Writing in Neuron that antipsychotics’ “functional consequences and the subcellular sites of their accumulation in nervous tissue have remained elusive,” researchers from Germany and Denmark find that antipsychotics accumulate in synaptic vesicles where, having reached sufficient concentration, are expelled into synaptic spaces when neurons are excited. The authors theorize that this period of accumulation accounts for “the slow development of the full therapeutic action of the drugs” which theoretically occurs within the same 4-6 week time range.
Tischbirek, C. Wenzel, E. et. al; “Use-Dependent Inhibition of Synaptic Transmission by the Secretion of Intravesicularly Accumulated Antipsychotic Drugs,” Neuron, released online June 7, 2012
Related Items:
Sanders, L. “Why Antipsychotics Need Time to Kick In,” Science News, June 6, 2012
Morton, A. Cousin, M; “The Best Things Come in Small Packages– Vesicular Delivery of Weak Base Antipsychotics,” Neuron, released online June 6, 2012
Note from Kermit Cole, “In the News” editor:
I have always found the search for an explanation for psychotropics’ supposed 4-6 week lag between the immediate and “therapeutic” effects interesting. I think that this has not, in fact, been the experience of many people and that, when it has, there are explanations other than merely physiological ones that could explain what occurs during this time. With some trepidation, I look forward to ideas that may explain what this study attempts to explain.
In the hope of a lively discussion, I am pasting the study’s discussion section and concluding remarks below.
Discussion
During treatment, APDs and other psychotropic drugs accumulate in the brains of patients. In the present work, we studied the subcellular localization of APD accumulation in acidic organelles and identified functional consequences of this phenomenon. We demonstrated that accumulated APDs are secreted from synaptic vesicles upon exocytosis, leading to increased extracellular drug concentrations during neuronal activity. The secretion of APDs in turn was able to inhibit synaptic transmission in a use-dependent manner.
Increase of Extracellular Concentrations by Activity-Dependent Secretion of APDs
We found that synaptic transmission as measured by synaptic vesicle exocytosis was reduced by APDs in low micromolar concentrations. This concentration range raised our concerns because it has been convincingly demonstrated that the clinical efficacy of APDs correlates with effects observed for nanomolar concentrations (Seeman et al., 1976). Additionally, APDs acutely inhibit sodium channels in low micromolar concentrations (Figure 6), which in previous work were found unlikely to be achieved extracellularly during APD therapy (Baumann et al., 2004). Thus, instead of therapeutic benefits, continuously present micromolar APD concentrations were related mainly to side effects of the drugs (Ogata et al., 1989).
A major part of our study was, therefore, devoted to demonstrate that the accumulation of APDs in synaptic vesicles (Table 1; Figures 1 and 2) results in high APD concentrations within these confined compartments. Upon activity, synapses release their micromolar APD content into the synaptic cleft (Figure 3). We confirmed the activity-dependent release by in vitro fluorescence microscopy and in vivo data from experiments with freely moving rats treated with HAL. The released APDs have an inhibitory effect on signal propagation by promoting sodium channel inactivation (Figures 6 and 7). Even the extracellular HAL concentrations in the nanomolar range were sufficient to exert a use-dependent inhibitory action under prolonged stimulation (Figures 6 and 7). Accordingly, APD concentrations inhibiting sodium channels are likely to be reached at least locally during neuronal activity. Overall, both inhibition of sodium channels and activity-dependent secretion contribute to the use-dependent action of the drugs. The present work, thus, suggests a mechanism wherein the presence of APDs in synaptic vesicles results in increased extracellular APD concentrations upon neuronal activity, leading to autoinhibitory feedback on synaptic transmission.
Potential Implications of APD Accumulation and Secretion Affecting the Understanding of Therapeutic Actions of APDs
While the therapeutic effect of APDs starts soon after application, it usually reaches its maximum after 4–6 weeks (Agid et al., 2003; Leucht et al., 2005). The effects on synaptic transmission reported here, which are based on the accumulation of the drugs, might contribute to the slow development of the full therapeutic action of the drugs because tissue accumulation occurs within the same time range (Kornhuber et al., 1999). Accordingly, accumulation and secretion effects could explain the beneficial effects of electroconvulsive therapy (ECT) during APD treatment, which are not observed when ECT is performed without APD therapy (Falkai et al., 2005). In light of our findings (Figures 3 and 4), the concentration of APDs available locally is likely to be increased acutely upon ECT-induced seizures.
Physiologically, precisely mediated negative feedback inhibition of neocortical pyramidal cells is necessary for the generation of synchronized high-frequency oscillations, which are related to attention and perception, and whose disturbance has been linked to the pathophysiology of schizophrenia (Uhlhaas and Singer, 2010). Such a deficit in synchronization has, for example, been found in psychotic patients prior to antipsychotic treatment (Gallinat et al., 2004) and chronically ill patients (Ferrarelli et al., 2010; Uhlhaas et al., 2006).
The autoinhibition of synaptic transmission described here by the secretion of accumulated APDs could be beneficial to the generation of synchronized neuronal oscillations in schizophrenia. Our data underline the importance of measuring the neuronal oscillation patterns of unmedicated patients, or patients free of symptoms after sufficient antipsychotic therapy and in an already accumulated drug state. If the secretion of APDs and the associated selective modulation of synaptic transmission were important for the treatment of schizophrenia, then one could further speculate that an enriched environment (Oshima et al., 2003; Tost and Meyer-Lindenberg, 2012) is useful for patients under medication, whereas it would harm the psychotic, not yet treated patient.
Concluding Remarks
Taken together, our study proves the concept of APD accumulation first suggested by Rayport and Sulzer (1995) and defines synaptic vesicles as organelles that exert accumulation- and use-dependent inhibitory functional effects. Although we found more pronounced inhibitory effects of APDs in striatal tissue (Figure 7), which hosts the receptors that bind the drugs in nanomolar concentrations (in this case DA receptors), our current results are limited with respect to other substance classes or synapse types. It will therefore be interesting to investigate the autoinhibitory effects of psychotropic drugs accumulated in synaptic vesicles on specific network activity profiles within cortical (Goto et al., 2010) and subcortical (Kellendonk, 2009) pathways as well as various neurotransmitter systems (Lisman et al., 2008), especially DA signaling, and differential effects of other classes of psychotropic drugs (Sulzer, 2011).
I prefer Giovanni Fava’s and Paul Andrews’s theory: The nervous system compensates for the activity of the drug until those natural compensatory or regulatory mechanisms are overcome. At that point, the drug becomes “therapeutic.”
This also accounts for the fact that many people feel adverse effects of medication very quickly, before “therapeutic” effects.
It does not contradict the above vesicular theory, the vesicular accumulation being evidence natural compensatory mechanisms are being overwhelmed, as they would normally clear the synaptic vesicles.
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Disturbances in the cognitive functions, attention and perception can be assessed easily enough via interpersonal interaction that occurs quite naturally during verbal communication between human beings. The physiological underpinnings of these cognitive functions have been seen on PET scans–non-invasive imaging that is accomplished while a person remains both fully conscious and comfortable. Additionally, dysfunction of these cognitive processes is improved via *cognitive remediation* therapy- (Tykes & Wilkes- Kings College of London). Columbia University hosts conferences annually on Cognitive Remediation in Psychiatry( 7+ years, I think) I attended one in 2009- It was astounding! However, there isn’t much of a following in the U.S.–yet.
Additionally, vestibular therapy, like Ballametrics developed by Dr. Belgau, who developed a balance board and various techniques for stimulating the cerebellum (hind brain- or reptilian brain), initially used his therapies with kids who were labeled, ADD-ADHD or with various learning disabilities that forced them out of mainstream classrooms- or on to drug trials. With the advent of PET scans, it was possible to observe how the cerebellum-sensory motor coordinator- fired neuro nets that acted as stimulus for improved functioning of collaborative brain activity in the cerebral cortex—responsible for *attention* and *perception*.
When I wrap my own mind/brain around the findings of this article, I experience a sinking feeling. I really don’t understand why there is ongoing investigation of neurotransmitter activity–as there has been no scientifically established connection that proves causation of *psychotic* experiences. and there is no evidence, of which I am aware, that *patients* report improvement in their attention and perception abilities–or rather, evidence that *antipsychotics* restore normal functioning as a subjective finding. In fact, I have only encountered *patients* who complain about the dullness and lack of interest in their surroundings as *the effect* of antipsychotics.
I guess I see no reason to seek an explanation for how antipsychotics work, because I don’t believe there is a reason to believe they are working! I guess this sounds smug…. but then I have to reiterate what has been discovered without invasive means and the introduction of toxic substances AND how the information regarding the underlying malfunctioning cognitive processes can be utilized. Therapies that depend on human interaction, guidance, coaching- rather than toxic substances may ultimately be superior just because they stimulate reconnection of the *patient* to others and their environment—in non threatening ways—without tampering or trying to control the mind/brain. Still, these two (of many) strategies for remediating the cognitive processes that are linked to *psychotic states* have a firm grounding in real science.
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There is validity in trying to find out what’s happening with the drugs at the cellular level.
I agree, though, such research is predetermined to support drug prescription — as though finding the drugs actually *do something* to cells is evidence that the something is beneficial.
Now we may know how the drugs “work” — what bearing does that have on whether they are good or bad for humans?
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So, then any laboratory specimen used for these experiments is sacrificing something for—WHAT PURPOSE?
Biomedical ethics relies on , or maybe, defaults to, is a better way of expressing the application of Kant’s “categorical imperative” -specifically, the second formulation, which states:
“Always act so as to treat humanity, either yourself or others, always as an end and never as only a means.”
Where there is a so much evidence that antipsychotics, indeed all psychotropic drugs were put on the market with so little regard for people recruited into RCTs or patients receiving the drugs after they were on the market , other than to fulfill purposes of those who have gained financially from their use, it’s hard to imagine any *good* resulting from ever more extensive studies. The after market patients/people receiving these drugs are completely uniformed of this, and sometimes coerced into participating in what amounts to *experimental medicine* on the public at large.
Not only is this backwards with regard to what medical research used to look like, (investigating known diseases) and the purpose for which it was employed (discovering safe/effective treatments for diseases)— it is becoming all too obvious that there is a predominant agenda operating without opposition that is endowed with both wealth and power. The agenda is the existence, the maintenance and the prospering of *itself*.
Here’s an even deeper philosophical interpretation of the experiments on animals conducted to produce the conclusions in the article here. Hippocrates admonished against invasive procedures- in all but emergency situations. Descartes discussed the human capacity for deductive reasoning and developing understanding through empirical evidence that needed only keen observation skills and careful, accurate documentation of one’s observations. The common denominator for these ways of thinking about what humans can or should do to other living beings is based on a reverence for life itself. Kant focused exclusively on the human capacity for rationality – but his ethical theories still stipulate *good will* or having a cause for higher good when carrying out some action that will create consequences for another human being.
The moral of the story may be that the lacking of humanity in the premise of these research studies and RCTs will produce nothing of value for humanity—in the conclusions.Or…
making a silk purse from a sow’s ear is too whimsical a goal to entertain seriously.
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It sounds to me like the brain is able to recognize a neurotoxin when it sees one, and tries to remove it from the synapse as much as possible until it can’t do so anymore. It’s a great argument for not using antipsychotics, because the brain is clearly smart enough to know they are not good for it.
—- Steve
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