Pretest self-assessment question (answer at the end of the case)
How does an alpha-2a receptor agonist really improve attention?
A. It lowers brainstem NE output similar to its antihypertensive effects
B. It promotes DA activity in the DLPFC secondarily
C. It lowers GABA activity, which allows greater glutamate activity in the thalamus
D. It allows fine tuning of cortical pyramidal glutamate neurons to improve signal to noise ratios in frontocortical information processing
Patient evaluation on intake
31-year-old man with a chief complaint of anxiety of “different types”
Patient states that he “has been successful in graduate school, has financial worries, but states that he worries and is tense most of the time”
Psychiatric history
Has been anxious for many years, mostly since college and now graduate school
Working part-time and going to school part-time and feels “torn in many directions”
Generally is tense, restless, irritable, and worries about things even outside school and work
– When legitimate stressors diminish, the anxiety lowers, but is still present and discouraging
This causes him to be argumentative and temperamental most of the time
He says he is active and likes to stay busy all of the time, but he wonders if “he is doing too much, as he has no time for all of the things” he wants to do
Social and personal history
Graduated high school, college, and is enrolled in a graduate-level training program for family counseling
Gainfully employed now in a clinical setting
Married and without children
Does not use drugs or alcohol
Family history
Father has AUD
Distant family members have probable bipolar disorder
Medication history
There was serendipitous anxiety relief when his PCP placed him on hydroxyzine (Vistaril) 50 mg/d for an allergic skin reaction
– This helped to “calm him down” but was only temporary
Has taken the SSRI paroxetine (Paxil) 40 mg/d but had a difficult time balancing its anxiolytic effects and its sexual side effects
Next, he responded to a radio advertisement for an anxiety research study and he was placed on an SGRI antiepileptic, tiagabine (Gabitril), as an augmentation strategy, which he found moderately beneficial at a dose of 12 mg/d
Psychotherapy history
Patient has seen a few psychotherapists for both supportive psychotherapy and PDP
He reports having psychological issues regarding his father, who was abusive and an alcoholic
– Psychotherapy has been very helpful
– There is no DSM-5 evidence of PTSD despite this history
Patient evaluation on initial visit
Patient suffers from chronic GAD symptoms that fluctuate over time
Clear stress-based, adjustment disorder-driven causes of anxiety are superimposed over a baseline of persistent GAD symptoms
Despite these symptoms, he is coping fairly well at work and in relationships
Has been compliant with medication management, but has somewhat fragmented care in that he was seeing different providers who were monitoring his individual medications separately
Does not appear to be at risk for any suicidal attempts
Experiences minor sexual side effects and fatigue from his current medications
Question
In your opinion, does this combination of medications make clinical sense?
Yes
No
Attending physician’s mental notes: initial evaluation
This patient has chronic GAD without many comorbidities
His GAD exacerbations are often triggered by social stressors
He is motivated, bright, and compliant
His medication regimen is interesting, and even though it was provided by three different clinicians, it makes rational sense
– First, the paroxetine-CR was causing side effects at higher doses, thus augmenting with other agents while keeping paroxetine-CR at a low therapeutic dose makes clinical sense
– Second, hydroxyzine (Vistaril/Atarax) was being used as an anti-allergy medication, but it is approved as an antihistaminergic anxiolytic
– Third, tiagabine (Gabitril) is an anti-epilepsy medication that has failed monotherapy trials in GAD and PTSD, but has some supportive data as an augmentation strategy for TRA when combined with SSRIs
It is a GAT1 GABA reuptake inhibitor that functions to increase endogenous synaptic GABA levels
Idiosyncratically, this may cause seizures in non-epileptics who are prescribed this medication in off-label situations
– Fourth, this regimen facilitates serotonin by blocking the SERT, or reuptake pump, antagonizes histamine activity at the H1 receptor, and facilitates GABA by blocking GAT1 transporters
All of these mechanisms are complementary, do not overlap in pharmacodynamic redundancy, and look to manipulate neural pathways involved in the etiology of anxiety
Question
Which of the following would be your next step?
Increase the paroxetine (Paxil-CR)
Increase the tiagabine (Gabitril)
Increase the hydroxyzine (Vistaril)
Augment the current medications with a fourth agent such as an NRI, a 5-HT1A receptor partial agonist, or a BZ anxiolytic
Consider him a partial responder on this regimen, which is unacceptable, and streamline and convert him to a less complicated regimen with an SNRI, TCA, or MAOI monotherapy
Attending physician’s mental notes: initial evaluation (continued)
The combination the patient presents with is a good one, covering many mechanisms of action that are individual, yet complementary
There is a significant family history of addiction, so avoiding BZs makes sense
He has room to increase any one of his three current medications, but this will likely exacerbate his sexual and fatigue-based side effects further, which the patient will not appreciate
Further investigation
Is there anything else you would especially like to know about this patient?
What about details concerning his past trauma history?
– Grew up in less than ideal circumstances with an alcoholic and verbally abusive father
– Denies overt reliving symptoms but clearly has hyperarousal (worry, muscle tension) thought currently to be from GAD
– Denies avoidant or phobic behavior
– Feels psychotherapy has been very helpful
What about details regarding personality style and coping skills?
– The patient is socially engaging, hard working, and very active
– If he is not working, he is exercising and being active
– Never seems to sit still as he has always been a busy person
– Keeping busy and exercising allows him to remain calm and more focused
– Feels he would be distracted and less attentive if he did not have time to exercise
Case outcome: first interim follow-up visit four weeks later
Declines escalating the SSRI due to sexual side effects
Felt tiagabine (Gabitril) dosing is reasonable but mildly fatiguing
As hydroxyzine (Vistaril/Atarax) is the lowest therapeutically dosed of the three, he opts to increase this up to 100 mg/d at the risk of daytime sedation
– Returns acknowledging the same symptoms as his first appointment
– States that he is too tired on the increased hydroxyzine dose to continue it
Question
Do you find hydroxyzine a reasonable anxiolytic?
Yes, for short-term, adjustment-based anxiety symptoms
Yes, for longitudinal anxiety treatment
Yes, especially for use in patients who cannot risk taking a BZ anxiolytic, i.e., addictive patients
Yes, for treating GAD and agitation but not for PD or OCD
No
Attending physician’s mental notes: second interim follow-up visit at two months
This was easy in that escalating the SSRI seems to be helping gradually
He is now about 50% better with global improvement in his GAD symptoms and agrees to continue the SSRI and off-label SGRI
Will need to discuss with him long-term maintenance on the SSRI and also some pharmacologic antidotes if his sexual side effects become intolerable or threaten poor medication adherence in the future
Tiagabine (Gabitril) has a limited evidence base where switching from an SSRI to tiagabine monotherapy may maintain efficacy while alleviating SSRI sexual dysfunction
Case outcome: second interim follow-up visit at two months
The patient is tapered off hydroxyzine altogether and begrudgingly agreed to try a higher dose of paroxetine (Paxil-CR) at 37.5 mg /d while continuing the tiagabine (Gabitril) 12 mg/d
– A moderate reduction in anxiety symptoms occurs
– There were greater sexual side effects noted
– Can see the benefit of the increased SSRI dosing
Felt to be 20%–30% better compared to the last appointment
Question
If he continues toward full symptom remission, but develops major sexual side effects, what would you do?
Just switch to tiagabine (Gabitril) monotherapy
Lower the SSRI and try a less sexual side effect-prone drug, such as bupropion-XL (Wellbutrin-XL), trazodone-ER (Oleptro), mirtazapine (Remeron), vilazodone (Viibryd)
Add bupropion-XL (Wellbutrin-XL) at doses of 300 mg/d or more to the SSRI/SGRI combination to alleviate his sexual dysfunction
Add buspirone (BuSpar) to alleviate his sexual dysfunction
Add sildenafil (Viagra) to alleviate his sexual dysfunction
Lower the SSRI and switch to a BZ as they have lower incidence of sexual side effects
Case outcome: interim follow-up visits through five years
The patient completes graduate school and finds a permanent job in his field of choice
Reports much new performance anxiety and hyperarousal around this
There is now stress in other areas of his life as well, but these create more dysphoria and despondency suggesting possible onset of depressive illness
Tolerates the same medication regimen with good effects until late in his fifth year of treatment when the adjustment issues and his GAD symptoms begin to escalate
Begins seeing his psychotherapist again, and is unwilling to increase his SSRI any further
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