Case debrief

Both patients were treated with the “start low, go slow” geriatric pharmacology mantra

Both were given more monotherapies than polypharmacy approaches

Both patients received psychotropics from all major classes

Sadness and dysphoria seemed to be easily treated

However, a docile indifference and apathy were left as residual symptoms that were untreated despite use of several classes of antidepressants, stimulants, and even ECT in one of the patients

During the course of treatment, all laboratory values were normal

CT, MRI, and positron emission tomography (PET) scans were also ordered

• – In Patient #1, findings revealed slight hypoactivity in temporal lobes and mild ventriculomegaly, suggesting a picture of early Alzheimer’s disease and possible vascular disease versus age-associated degeneration

• – In Patient #2, generalized atrophy was also noted but no activity difference among various brain areas

• – Both patients had some subcortical infarcts and leukomalacia

Take-home points

These imaging findings are not necessarily classic for vascular depression due to the absence of marked numbers of subcortical lacunar infarcts

It is more likely that these patients suffer from DEFS as there were minimal subcortical lesions but overall atrophy instead

Clinically, these two patients were not psychomotor impaired, suggesting less subcortical neurodegenerative damage, but felt to have more atrophy and cumulative disruptions of frontocortical tracts allowing for the clinical presentations noted

Both patients exhibited executive dysfunction and had little familial genetic depression loading or risk

• – The absence of psychomotor slowing, presence of executive dysfunction, and lack of familial risk factors again suggests that DEFS might be a better working diagnosis than vascular depression or dementia

• – Often these vascular depression and DEFS patients are minimally responsive to serotonergic antidepressants, as was found in this case

• – However, they were also unresponsive to all antidepressants as well

Tips and pearls

MDD, vascular depression, and DED all involve similar clinical presentations and symptomatology

The following table suggests ways to better delineate each clinical entity

The following images help to visualize how neurocircuitry, when degraded by infarcts, aging-related atrophy, and neurodegenerative dementia processes, may disrupt usual brain functioning and allow psychiatric symptoms to develop

• – Any breakage in this circuitry could allow for executive dysfunction symptoms. In these cases, apathy may have developed as the frontal cortex does not receive impulsive drive or initiative signals from subcortical structures due to neuronal tract disruption via aging-related atrophy

Several important prefrontal corticocortical circuits are shown. The anterior cingulate cortex (ACC) has corticocortical interactions with the dorsolateral prefrontal cortex (DLPFC) and the orbital frontal cortex (OFC). The OFC, in turn, has corticocortical interactions with the hippocampus (H). The DLPFC has only sparse direct connections with the amygdala (A) and hippocampus.

This three-dimensional figure depicts a hypothetical corticostriatal–thalamic–cortical (CSTC) neural loop, or circuit, for executive functions, which involves the DLPFC and the rostral (top) part of the caudate within the striatal complex

There are many CSTC loops that also connect brain areas together, and when in balanced communication, psychiatric symptoms are not present

• – Again, if damage or atrophy occurs anywhere along these neural circuits (depending on which prefrontal region is involved), psychiatric symptoms may develop as one brain area may now be hypofunctioning while others are hyperfunctioning. This imbalance may allow for clinical psychiatric symptoms to manifest

• – In these cases, the patients seemed to have no drive to move off their couches. If the depicted neural loop were disrupted, the patients may not have been aware that so much time had passed while sitting on the coach and may have developed an inability to plan and schedule their days as part of their executive dysfunction symptomatology

Table 7.1. Symptoms of major depression, vascular depression, and depression–executive dysfunction syndrome

Presentation	Major depression	Vascular depression	DED
Full DSM symptoms possible	+	+	+
Psychomotor slowing predominant	+/−	+	−
Indifference/apathy predominant	+/−	+	+
Executive dysfunction predominant	+/−	+	+
Caused by lacunar infarcts and medial frontal lobe dysfunction	−	+	−
Caused by brain atrophy, other etiologies, and frontocortical tracts dysfunction	−	−	+

Figure 7.1. Key corticocortical circuits.

Figure 7.2. Hypothetical corticostriatal–thalamic–cortical loop for executive function.

Posttest self-assessment question and answer

Which are correct regarding vascular depression?

A. There is evidence that cerebrovascular disease creates vulnerability to depression, as well as cognitive impairment and peripheral neurologic signs

B. Clinical presentation suggests a medial frontal lobe syndrome with psychomotor retardation, apathy, and marked disability

C. Cerebrovascular lesions on neuroimaging results in poor outcomes, including persistence of depression with unstable remission and increased risk for dementia

D. DED is similar but may have multifactorial causes, that is, vascular disease, aging-related changes, degenerative brain disease, combined in a cumulative or synergistic effect

E. All of the above

Answer: E

Vascular depression assumes that there are vascular insults in subcortical brain areas usually involving lacunar infarcts or leukomalacia around the ventricles. These injuries disrupt neural connections, most likely in mediofrontal areas, causing the symptoms noted in (B) and the clinical outcomes noted in (C). DED is similar but posits that there still may be frontocortical disruptions, but vascular insults are not necessarily required; rather atrophy and cell death may cause the disruptions alone. The final common pathway of neurocircuitry disruption may yield apathy, executive dysfunction, and psychomotor impairment, which appears similar to those symptoms noted in MDD. In both of the cases described here, the patients’ affective depression symptoms responded somewhat. They were not sad. Their brain atrophy and its resultant apathy and executive dysfunction symptoms did not respond to treatment.

References

1.Stahl SM. Stahl’s Essential Psychopharmacology, 4th edn. New York, NY: Cambridge University Press, 2013.

2.Stahl SM. Stahl’s Essential Psychopharmacology Prescriber’s Guide, 5th edn. New York, NY: Cambridge University Press, 2014.

3.Alexopoulos GS, Meyers BS, Young RC, et al. ‘Vascular depression’ hypothesis. Arch Gen Psychiatry 1997; 54:915–22.

4.Alexopoulos GS. The vascular depression hypothesis: 10 years later. Biol Psychiatry 2006; 60:1304–5.

Patient file

The Case:

The lady who had her diagnosis altered

The Question:

When are symptoms psychotic or dissociative?

The Psychopharmacological dilemma:

Finding an effective treatment for dissociative, depressed, psychotic patients while not ruining the outcomes of their previous bariatric weight-loss surgeries

Pretest self-assessment question (answer at the end of the case)

Which of the following approaches likely has the most evidence to support its use as a weight-loss strategy in patients suffering from antipsychotic-associated weight gain (AAWG)?

A. Orlistat (Xenical)

B. Sibutramine (Meridi 4)

C. Fenfluramine (Pondi Min)

D. Topiramate/phentermine combination (Q-Symia)

E. Metformin (Glucophage)

F. Naltrexone/bupropion combination (Contrave)

G. Lorcaserin (Belviq)

H. Bariatric surgery