Pretest self-assessment question (answer at the end of the case)
What pharmacologic properties of quetiapine (Seroquel) lend themselves to providing clinical antidepressant and anxiolytic properties?
A. 5-HT1A partial receptor agonism (similar to buspirone [BuSpar], vilazodone [Viibryd])
B. Norepinephrine reuptake inhibition (NRI) properties (similar to bupropion-XL [Wellbutrin-XL])
C. Histamine-1 (H1) receptor antagonism (similar to hydroxyzine [Vistaril], doxepin [Silenor])
D. Selective serotonin reuptake inhibitor (SSRI) properties similar to fluoxetine (Prozac)
E. GABA-A receptor modulating properties similar to diazepam (Valium)
F. A, B, and C
G. All of the above
Patient evaluation on intake
83-year-old man states he has been anxious for at least 40 years and is not getting better in the primary care setting
Psychiatric history
Onset of GAD in his 40s. Has fluctuating course of GAD ranging from mild to incapacitating. He states he has always had some level of anxiety and cannot recollect a substantial anxiety-free period
He was actually doing well per his standards until about 18 months prior to the first office visit and felt his medications “controlled” his anxiety but did not alleviate it
Has had increasing medical problems with age and has developed a hypochondriacal component to his GAD. He has become increasingly concerned about death and dying as a result of his medical issues, which is felt to be adjustment-based and somewhat set in reality, but he also has marked anxiety about medications and their possible side effects shortening his life further
A review of psychiatric symptoms surprisingly shows no depression, psychosis, mania, other anxiety disorder, SUD, or personality disorder
He had two to three voluntary, private psychiatric hospitalizations in the 1970s due to insomnia and worry. He states insomnia is a chief complaint again now. He has had no suicide attempts
– In the past he has gone to eclectic, supportive psychotherapy but has had no formal CBT or PDP interventions
– He has been treated pharmacologically by his PCP
Previous medication trials included:
Social and personal history
Is married
Gainfully employed in the engineering field for 50 years and is now retired and financially stable
Was once very active but his medical problems have now precluded him from many of his usual activities
Does not drink alcohol, smoke cigarettes, or take drugs of abuse
Medical history
Has survived prostate cancer
Myelodysplastic syndrome requires transfusions with transient iron toxicity
Osteoporosis
HTN
Family history
Denies significant family mental health issues
Current psychiatric medications
Current medical medications
Question
Based on what you know about this patient’s history and current symptoms, would you consider him to be suffering from treatment-resistant anxiety (TRA)?
Yes
No
What type of treatment might you suggest next?
Maximize his doxepin (Sinequan) to full TCA therapeutic dosing
Add a BZ–sedative in combination
Add or switch to buspirone (BuSpar), a 5-HT1A partial agonist anxiolytic
Switch to an SNRI like: venlafaxine-XR (Effexor-XR), duloxetine (Cymbalta), desvenlafaxine (Effexor-XR), levomilnacipran (Fetzima)
Refer for CBT
Attending physician’s mental notes: initial evaluation
Patient has marked chronic history of non-comorbid GAD. He has never been symptom free but has had relatively long periods of well-controlled symptoms that are mild in nature
Patient had 10–20 years of effective care with moderate-dose BZ sedatives. Why were these stopped? Addiction? Ataxia? Apnea?
TRD is gaining ground as a clinical entity and approvals exist for TRD (olanzapine–fluoxetine combination [Symbyax], VNS, TMS, quetiapine [Seroquel])
He appears to have much hypochondriacal thought, which may make prescribing side effect-prone medications tenuous and hurt compliance
Collaboration with primary care and/or hematology is warranted
Geriatric age may make dosing psychotropics proceed slowly and cautiously
Further investigation
Is there anything else you would especially like to know about this patient?
Does he really have no psychiatric comorbidity, and does his medical history contribute to his anxiety?
– Hypochondriasis (illness anxiety disorder in the DSM-5) is defined as a preoccupation with fears of having, or the idea that one has, serious disease based on the person’s misinterpretation of bodily symptoms This type of anxiety must persist despite appropriate medical evaluation and reassurance. In addition, it cannot be better accounted for by GAD. This patient reports that his anxiety symptoms regarding medical health really began a few years back when he started to have significant medical problems such as cancer. Prior to this, he reports that he was not preoccupied with his medical conditions or symptoms
Primary insomnia occurs when the predominant complaint is difficulty initiating or maintaining sleep, or having non-restorative sleep. The insomnia must cause significant distress or impairment. Previously, it was felt that insomnia must not occur exclusively during the course of another mental disorder such as MDD or GAD
– However, the DSM-5 allows insomnia to be a stand-alone, comorbid psychiatric entity if it is a focus of clinical attention. It may not need to be declared if insomnia is primary, or secondary to another psychiatric or medical disorder
– This patient reports classic “clock-watching” fear and phobia at nighttime. He reports these symptoms began after reading a report that patients who sleep less than eight hours are more likely to die of cardiac arrest
Adjustment disorder is the development of an emotional or behavioral set of symptoms in response to an identifiable stressor. These symptoms are clinically significant in that the patient shows marked distress that is in excess of what would be expected from exposure to the stressor or that the patient has significant impairment in functioning. Again, for this DSM-5 diagnosis, the adjustment does not meet criteria for MDD, anxiety disorder, etc. This patient’s GAD symptoms have been ongoing for many years, but they seem to be exacerbated by adjustment-related issues due to his age, more severe medical conditions, threat of mortality. His insomnia and illness anxiety seem to fit under the rubric of generalized anxiety, but chronologically seem to be fueled by real-world stressful issues causing an exacerbation of GAD symptoms
Iron deficiency/iron toxicity: iron deficiency often results in anemia and a clinical picture more consistent with depression or dementia. Iron toxicity, however, is mostly asymptomatic. Nonspecific early symptoms (such as abdominal discomfort and fatigue) may delay diagnosis until severe damage to the heart or liver produces clinically apparent symptoms. Anxiety exacerbation is not typical
Question
Based on what you know about this patient’s history, current symptoms, and treatment responses, do you think that a bona fide, formal trial of established psychotherapy is warranted?
Attending physician’s mental notes: initial evaluation (continued)
The patient is clearly suffering from a baseline of moderate to severe GAD, which appears to be complicated by adjustment disorder. He is reaching the end of his life span and is having pertinent medical issues that have increased his anxiety about mortality. As a result, he is much more functionally fixated about bodily sensations, side effects, and minor medical issues, which makes him appear to have illness anxiety
The patient also seems very fixated about obtaining adequate sleep and has developed intense fear about a lack of sleep and the impact it will have on his life span. Insomnia is clearly part of GAD, but this patient’s intense fear may need to be addressed clinically in a similar manner as the phobia associated with primary insomnia
The recent PCP has done an excellent job of escalating two antidepressant agents and adding a third antidepressant that is known for inducing sleep. He has “gone the distance” likely as much as a primary care clinician can for treating this TRA. The patient, therefore, is currently on a therapeutic and reasonably aggressive psychopharmacology regimen, but without a response
Again, if the combination of SSRI plus a BZ has been effective in the past, why have BZs not been used recently? There is no history of obstructive apnea, gait instability, cognitive impairment, addiction, etc.
Case outcome: interim follow-ups through one month
The patient is medically cleared in that there is no obvious contribution of his medical problems with regard to causing his psychiatric problems. His red cell count and iron levels are adequately monitored and treated. His blood pressure is well controlled. There is no evidence of metabolic disorder
The patient was offered a formal trial of CBT to address his generalized anxiety and phobia issues but he declined
As the patient seemed relatively comfortable on his current set of medications with regard to tolerability, knowing that he would have anxious difficulty changing medications or adding new medications, it was decided to keep him on the current medications
However, augmentation with the previously tried “as needed only” BZ, lorazepam (Ativan), was discussed. The patient states that he had no issues with the sedatives outside becoming aware that they were possibly addictive, which made him and his wife worried; therefore, he stopped them. With permission, this was also discussed with his spouse who corroborated his story
Lorazepam (Ativan) 0.5 mg/d was initiated as a standing dose and added to the current medication regimen
Question
If the patient responds dramatically to the addition of this BZ, what would you consider next?
Continue all four medications. He has treatment-resistant GAD and this pharmacodynamic regimen of complex polypharmacy is likely required to prevent relapse
As he was minimally responsive to maximal doses of escitalopram (Lexapro) and mirtazapine (Remeron), his marked recovery on the BZ suggests that the antidepressant treatments are no longer needed and they should be systematically tapered off
Continue the fully dosed, therapeutic escitalopram (Lexapro) and mirtazapine (Remeron) but discontinue the subtherapeutically dosed doxepin (Sinequan) in order to streamline his medications
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