Psychopharmacology’s blind spot
As I started to discuss in a previous post, psychopharmacology has a blind spot: the accumulation of antidepressants (ADs) in human brains over time. And I don’t just mean the accumulation that occurs during the weeks to months minimally required for a person to respond positively to ADs, but also the long-term accumulation following years of chronic AD use. Unfortunately, the blind spot is exacerbated by reports of trace amounts of ADs in the serum and cerebral spinal fluid (CSF) of responders, which only encourages psychopharmacologists to dismiss AD accumulation as gratuitous. However, serum and CSF drug levels don’t accurately census subcellular and membranous reservoirs of ADs, which old theory predicts and new experiments bear out.
In order to eliminate this blind spot, psychopharmacologists have to stop ignoring the direct effects of ADs on membranes, even if some of these effects are observed in cellular models in the lab or at doses that are ostensibly “too high” to be clinically relevant. (For more on the specious “too high” concentration argument, see my recent post about worms on Prozac). That’s obviously easier said than done.
So let’s start where we have consensus. First, everyone agrees that ADs (tricyclics + SSRIs) are slow acting. Second, everyone agrees that the effects of ADs on serotonin reuptake are fast. The uncertainty arises when atttempts are made to reconcile the rapid inhibition of serotonin reuptake by ADs in all experimental model systems examined with the slow-to-emerge neurogenesis induced by ADs in specific brain regions of chronically dosed rodents, changes which presumably also occur in the brains of people taking ADs.
Is that time lag the result of a slow cascade of physiological adaptations triggered directly by increased synaptic serotonin concentrations? Or are there non-serotonin-based, slow-acting mechanisms involved as well?
One important clue comes from a simple electron microscopy study described in an elegant paper by Renate Lüllman-Rauch’s group from 1979, and published in Biochimica et Biophysica Acta (my favorite journal name to say aloud). The authors used transmission electron microscopy and the freeze-fracture technique to examine various tissues, including retinas and adrenal glands but alas not brains, of rats that were chronically treated with the phenethylamine drug chlorphentermine. Chlorphentermine was once used as an appetite suppressant, not surprising given its structural similarity to amphetamine. (As an aside, sertraline/Zoloft, a major focus of the Perlstein Lab, is actually a chemical descendent of amphetamine).
It was known back in 1979 that lipophilic weak bases like chlorphentermine induce the formation of “myeloid bodies,” or densely packed, often concentric, arrays of phospholipids. The mechanistic interpretation is that acidic phospholipids are bound to amphipathic weak base drugs, and the resulting drug-lipid complexes are no longer recognized by the digestive enzymes (e.g., phospholipases) that normally break down phospholipids in the maintenance of cellular membrane homeostasis.
I’ve taken the liberty of reproducing several stunning electron micrographs from the Lüllman-Rauch paper, which tell better than a thousand words what chlorphentermine accumulation looks like in animal tissues.
Two myeloid bodies are indicated by orange arrows. They are located inside lysosomes, degrading organelles where all cellular components, including phospholipids, are recycled. High-resolution magnifications revealed the fine structure of those inclusions, which are indicative of lamellar phase phospholipids:
The authors also observed non-lamellar (i.e., non-bilayer) architecture, namely hexagonal phase lattices:
My lab has produced very similar images of hexagonal lattices, but from yeast cells treated with the SSRI Zoloft. These images are obviously 2-D slices. So what is the 3-D structure of those chlorphentermine-induced inclusions? Here was an artist’s rendition of the freeze-fracture data, revealing concentric bundles of hexagonal tubules of phospholipids:
Besides providing visually arresting proof of phospholipidosis in response to chronic chlorphentermine accumulation, the authors noted that phospholipid inclusions were different in different cell types, in this case retina vs. adrenal tissue:
“The above-mentioned biochemical and physicochemical knowledge supports the interpretation of the present findings, namely that retinal pigment epithelium prefers to accumulate the phospholipids in hexagonal rather than in lamellar phase. In other types of cells, which develop both types of inclusion bodies, the composition of stored lipids as well as the local conditions may be different such that both lipid phases, and additionally transitions between both, may occur.”
The question you’re probably asking yourself right now is, do antidepressants induce cell membrane changes in the human brain over long time scales, and is it required for their therapeutic efficacy? The short answer is no one seems to have looked carefully. In the next post on psychopharmacology’s blind spot, I’ll dig a little deeper..