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Guanfacine For ADHD: An Effective Treatment & Adjunct

Guanfacine is a drug that was developed primarily for the treatment of hypertension (high blood pressure).  It has been proven as an effective medication to reduce both systolic and diastolic blood pressure via its effect on Alpha-2 adrenergic autoreceptors.  It functions by stimulating these receptors (as an agonist) and reducing activation of the sympathetic nervous system – specifically the peripheral branch to promote lower blood pressure.

In addition to treating hypertension, the drug is sometimes prescribed off-label to help reduce anxiety disorders, insomnia, tic disorders, and to mitigate severe drug withdrawal symptoms.  The FDA eventually approved various formulations of Guanfacine for the treatment of ADHD.  The drug is thought to elicit a similar effect to Clonidine, increasing stimulation of the prefrontal cortex – thereby improving attention and reducing hyperactivity.

The drug can be utilized as a standalone treatment for ADHD, or may be prescribed as an adjunct to a psychostimulant.  In the psychiatric community, this drug is considered a second-line treatment for ADHD in that it is very effective for symptomatic reduction, but not quite as effective as a psychostimulant.  Some individuals with specific subtypes of ADHD and/or various comorbidities may derive significant benefit from Guanfacine.

  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC161643/

Guanfacine for ADHD: The Research

Below is an array of research analyzing Guanfacine for the treatment of attention-deficit/hyperactivity disorder.  Studies began analyzing Guanfacine extensively for attentional deficits in the 1990s, and increased research was published in the 2000s.  The overwhelming evidence demonstrating Guanfacine’s efficacy resulted in its FDA approval for ADHD.

1995: In the 1990s, researchers had noted that those with Tourette’s syndrome often experienced comorbid ADHD.  Tourette’s often results in hyperactivity, inattentiveness, and impulsive behaviors.  The attentional-deficits and hyperactive behavior was thought to be more detrimental than their “tics” and often played a role in influencing the frequency and severity of the tics.

Researchers speculated that Guanfacine may have been helpful for improving ADHD symptoms among those with Tourette’s syndrome.  They tested the hypothesis on 10 children (ages 8 to 16) diagnosed with Tourette’s and comorbid ADHD.  Results from the study demonstrated that Guanfacine significantly decreased cognitive errors (commission and omission) and tics (motor and phonic).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7559307

2001: A study published in 2001 analyzed the efficacy and safety of Guanfacine among children diagnosed with tic disorders and ADHD.  A total of 31 participants for the study were recruited from a specialty tic disorders clinic.  Some of the participants would take a placebo, while others would take Guanfacine spanning over the course of 8 weeks.

Participants were evaluated every 2 weeks to verify safety as well as dosing.  Results suggested that after the full 8 weeks of treatment, those taking the Guanfacine improved by 37% according to a teacher-rated ADHD scale.  Those taking the placebo only improved by 8%, suggesting superior efficacy of Guanfacine.

A total of 9 participants receiving Guanfacine were blindly rated in accordance with the CGI scale (Clinical Global Improvement).  According to the CGI scale, they were noted as being “much improved” or “very much improved.”  By comparison, none of the participants receiving the placebo reported any improvement on the CGI scale.

Parental ratings of hyperactivity did not significantly differ between the individuals taking Guanfacine and those taking the placebo.  Very notably was the decrease in errors on the Continuous Performance Test among those receiving the Guanfacine. It was reported that “commission errors” decreased by 22% and “omission errors” by 17%; all errors increased among those receiving the placebo.

Those taking Guanfacine also experienced significant reductions in severity of tics (by 31%) whereas there was no reduction among the placebo group.  No significant adverse reactions were reported.  Researchers concluded that Guanfacine is both an effective and safe intervention for children diagnosed with tic disorders and ADHD.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11431228

2001: A small-scale study in 2001 went as far as to compare the efficacy of Guanfacine to that of dextroamphetamine.  Dextroamphetamine is considered the right-handed stereo-isomer of amphetamine and is the active ingredient of Vyvanse.  It also accounts for 75% of Adderall’s formulation of “mixed amphetamine salts” and is regarded as a highly potent psychostimulant.

This study was conducted on 17 adults that met DSM-IV criteria for ADHD.  The study was considered double-blind and placebo-controlled.  To measure the efficacy of treatment, various scales were used including the: ADHD Behavior Checklist for Adults and Copeland Symptom Checklist for Adult ADD.  In addition, cognitive performance was evaluated thoroughly with the Stroop Test and Controlled Oral Word Association Test.

Results of the study indicated that both drugs significantly reduced ADHD symptoms compared to a placebo.  Both drugs improved cognitive function to a significant extent, and Guanfacine was superior to dextroamphetamine for certain measures (e.g. Color-Word testing).  Although the study was small, there is evidence to suggest that Guanfacine is equally effective to dextroamphetamine and may be superior at improving specific aspects of cognitive function.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11270920

2007: A study published in 2007 documented the fact that Guanfacine was routinely utilized as an off-label ADHD treatment for children and adolescents – years before its actual approval.  Researchers noted that many small placebo-controlled studies have found Guanfacine beneficial for reducing symptoms of attention-deficit/hyperactivity disorder.  They further documented that Guanfacine appears to be effective for the treatment of ADHD in children.

They also suggested that the extended-release formulation of Guanfacine was likely also effective.  The most noteworthy side effect associated with this drug was sedation.  This research was published prior to the FDA’s approval of the drug.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18078429

2008: Prior to the FDA approval of Guanfacine, it was investigated in a study with 240 children (ages 6 to 17) that had been diagnosed with ADHD.  The study was randomized, open-label, and was considered long-term in that it spanned over the course of 2 years.  Researchers were able to gather more evidence regarding the efficacy and safety profile of Guanfacine XR.

The starting dosage of Guanfacine XR was administered at 2 mg per day and titrated to a maximum of 4 mg per day if necessary.  Efficacy was determined by the ADHD Rating Scale (ADHD-RS-IV).  Results of the study suggested that long-term treatment with Guanfacine XR was safe and efficacy was maintained for the full 24 month (2 year) period.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19179940

2009: Another study set out to compare the effectiveness of Guanfacine XR (extended-release) with that of a placebo among children and adolescents diagnosed with ADHD.  The study was conducted in a double-blind, parallel-design, randomized format among those ages 6 to 17.  Baseline ADHD severity was recorded with the ADHD Rating Scale IV (ADHD-RS-IV).

The study spanned over a period of 9 weeks, and participants received either Guanfacine XR in doses of 1 mg, 2 mg, 3 mg, or 4 mg – or a placebo.  Those receiving the Guanfacine XR experienced significant symptomatic reduction according to the ADHD-RS-IV compared to the placebo.  There were some unfavorable side effects reported among Guanfacine users – but most dissipated by the end of the study.

This provides more evidence suggesting that the extended-release format of Guanfacine is effective for reducing symptoms of ADHD.  Though there may be some unfavorable side effects, most aren’t severe and/or resolve throughout the course of treatment.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19106767

2012: By 2012, the FDA had approved Guanfacine XR for the treatment of ADHD in children and adolescents.  Researchers conducted a post-hoc analysis that attempted to highlight the drug’s effect on hyperactivity-impulsivity and inattentiveness.  To accomplish this, the researchers compiled data from 2 large double-blind, placebo-controlled trials with a total of 631 participants.

The ADHD Rating Scale (ADHD-RS-IV) was used to determine symptomatic improvement as a result of Guanfacine treatment.  Specific subscale measures were able to determine levels of hyperactivity-impulsivity and inattentiveness.  Results suggested that Guanfacine XR significantly improved subscale measures of hyperactivity-impulsivity and inattentiveness – compared to a placebo.

This provides more evidence solidifying the already-established efficacy of Guanfacine for the treatment of ADHD.  It doesn’t appear to be more effective for specific types of ADHD compared to others; significant efficacy is attained regardless of subtype.

  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373219/

2013: By 2013, Guanfacine formulations had been formally approved by the FDA for the treatment of ADHD.  However, the long-acting formulation of Guanfacine XR (extended-release) hadn’t been extensively researched.  To gather more data on the safety and efficacy of the extended-release format, researchers conducted a placebo-controlled, double-blind, dosage-optimized study among children ages 6 to 12.

All of the 333 participating children had been formally diagnosed with ADHD.  To measure the effect of Guanfacine, researchers measured symptomatic severity at a “baseline” (pre-treatment) with an ADHD Rating Scale (ADHD-RS-IV).  The children were divided into three groups: the first received Guanfacine XR in the morning + placebo in the evening; the second received a placebo in the morning + Guanfacine XR in the evening; the third received a placebo in the morning and evening.

After 8 weeks of treatment, the ADHD Rating Scale scores were compared to baseline scores.  The two groups taking Guanfacine XR (regardless of morning or evening) experienced significant reduction in ADHD symptoms compared to placebo.  Efficacy didn’t significantly differ among those taking Guanfacine in the morning compared to those taking it at night.

The most common adverse effect from Guanfacine was sleepiness.  Researchers suggested that Guanfacine is an effective as a monotherapeutic treatment for ADHD, regardless of the time of day in which it is administered.  This study verifies both the safety and efficacy of Guanfacine extended-release format among children with attention-deficit/hyperactivity disorder.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23972694

2013: An interesting study was published in 2013 that analyzed the efficacy of Guanfacine compared to the popular non-stimulant drug Strattera (Atomoxetine).  At the time of this study, both of these drugs had been granted FDA approval for the treatment of ADHD.  However, it was unknown as to whether one drug was likely to be universally more effective than the other for symptomatic reduction.

Although no head-to-head studies had been conducted comparing these two drugs, researchers used a “matching-adjusted indirect comparison” (MAIC).  This is a method that accounts for individual patient data from clinical trials as well as cumulative data to estimate the “relative efficacy” of each drug.  This type of comparison may be less accurate than a direct head-to-head comparison, but is still thought to provide realistic data.

Studies included in the analysis were only those that had comparable trial designs and characteristics.  Researchers compared the efficacy of the drugs by utilizing ADHD Rating Scale (ADHD-RS-IV) scores.  Results from the study suggested that Guanfacine XR (extended-release) was superior in efficacy to Strattera (Atomoxetine) for the treatment of ADHD.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23975660

2014: It is known that many children with ADHD have comorbid sleep problems.  Researchers conducted a study to analyze the impact of Guanfacine XR (extended-release) on 29 children (ages 6 to 12) with ADHD and sleep abnormalities.  They specifically utilized polysomnography (PSG) to track the impact of Guanfacine XR on sleep.

Polysomnography is capable of measuring brain waves, oxygen levels (in blood), heart rate, breathing, and bodily movements.  The study was double-blind, randomized, and placebo-controlled and spanned over the course of approximately 5 weeks.  Guanfacine XR was found effective for reducing symptoms of ADHD, total sleep time was actually reduced among those taking Guanfacine XR compared to a placebo.

This research verifies that Guanfacine remains an effective option for ADHD, but should not be regarded as a drug to improve sleep among those with sleep disturbances.  That said, this was a small scale study and was only conducted among children.  It is unknown whether the same effects would be observed in adolescent and adult populations.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25376194

2014: In 2014, researchers reviewed evidence of Guanfacine’s efficacy for the treatment of ADHD; both as a monotherapy and adjunct.  They specifically focused on studies conducted in children and adolescents (ages 6 to 17).  To conduct the analysis, researchers scoured both PubMed and PsychInfo from 1990 to 2014 and included all controlled or open trials.

Based on the cumulative body of evidence, researchers concluded that Guanfacine is an effective treatment for ADHD among individuals 6 to 17 years old.  Although it is regarded as a second-line treatment, it is still clinically effective and also can be utilized as an adjunct to psychostimulants.  Evidence documenting its efficacy is greater among adolescent populations than children.

This review provides more evidence to support the efficacy of Guanfacine for ADHD.  Study authors go as far as to suggest that it may be a beneficial drug for ADHD-related comorbidities.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24992513

How Guanfacine Treats ADHD: Mechanism of Action

It is relatively unclear regarding the specific mechanisms by which Guanfacine is able to reduce ADHD.  It functions as an Alpha-2 adrenergic agonist, which stimulates adrenergic receptors in the brain – specifically the Alpha-2A receptor.  The Alpha-2A receptor can be located on presynaptic norepinephrine neurons and other various postsynpatic neurons.

Norepinephrine alteration: The agonist effect of Guanfacine on presynaptic norepinephrine neurons results in a reduction of norepinephrine release.  This also minimizes activity of norepinephrine neurons in the locus coeruleus (LC).  It also elicits potent agonist effects upon postsynaptic neurons.

Prefrontal cortex functionality: The mechanism by which Guanfacine reduces ADHD is thought to be related to its effect on the prefrontal cortex (PFC).  Specifically, Guanfacine bolsters prefrontal functionality – thereby improving ADHD-related prefrontal dysfunction.  This results in improved attention, reduced impulsivity, and less hyperactivity.

Increased connectivity: Electrically, Guanfacine has been shown to increase connectivity between various prefrontal cortex networks.  Neurophysiological data indicates that Guanfacine stimulates Alpha-2A receptors on the dendritic spines of pyramidal cells.  It achieves this effect by inhibiting production of cAMP, which triggers a cascade effect that results in a closing of ion channels.

Closing ion channels: When ion channels are open, membranes can “leak” and dysfunction ensues. By closing the ion channels, prefrontal network firing improves – which contributes to significant improvements in both attention and behavior.  As a result, there is also likely increased blood flow to the prefrontal cortex as a result of Guanfacine’s mechanism.

It may also help regulate the release of norepinephrine throughout the brain – specifically from the locus coeruleus. In cases of ADHD, the locus coeruleus fires at irrelevant stimuli – thereby resulting in distractibility.  Guanfacine regulates the release of norepinephrine in the locus coeruleus, and therefore only fires when necessary to improve attention.

  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526381/

Advantages of using Guanfacine for ADHD

Below is a list of advantages associated with using Guanfacine for the treatment of ADHD.

  • Adjunct option: Guanfacine is a clinically proven drug for ADHD, but can also be used as an adjunct to a psychostimulant.  It is thought that the effect of Guanfacine may act synergistically to the effect of a psychostimulant drug like Adderall.  The combination of the two drugs may improve attention better than either drug in monotherapeutic format.
  • Alternative mechanism of action: The mechanism of action for Guanfacine is unlike most ADHD medications.  It functions as an Alpha-2A adrenergic receptor agonist and improves attentional deficits by strengthening connectivity in the prefrontal cortex.  Some may prefer this drug to psychostimulants for the fact that it will not increase stimulation to the point of anxiety.
  • Anxiety reduction: There is some evidence to suggest that the drug decreases anxiety.  While it may not successfully treat anxiety disorders, it is commonly prescribed off-label for anxiety reduction.  It accomplishes this by toning down activity in the peripheral branch of the sympathetic nervous system.
  • Appetite neutral: Those taking the drug are unlikely to experience any significant change in appetite.  Many people taking psychostimulants report feeling satiated despite a lack of actual food intake.  Individuals that don’t want to compromise their appetite with a psychostimulant may prefer Guanfacine.
  • Blood pressure reduction: Should an individual have high blood pressure in addition to ADHD, this drug may successfully treat both problems simultaneously.  Those with high blood pressure may be satisfied with the reduction in both systolic and diastolic blood pressure from Guanfacine.
  • Calm focus: Some people report feeling over-hyped or too stimulated with psychostimulant-based medications.  Guanfacine is capable of producing a calmer focus and actually reduces activity in the sympathetic nervous system – a branch of the autonomic nervous system responsible for producing stress.
  • Children / adolescents: Many studies have analyzed the effect of Guanfacine for treating ADHD in children and adolescents.  The drug’s track-record is considered slightly better for adolescents than children, but it is safe and effective in both populations.  Those that don’t want their children taking a psychostimulant may opt for Guanfacine.
  • Extensively researched: This isn’t some “brand new” drug just hitting the market with little research.  It has been approved since the 1980s as an antihypertensive drug, and researched since the early 1990s for the treatment of ADHD.  The long-term safety of Guanfacine is well-established.
  • Side effects: There aren’t significant side effects associated with Guanfacine other than sedation.  In most cases, the side effects will be transient and will subside as an individual continues treatment.  This makes Guanfacine universally well-tolerated.
  • Weight neutral: Those that are underweight, skinny, or trying to gain weight may have a difficult time coping with the weight loss on psychostimulants.  Psychostimulants act as dopamine reuptake inhibitors (DRIs) and suppress appetite, speed metabolism, and increase physiological energy.  Guanfacine is weight neutral in that you shouldn’t gain or lose weight as a result of treatment.
  • Withdrawal: Those discontinuing psychostimulants often face severe withdrawal symptoms such as: fatigue, low energy, sleepiness, and cognitive impairment.  Discontinuation of Guanfacine isn’t associated with severe withdrawal symptoms.  In fact, some may argue that there are no significant discontinuation effects from Guanfacine.  Compared to Adderall withdrawal, discontinuing Guanfacine is nothing.

Source: http://www.ncbi.nlm.nih.gov/pubmed/7007059

Disadvantages of using Guanfacine for ADHD

Below are some disadvantages associated with using Guanfacine for the treatment of attention-deficit/hyperactivity disorder.

  • Brain fog: Despite the fact that the drug ramps up prefrontal activity, this doesn’t always translate to attentional improvements.  The fact that the drug reduces activity in the sympathetic nervous system may result in reduced arousal, which may promote increased brain fog.  Additionally, the sedation experienced as a side effect may also contribute to a worsening of attention span.
  • Low blood pressure: Those who have low blood pressure may want to avoid Guanfacine.  This is a medication that will further reduce blood pressure, which could result in adverse effects.  Low blood pressure can cause dizziness, weakness, fatigue, and impairment in concentration – the exact opposite of what people with ADHD need.
  • Potency & efficacy: Many doctors only prescribe Guanfacine as a second-line option.  In other words, traditional psychostimulant treatments are first tested due to increased potency.  While comparative studies suggest that Guanfacine may be of equal efficacy to psychostimulants, most experts believe that psychostimulants are superior in efficacy due to their ability to increase dopamine levels.
  • Sedation: Some studies estimate that 1/3 individuals taking Guanfacine will experience sedation.  In many cases the sedation is transient and will subside over time, but in other cases the sedation is problematic for functioning.  If you feel too sedated to exercise, work, and have low energy – you may dislike Guanfacine.
  • Sleep time: One study speculated that Guanfacine would improve sleep.  Researchers found that Guanfacine actually reduced sleep time, despite increases in sedation.  Based on the results from that study, some may find that Guanfacine reduces sleep time and possibly impairs sleep quality.

Is there any evidence to suggest Guanfacine is ineffective?

There is no evidence to suggest that Guanfacine is ineffective for the treatment of ADHD.  Nearly every published report indicates that Guanfacine is significantly more effective than a placebo for the treatment of ADHD.  In a small-scale study comparing Guanfacine to dextroamphetamine, it was found to be just as effective for reducing ADHD symptoms and even more effective for specific cognitive functions.

Is using Guanfacine plus a psychostimulant more effective?

There is no formal evidence suggesting that utilizing Guanfacine as an adjunct to a psychostimulant is more effective for treating ADHD than a standalone psychostimulant.  In most cases efficacy of a combination (Guanfacine plus a psychostimulant) compared to a psychostimulant monotherapy is subject to individual variation.  That said, some researchers speculate that the combination may provide synergistic effects, thus eclipsing efficacy of monotherapeutic options in select individuals.

Optimal usage of Guanfacine for ADHD: Who is most likely to benefit?

Guanfacine is generally effective for individuals with ADHD, however some individuals may derive additional benefit from the drug based on comorbid diagnoses or conditions.

  • Anxiety disorders: Despite the fact that Guanfacine isn’t formally approved to treat anxiety, it is thought to be helpful.  It is commonly prescribed to help reduce anxiety associated with drug withdrawal and reduces sympathetic stimulation.  Therefore if you have ADHD with comorbid anxiety (or vice-versa) – this could be an effective option.  It may be preferred over benzodiazepines due to the fact that benzodiazepines are linked to dementia, have a rapid-tolerance onset, and are addictive.
  • Certain ADHD subtypes: There appears to be no significant evidence that Guanfacine is better at targeting hyperactivity compared to inattentiveness.  That said, the evidence for no superior efficacy for one subtype over the other is limited to one scientific review.  Due to the drug’s mechanism of action, some speculate that it may be superior for those with ADHD influenced by sympathetic overactivation (e.g. the overfocused subtype).
  • Hypertension: Those with high blood pressure may derive additional benefit from Guanfacine due to the fact that it is approved to treat hypertension.  If you have both high blood pressure and ADHD, or high blood pressure caused by a psychostimulant, this drug may be an effective intervention.
  • Poor response to psychostimulants: Not everyone responds favorably to psychostimulants.  Some people cannot tolerate the high degree of physiological stimulation, while others don’t derive enough benefit from psychostimulant drugs.  In the event that a person achieves a suboptimal response to psychostimulants, Guanfacine may be helpful.
  • Stress: Those with ADHD and high stress, or even stress that exacerbates ADHD symptoms may benefit from Guanfacine.  The drug clearly targets the sympathetic nervous system, which helps mitigate the stress response.  In addition, it ramps up prefrontal cortex activity which can buffer both stress and ADHD.
  • Tourette’s syndrome: Guanfacine has been found effective for treating inattentiveness, impulsivity, and hyperactivity related to Tourette’s syndrome.  It also has been proven to decrease the intensity and number of “tics” experienced.  This drug may be an optimal intervention for those with Tourette’s syndrome and ADHD.

How does Guanfacine compare to Clonidine for ADHD?

Both Guanfacine and Clonidine are considered Alpha-2 adrenergic agonists.  They’ve each been granted FDA approval for the treatment of hypertension as well as ADHD.  The mechanisms by which they target ADHD are thought to be similar.  However, there are some subtle differences in the mechanisms that may result in certain individuals responding better to one versus the other based on individual neurophysiology.

Clonidine stimulates all three Alpha-2 receptor subtypes including the A2A, A2B, and A2C – plus it stimulates the imidazoline receptor.  Guanfacine only stimulates the Alpha-2A (A2A) receptor, meaning it is more selective than Clonidine.  Clonidine is regarded as being nearly 10x greater potent than Guanfacine at presynaptic receptors, whereas Guanfacine is more potent at postsynatpic receptors.

There appears to be no significant difference in efficacy between these two drugs – certain individuals may respond better to one over the other.  Side effect profiles are similar between the two drugs, as are discontinuation symptoms. Clonidine may be slightly more effective for treating ADHD-related sleep abnormalities compared to Guanfacine – which has been shown to reduce sleep time.

Have you used Guanfacine for ADHD?

If you’ve used Guanfacine to treat your ADHD, feel free to share your experience in the comments section below.  To help others get a better understanding of your situation, discuss the dosage of Guanfacine you took, how long you’ve used it, and whether you took it as a standalone treatment or adjunct to a psychostimulant.  If you took it as an adjunct, mention whether you subjectively noticed an increased reduction in ADHD symptoms when it was added.

If you found that the drug was ineffective, exacerbated your ADHD, or triggered unwanted side effects, also mention it.  Those who were taking the drug to treat hypertension may also comment discussing whether it noticeably enhanced cognitive function – specifically related to inattentiveness, hyperactivity, and/or impulsivity.

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