this study’s results.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23020711

2011: Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial.

Katzman, Brawman-Mintzer, Reyes, et al. (2011) conducted a randomized, double-blind, placebo-controlled trial to evaluate the tolerability and efficacy of quetiapine XR as a long-term maintenance therapy for the treatment of generalized anxiety disorder.  The primary outcome measure was time from treatment initiation to an anxiety episode.  Secondary outcome measures included scores on the following scales: HAM-A (Hamilton Anxiety Rating Scale), CGI-S (Clinical Global Impressions Scale), and Q-LES-Q (Quality of Life, Enjoyment and Satisfaction Questionnaire).

After an open-label 4-to-8-week “run in,” a total of 432 participants were stabilized on quetiapine XR (50-300 mg/day).  Following stabilization on quetiapine XR, participants were assigned at random to either: continue receiving quetiapine XR (216 participants) OR get switched to receiving a placebo (216 participants).  Results indicated that significantly fewer participants receiving quetiapine XR (10.2%) experienced a resurgence of anxiety during treatment compared to those receiving the placebo (38.9%).

Additionally, secondary outcomes revealed that quetiapine XR recipients exhibited significant improvements on HAM-A, CGI-S, and Q-LES-Q scores – compared to placebo recipients.  Side effects associated with quetiapine XR included: constipation, dizziness, fatigue, headache, nasopharyngitis, sedation, and somnolence.  Based on the results of this study, it appears as though quetiapine XR (at doses between 50 mg/day and 300 mg/day) is an effective long-term monotherapeutic option for patients with generalized anxiety disorders.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20881846

2011: A randomized, double-blind study of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder.

Khan, Joyce, Atkinson, et al. (2011) examined the efficacy of quetiapine XR as a monotherapy for patients with generalized anxiety disorder.  A randomized, double-blind, placebo-controlled trial with 951 patients, each of whom had been diagnosed with generalized anxiety disorder, was conducted over a 10-week duration.  The 951 patients were assigned at random to receive quetiapine XR at 50 mg/day (234 patients), 150 mg/day (241 patients), 300 mg/day (241 patients) OR a placebo control (235 patients).

Prior to the trial, the severity of patients’ anxiety was assessed using the Hamilton Anxiety Rating Scale (HAM-A).  The primary outcome measure was the change in total HAM-A score from pre-treatment (baseline) throughout Week 8.  Results indicated that recipients of quetiapine XR at 50 mg/day and 150 mg/day doses exhibited significant reductions in total HAM-A scores compared to the placebo at Week 8, however, the recipients of quetiapine at the 300 mg/day dose did not.

The Clinical Global Impressions Scale (CGI-S) served as another outcome measure and revealed significant symptomatic improvement among those receiving quetiapine XR at 50 mg/day and 150 mg/day – compared to the placebo and quetiapine XR 300 mg/day recipients.  Pittsburgh Sleep Quality Index scores revealed significant improvements among those receiving any dose of quetiapine XR – compared the placebo group.  Moreover, it appeared as though quetiapine XR facilitated a rapid anxiolytic effect, providing statistically significant anxiety reduction within just 1 week of administration – regardless of the dose.

Some side effects were reported with quetiapine XR including: dizziness, dry mouth, fatigue, headache, sedation and somnolence – all of which are consistent with other research.  It was concluded that monotherapeutic administration of quetiapine XR is an effective treatment for generalized anxiety disorder, but only when administered at 50 mg/day or 150 mg/day.  Although there are some potential unwanted side effects that may occur during treatment, this study supports the therapeutic usefulness of quetiapine XR as an anxiolytic.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21694613

2010: Quetiapine: novel uses in the treatment of depressive and anxiety disorders.

Ravindran, Al-Subaie, and Abraham (2010) discuss the fact that although quetiapine is not FDA approved for the treatment of anxiety disorders, it is commonly prescribed off-label to children and adults for this purpose.  The aforestated trio of researchers conducted an investigational review that examined the safety and effectiveness of quetiapine as an off-label intervention for persons with anxiety disorders.  After analyzing the available literature, researchers noted that there is “strong” evidence to support the off-label prescribing of quetiapine to those with generalized anxiety disorder (GAD).

There’s also mounting evidence to support the adjunct usage of quetiapine among persons with OCD (obsessive-compulsive disorder).  Researchers also discuss the fact that quetiapine’s usefulness as an anxiolytic may extend beyond generalized anxiety disorder to other types of anxiety.  Nonetheless, this report indicates that quetiapine is useful for persons with generalized anxiety disorder, especially over the short-term.

That said, better quality research is needed to elucidate quetiapine’s effectiveness for all types of anxiety disorders.  Moreover, while quetiapine is effective and tolerable over a short-term, its long-term tolerability and anxiolytic sustainability necessitate investigation.  Still, it is evident that quetiapine can help with some forms of anxiety as a monotherapy and adjunct.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20795889

2009: Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies.

Lydiard, Culpepper, Schiöler, et al. (2009) pooled results from 2 double-blind, randomized, placebo-controlled trials to determine whether quetiapine monotherapy attenuated symptoms of anxiety among persons with bipolar depression.  Researchers conducted a post hoc assessment of anxiety symptoms in 1,051 patients diagnosed with bipolar depression (in accordance with DSM criteria).  All patients had participated in 1 of 2 trials in which quetiapine was administered at dosages of 300 mg/day or 600 mg/day – over an 8-week duration.

The degree to which quetiapine treated anxiety was determined based upon change in scores on the HAM-A (Hamilton Anxiety Rating Scale).  At the initiation of trials, HAM-A scores were similar at baseline among recipients of quetiapine and the placebo.  Within just 1 week of treatment, a significant anxiolytic effect was observed among recipients of quetiapine (regardless of dose) compared to the placebo; this was evidenced by reductions in HAM-A scores.

Initial anxiety reductions observed in the first week of treatment persisted throughout the 8-week duration.  Both quetiapine dosages (300 mg/day and 600 mg) yielded significant reductions of HAM-A scores compared to the placebo.  Although some side effects occurred among recipients of quetiapine (e.g. dizziness, dry mouth, sedation, somnolence), quetiapine proved tolerable and effective for the treatment of anxiety among individuals with bipolar depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19956459

2008: New developments in the management of major depressive disorder and generalized anxiety disorder: role of quetiapine.

Baune (2008) noted that quetiapine effectively treats neuropsychiatric conditions such as schizophrenia and bipolar disorder, however, it hasn’t been thoroughly assessed as a treatment for major depressive disorder and generalized anxiety disorder.  For this reason, Baune conducted a review of the literature to analyze the efficacy, safety, and tolerability of quetiapine for major depression and generalized anxiety.  The literature indicated that standalone or adjunct quetiapine (50-300 mg/day) is effective when administered as a short-term or maintenance intervention for both major depression or generalized anxiety.  It was concluded that quetiapine is a promising therapy for the treatment of major depression and anxiety, however, its sedative side effects may lead some patients to discontinue.  Still, this is yet another report suggesting that quetiapine is effective for anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19337458

2007: Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study.

McIntyre, Gendron, and McIntyre (2007) conducted a double-blind, placebo-controlled pilot study to determine the efficacy of quetiapine as an adjunct to SSRIs or an SNRI for the treatment of major depressive disorder plus comorbid anxiety and residual depressive symptoms.  A total of 58 individuals were recruited for participation, each of whom had been formally diagnosed with major depressive disorder.  Additionally, all participants exhibited Hamilton Anxiety Rating Scale (HAM-A) scores exceeding 14, indicative of anxiety, plus either HAM-D scores above 18 or CGI-S scores above 4, indicative of residual depression.

Initially, participants received either an SSRI or the SNRI venlafaxine at therapeutic dosages for a minimum of 6 weeks.  Next, all participants were assigned at random to receive either: quetiapine OR a placebo – as an adjunct to the SSRI or venlafaxine.  To determine the therapeutic efficacy of adjunct quetiapine, researchers compared the average change in HAM-A and HAM-D scores from baseline through an 8-week duration.

Results indicated that recipients of quetiapine exhibited significantly greater score reductions on the HAM-A and HAM-D from baseline than recipients of the placebo.  Specific data revealed significantly improved HAM-A scores by ~12.5 points and HAM-D scores by ~11.2 points among recipients of quetiapine, indicating marked reductions of anxious and depressive symptoms.  Comparatively, placebo users exhibited changes of HAM-A by ~5.9 points and HAM-D by ~5.5 points, suggesting an insignificant therapeutic effect.

Additionally, the anxiolytic and antidepressant efficacy of adjunct quetiapine was significant over the placebo within just 1 week and remained significant throughout the 8-week trial duration.  An estimated 62% of quetiapine recipients exhibited a substantial reduction in anxious symptoms (by at least 50%) compared to 28% of placebo recipients.  Furthermore, an estimated 48% of quetiapine recipients exhibited a substantial reduction in depressive symptoms (by at least 50%) compared to 28% of placebo recipients.

Nonetheless, this study supports the usefulness of adjunct quetiapine as an intervention for persons with major depression with comorbid anxiety plus residual depressive symptoms – when administered along with an SSRI or venlafaxine.  An average quetiapine dose of 182 mg/day was utilized in this study and no significant tolerability issues were reported.  Moreover, adjunct quetiapine appeared more effective in reduction symptoms of anxiety than residual depression, suggestive of a robust anxiolytic effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17177199

2006: Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: a secondary analysis from a randomized, double-blind, placebo-controlled study.

Hirschfeld, Weisler, Raines, et al. (2006) discussed the fact that quetiapine monotherapy appears effective for the treatment of bipolar depression.  That said, researchers wanted to understand whether quetiapine alleviated comorbid symptoms of anxiety among those with bipolar depression.  For this reason, the anxiolytic effect of quetiapine administration in a multicenter, double-blind, randomized, fixed-dose, placebo-controlled trial was analyzed.

A total of 542 outpatients with bipolar depression were assigned at random to receive quetiapine (300 mg/day or 600 mg/day) OR a placebo for a duration of 8 weeks.  Severity of anxiety of participants at baseline was determined based on data from the HAM-A, and anxiety-related sections of the MADRS and HAM-D scales.  Results indicated that, by week 8, quetiapine users with bipolar 1 depression (300 mg/day and 600 mg/day) exhibited significant reductions in HAM-A scores compared to placebo users, indicating attenuation of anxious symptoms.

Comparatively, individuals with bipolar 2 depression failed to exhibit significant reductions in HAM-A scores by Week 8 compared to the placebo users.  That said, on all secondary measures of anxiety, patients with bipolar depression, regardless of type-1 or type-2, exhibited significant score reductions compared to a placebo.  This suggests that standalone quetiapine effectively reduces anxiety among patients with bipolar depression, however, the anxiolytic effect may be more robust among those with the bipolar type-1 compared to type-2.

It is possible that 300 mg/day and 600 mg/day dosages may have been too high for a subset of patients, perhaps compromising the therapeutic efficacy of quetiapine.  It is also possible that quetiapine would’ve been more effective as an adjunct among a subset of patients compared to a monotherapeutic intervention.  Nonetheless, this research supports the usefulness of quetiapine monotherapy among patients with bipolar 1 depression plus comorbid anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16649820

2005: Low-dose risperidone and quetiapine as monotherapy for comorbid anxiety and depression.

Galynker, Khan, Grebchenko, et al. (2005) mention that approximately 80% of individuals diagnosed with generalized anxiety disorder (GAD) exhibit a comorbid mood disorder, most typically of which is major depression.  It was further noted that atypical antipsychotics are regularly prescribed off-label as adjuvant therapies for the aforementioned conditions – anxiety and depression.  Although atypical antipsychotics were regularly utilized off-label as adjuvant anxiolytics and antidepressants, no studies had investigated the efficacy of atypical antipsychotics as a monotherapy for anxiety and/or depression.

For this reason, researchers presented a series of case reports in which patients with generalized anxiety disorder, major depression, or anxiety plus depression – received quetiapine or risperidone as monotherapies.  A total of 36 adult patients were discussed in this report: 22 with diagnoses of generalized anxiety disorder and 14 with diagnoses of generalized anxiety disorder plus panic.  It was noted that 27 of the 36 patients had been diagnosed with comorbid major depression.

Of the 36 patients, 13 received quetiapine which was initiated at a dosage of 25 mg/day at bedtime.  Over a 2-week duration, patients were titrated upwards by adding 25 mg/day to their daily dose until hitting 100 mg/day.  After the patients reached 100 mg/day, the rate of titration was doubled such that they added 50 mg/day until reaching a peak dose of 300 mg/day.

Measures of anxious and depressive symptoms were collected from each of the patients at pre-treatment baseline with scales such as the HAM-A (Hamilton Anxiety Rating Scale) and a modified HAM-D (Hamilton Depression Rating Scale).  Average baseline HAM-A scores were 24.92 for quetiapine recipients and 22.84 for risperidone recipients.  Average baseline HAM-D scores were 20.31 for quetiapine recipients and 24.95 for risperidone recipients.

Following treatment with quetiapine, HAM-A scores averaged 7.46 (dropping from ~24.92), whereas following treatment with risperidone, HAM-A scores averaged 5.68 (dropping from ~22.84).  After receiving quetiapine, HAM-D scores averaged 12.15 among quetiapine users (dropping from ~20.31) and averaged 6.37 among risperidone users (dropping from ~24.95).  Researchers documented that at least a 50% reduction on HAM-A scores was exhibited in 10 of 13 quetiapine users (77%) and 17 of 19 risperidone users (89%).

Additionally, at least a 50% improvement on HAM-D scores was observed in 4 of 13 quetiapine users (31%) and 16 of 18 risperidone users (89%).  It was concluded that quetiapine and risperidone appear effective as monotherapeutic interventions for the treatment of generalized anxiety disorder at dosages significantly lower than utilized to treat schizophrenia.  At lower doses, it is suspected that the anxiolytic effects associated with quetiapine and risperidone are mediated through 5-HT2A receptors, rather than dopaminergic receptors.

Despite the reported findings suggesting that standalone quetiapine and risperidone can effectively treat generalized anxiety disorder, these findings were not derived from a randomized controlled trial, nor a large sample size.  Lack of randomization and controlling plus the small sample size makes it impossible to know whether quetiapine and risperidone are legitimately effective anxiolytics, as a placebo effect may have yielded similar outcomes.  Moreover, researchers discuss risk of tardive dyskinesia associated with antipsychotics, recommending against antipsychotics as first-line treatments for anxiety disorders.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15816805

2004: Quetiapine is effective against anxiety and depressive symptoms in long-term treatment of patients with schizophrenia.

Kasper (2004) extracted and analyzed data from open-label extension phases of 3 RCTs in which quetiapine was administered to patients with schizophrenia.  The purpose of this data extraction and evaluation was to determine if any initial anxiolytic and/or antidepressant effects associated with quetiapine were maintained over an extended duration of treatment.  Measures of anxiety and depression were taken with the Brief Psychiatric Rating Scale (BPRS), a scale that includes anxiety, depression, guilt, and somatic symptoms.

Scores of anxiety and depression on the BPRS were recorded at OLE-baseline and at various checkpoints up to a 3-year duration.  It was discovered that average BPRS scores among quetiapine users were approximately -1.13 after a 6-week duration and -1.33 after the entire 3-year duration.  Kasper concluded that the effectiveness of quetiapine for the treatment of anxiety and depressive symptoms is maintained over an extended duration.

Although quetiapine proved effective over an extended duration, it would’ve been helpful to know whether the dosage was increased as a result of tolerance in some of the patients.  Perhaps the increased dosage explains the maintained long-term efficacy.  It would’ve also been useful to understand whether, if the dosage was increased, if incidence rates of adverse events and/or side effects increased.

Furthermore, it is unclear as to whether adjuvant therapies may have been administered to these patients, and if so, whether their respective dosages may have been modified over the 3-year term.  Perhaps many adjuvants contributed significantly to the long-term maintenance of depression and anxiety reduction in these patients.  Moreover, this study evaluated the long-term anxiolytic and antidepressant effect of quetiapine among patients with schizophrenia, and although results were favorable, they should not be extrapolated to patients with different neuropsychiatric diagnoses.  That said, the results presented in this study support the concept that quetiapine may be useful as an anxiolytic over an extended duration.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15368596

2003: Treatment for mood and anxiety disorders: quetiapine and aripiprazole.

Sajatovic (2003) was among the first to discuss the usage of atypical antipsychotics such as quetiapine and aripiprazole for the treatment of anxious and depressive disorders.  In this paper, it was noted that atypical antipsychotics have proven highly therapeutic for numerous neuropsychiatric disorders with a low risk of inducing extrapyramidal effects and tardive dyskinesia compared to older neuroleptics.  As a result of their lower risk profiles, the popularity of atypical antipsychotics has substantially increased.

In fact, Sajatovic suggests that an excess of 70% of atypical antipsychotic prescriptions are for off-label conditions.  At this time, reports suggested that quetiapine and aripiprazole could be helpful for persons with anxiety and/or major depression.  Though there wasn’t much quality data from randomized controlled trials at the time of this publication, it appears as though the preliminary speculation that quetiapine could treat anxiety proved accurate.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12857536

Verdict: Seroquel (Quetiapine) is an effective anxiolytic intervention

There are considerable data to support the efficacy of Seroquel (Quetiapine) for the treatment of anxiety disorders, especially generalized anxiety disorder.  The strongest data to support the anxiolytic efficacy of quetiapine are derived from systematic reviews and meta-analyses.  A systematic review conducted by Maneeton, Maneeton, Woottiluk, et al. (2016) evaluated quetiapine’s efficacy for the treatment of generalized anxiety disorder based on 3 randomized controlled trials across 2,248 patients.

Data from the review indicated that quetiapine XR (extended-release) was effective for the treatment of generalized anxiety disorder among adults when administered at 50 mg/day or 150 mg/day dosages.  A systematic review and meta-analysis conducted by Kreys and Phan (2015) also evaluated the efficacy of quetiapine XR for the treatment of anxiety.  This review concluded that quetiapine was effective and tolerable for the acute or long-term treatment of generalized anxiety disorder when administered as a monotherapy.

It also appeared as though quetiapine was likely effective for the treatment of anxiety when administered as an adjunct anxiolytic.  Evidence supports the idea that quetiapine may be equally as effective as SSRIs (selective-serotonin reuptake inhibitors) for the treatment of generalized anxiety disorder.  For example, results from an 8-week study by Merideth, Cutler, She, and Eriksson (2012) showed that quetiapine alleviated symptoms of generalized anxiety disorder as well as escitalopram, and better than a placebo.

In addition to proving effective for the treatment of generalized anxiety disorder, quetiapine appears useful for the attenuation of comorbid anxiety among individuals with primary diagnoses of bipolar disorder, major depressive disorder (MDD), and schizophrenia.  For example, Kasper (2004) analyzed 3 RCTs and discovered that that long-term administration of quetiapine to patients with schizophrenia maintained a robust anxiolytic effect for up to 3 years.  Another example is the finding by Lydiard, Culpepper, Schiöler, et al. (2009), derived from an analysis of 2 RCTs, in which quetiapine monotherapy (at 300 mg/day or 600 mg/day doses) significantly reduced anxiety among patients with bipolar depression over an 8-week duration.

Although there’s some evidence suggesting that quetiapine may be ineffective as an anxiolytic, most of this evidence is poor quality.  For example, a trial by Chen, Chen, and Wang (2012) found that quetiapine was ineffective compared to a placebo for the treatment of anxiety over an 8-week duration, however, this trial was extremely small-scale (incorporating just 35 patients), perhaps yielding inaccurate results.  Overall, there’s reliable evidence to substantiate the effectiveness of quetiapine for the treatment of generalized anxiety disorder.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26834458
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25689246
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22045039
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15368596
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19956459
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23020711

Who should consider Seroquel (Quetiapine) for anxiety?

Just because data support the efficacy of quetiapine for anxiety does not automatically imply that it should be used as an anxiolytic.  There are some serious risks and concerns associated with safety and tolerability of quetiapine (and other atypical antipsychotics), especially when administered over a long-term.  Additionally, it is worth noting that quetiapine has never been approved by the FDA for the treatment of anxiety, meaning it should not be considered a first-line anxiolytic.

For this reason, prior to the off-label usage of quetiapine for anxiety, a skilled psychiatrist should conduct a cost/benefit analysis to confirm that the hypothetical therapeutic benefits will outweigh any hypothetical deleterious effects.  That said, certain patients may be a good fit for receiving quetiapine to help manage symptoms of anxiety – based on their diagnoses.  Examples of viable quetiapine recipients include persons with: schizophrenia, bipolar disorder, refractory depression, and/or refractory anxiety.

  • Schizophrenia: Since quetiapine is an FDA approved as a first-line intervention for the treatment of schizophrenia, any patients with a primary diagnosis of schizophrenia plus comorbid symptoms of anxiety may be optimal candidates to receive quetiapine. Strong evidence supports the usefulness of quetiapine for the treatment of schizophrenia, as well as for the symptoms of anxiety.  Patients with schizophrenia plus comorbid anxiety may attain relief from all unwanted neuropsychiatric symptoms with a single daily dose of quetiapine XR.  One long-term study conducted among patients with schizophrenia reported that quetiapine effectively attenuated symptoms of comorbid anxiety over a 3-year duration.
  • Bipolar disorder: Quetiapine is also FDA approved as a first-line agent for the treatment of mania and depression implicated in bipolar disorder, making it an ideal intervention for anyone with bipolar disorder plus comorbid anxiety. Research supports the efficacy of quetiapine among patients with bipolar depression with comorbid anxiety.  Multiple randomized controlled trials conducted over an 8-week duration reported that quetiapine was effective for the treatment of bipolar depression with comorbid anxiety.  Some evidence suggests that quetiapine may be more effective for the treatment of comorbid anxiety among those with bipolar type-1 compared to those with bipolar type-2.
  • Major depression: Individuals diagnosed with refractory major depressive disorder often receive atypical antipsychotics such as quetiapine to augment a conventional antidepressant. In fact, quetiapine is FDA approved as an adjunct for the treatment of major depression.  The augmentation of an antidepressant with quetiapine is regarded as effective and tolerable.  For this reason, any patients with refractory depression plus comorbid anxiety may find that the quetiapine not only enhances mood, but alleviates their dreaded anxious symptoms.
  • Refractory GAD: Quetiapine may also be a reasonable intervention for persons exhibiting refractory generalized anxiety disorder. As was mentioned, there’s considerable evidence to support the usefulness of quetiapine as a standalone and adjunct anxiolytic for the treatment of generalized anxiety disorder.  Persons with refractory generalized anxiety disorder are known to have exhausted all traditional standalone and adjunct anxiolytic pharmacology (e.g. serotonergic antidepressants, benzodiazepines, etc.) without clinically significant responses.  For this reason, prescription of quetiapine either as a monotherapy or adjunct may be warranted.
  • Partial responders: Some individuals that experience partial, yet clinically inadequate, relief of anxious symptoms, may need an adjuvant medication to potential the therapeutic effect of the primary anxiolytic. Assuming various augmentation strategies have been tested by a psychiatrist without improvement, an option to consider is quetiapine.  In 3 of 5 trials testing adjunct quetiapine as an anxiolytic, it facilitated statistically significant benefit.

What’s the best dosage of Seroquel (Quetiapine) for anxiety?

Due to the fact that specific neuropsychiatric diagnosis, severity of anxiety, medical history, and medication regimen is subject to substantial individual variation – there’s no “optimal” dose of quetiapine that should be universally recommended for the treatment of anxiety.  Only a skilled, licensed psychiatrist is qualified to give dosing advice, and even then, dosing will be adjusted on a case-specific basis – not everyone responds to the same dosage.  That said, assuming quetiapine XR is being administered as a monotherapy for the sole treatment of generalized anxiety disorder, research supports its usage at dosages of 50 mg/day and 150 mg/day.

Some RCTs suggest that standalone quetiapine XR is effective for the sole treatment of generalized anxiety disorder at 300 mg/day dosages, however, the 300 mg/day dosages are less substantiated than 50 mg/day and 150 mg/day doses.  Among patients with comorbid anxiety and bipolar depression research suggests that 300 mg/day and 600 mg/day dosages of quetiapine XR facilitate therapeutic anxiolytic effects.  Despite the fact that therapeutic dosing ranges appear in the research, finding the most effective dose of quetiapine for your anxiety may require ongoing psychiatric calibration.

In most cases, quetiapine XR is administered at lower doses as an adjunct than as a monotherapy for anxiety due to the fact that, when administered as an adjunct, there’s increased likelihood of an interaction with the primary agent.  Furthermore, it should be noted that risk of adverse events and complications increase at higher quetiapine dosages.  For this reason, all users should work with their psychiatrist to find the minimal effective dose, or lowest quantity of quetiapine needed to provide significant anxiety reduction.

Have you tried Seroquel (Quetiapine) for anxiety?

If you’ve tried quetiapine for anxiety, feel free to document your experience in the comments section below.  From your perspective, was quetiapine: effective, partially effective, or ineffective as an anxiolytic?  If you had to rate the effectiveness of quetiapine on a scale from 1 to 10 for the treatment of your anxiety (with “1” being least effective and “10” being most effective), which numeric rating would you assign it?

In the event that you found quetiapine to be ineffective for anxiety, did it make your anxiety worse than before taking it?  To help others get a better understanding of your situation, provide some personal details such as: your specific anxiety subtype (e.g. generalized anxiety disorder), any comorbid psychiatric diagnoses (e.g. major depression), your daily dose and formatting of quetiapine (e.g. 150 mg/day, XR), and co-administered substances (e.g. medications, supplements, etc.).  In your subjective experience, do the anxiolytic benefits of quetiapine outweigh its side effects?

For those that found quetiapine to be effective for anxiety, how long did it take for the symptomatic reduction to occur after initiation of treatment (e.g. days, weeks, etc.)?  If you’ve been using quetiapine for a long-term for anxiety, has it maintained a robust anxiolytic effect at a stable dose, or have you had to increase the dosage due to onset of tolerance?  In summary, quetiapine can be a useful anxiolytic intervention among persons with schizophrenia, bipolar disorder, refractory depression with comorbid anxiety, and treatment-resistant generalized anxiety disorder, however, it will not work for everyone and patients should beware of risks prior to treatment.

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{ 1 comment… add one }
  • alsbells September 24, 2016, 3:30 pm

    I found Quetiapine to be an extremely effective anxiolytic. I would rate it 10/10 for its effectiveness. It essentially knocks you out. That’s my experience of it. The side effect of weight gain is the problem I have with quetiapine. Two separate times, separated by ten years, I gained up to 23-25kgs each time. Then I got well, lost the weight, then got sick ten years later and gained it back.

    I know I have been diagnosed with PTSD and borderline personality disorder. Earlier this year, I got down to less than half a quetiapine. I then experienced a major setback due to a major stress episode. Since March this year my anxiety worsened to what it was three years ago with my muscles contracting and staying stuck that way, in particular in my chest so its difficult to breathe or relax.

    Same as three years ago. But it’s worsened to where my genital tracts contract and it is painful. I feel the contraction in both passages and it makes me feel like I’m going to lose control of my bowels. One and a half months ago my quetiapine increased to 50mg at night with PRN 25mg. Sometimes maybe once a week I’ve noticed I have to take up to 50mg PRN. I am also on prazosin for PTSD 10mg at night and Venlafaxine 300mg/day, and naltrexone 50mg/day though I’ve been sober for seventeen months, I don’t care to come off it.

    I don’t want to return to drinking and I no longer have the kind of cravings I used to since I have been taking naltrexone regularly for the past year. The benefits outweigh the side effects. I do not know that I could function at all and I truly mean that – if I were not on quetiapine since my recent drawback. I can lose the weight, I have found it absolutely impossible to lose weight while on any amount of Q.

    25mg puts me to sleep even three years after taking it. It impairs my ability to stop myself snacking once I take my night meds. It makes me hungry once I take it, to the point where I will wake from sleep to eat. In the past I was told I used to eat and cook during my sleep but I would have none or very vague memories of doing that. I am fairly certain I was on more than 100mg per day when that was happening.

    I have tried everything and I do mean everything and nothing worked so instead of fighting it and causing myself more stress when thats the last thing I need, I would rather deal with the weight loss after I get off quetiapine, like I did in 2003, I lost all the excess weight within a year. The first time (after ten years of being well and off of it) I took Q in 2013 I was given 25mg and I slept for 24hrs.

    It was effective each time I took it but I would have panic attacks in between. I started on quetiapine in 2013 and it significantly improved to the point I was weaning off it in 2015 December-2016 January. Between 2013 September to 2015 October, I escalated up to the highest of 500mg/day (fairly certain I had 450mg prescribed and 50mg was PRN but not approved by my doctor but that’s what I was taking… approx time was July 2014-2015 at its highest).

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