Depression, statin-induced myopathy, the serotonin syndrome and malignant hyperthermia.
Why do pregnant women become depressed? If, as I have proposed in an
electronic discussion of depression (1) , depression is the product of an
intracerebral energy deficit, then the Daniel Atkinson energy charge
hypothesis might explain how an energy deficit might develop.
The AMP-activated protein kinase cascade is a sensor of cellular
energy charge "activated by cellular stresses that deplete ATP (and
consequently elevate AMP), either by inhibiting ATP production (e.g.,
hypoxia), or by accelerating ATP consumption (e.g., exercise in muscle).
Once activated, it switches on catabolic pathways, both acutely by
phosphorylation of metabolic enzymes and chronically by effects on gene
expression, and switches off many ATP-consuming processes" (2).
Might the demand for new protein synthesis in the mother, induced by
the hormonal changes in pregancy and/or the increasing steal of nutrient
substrate by the foetus, activate the protein kinase cascade in the
mother and thereby cause depression? Might treatment of the depression
with selective serotonin reuptake inhibitors compromise the foetus's
abilities to meet its ATP needs by inhibiting ATP production? Additionally
or alternatively in compromising the mother's ability to meet ATP needs
might selective serotonin reuptake inhibitors steal nutrients from the
foetus or even cannabalize the foetus to provide that nutrient, the heart
being especially vulnerable because of its workload?
In my electronic discussion of statin induced myopathy (3) I asked
whether statins might shift substrate dependence from glucose and fatty
acids to amino acids, my thesis being that in limiting the availablity of
fatty acids for ATP resynthesis statins might promote autophagy,
apoptosis and even necrosis of muscle cells to meet substrate needs for
ATP resynthesis. Might a similar process be implicated in the development
of congential abnormalities in the heart in babies born of mothers on
selective serotonin reuptake inhibitors?
The serotonin syndrome, seen in patients on selective serotonin
reuptake inhibitors, is charcterized by a combination of fever,
myoclonus, coma, seizures, cardiovascular collapse, and death. These
characteristics are reminiscent of those seen in malignant hyperthermia in
which muscular rigidity, tachycardia and hyperthermia develop.
Rhabdomyolysis may also develop. Acccording to Wikipedia the primary
biochemical abnormality in malignant hyperthermia is a greatly increased
Ca2+ release due to a lowered activation and heightened deactivation
threshold. The process of reabsorbing this excess Ca2+ is said to consume
large amounts of ATP and in so doing would presumably generate the
excessive heat from the increased rate of ATP hydrolysis. The muscle cell
is damaged by the depletion of ATP.
1. Kathryn Rost, Paul Nutting, Jeffrey L Smith, Carl E Elliott, and
Miriam Dickinson
Managing depression as a chronic disease: a randomised trial of ongoing
treatment in primary care
BMJ 2002; 325: 934.
2. D. Grahame Hardie *, Simon A. Hawley AMP-activated protein kinase:
the energy charge hypothesis revisited.
BioEssays. Volume 23 Issue 12, Pages 1112 - 1119
Rapid Response:
Depression, statin-induced myopathy, the serotonin syndrome and malignant hyperthermia.
Why do pregnant women become depressed? If, as I have proposed in an
electronic discussion of depression (1) , depression is the product of an
intracerebral energy deficit, then the Daniel Atkinson energy charge
hypothesis might explain how an energy deficit might develop.
The AMP-activated protein kinase cascade is a sensor of cellular
energy charge "activated by cellular stresses that deplete ATP (and
consequently elevate AMP), either by inhibiting ATP production (e.g.,
hypoxia), or by accelerating ATP consumption (e.g., exercise in muscle).
Once activated, it switches on catabolic pathways, both acutely by
phosphorylation of metabolic enzymes and chronically by effects on gene
expression, and switches off many ATP-consuming processes" (2).
Might the demand for new protein synthesis in the mother, induced by
the hormonal changes in pregancy and/or the increasing steal of nutrient
substrate by the foetus, activate the protein kinase cascade in the
mother and thereby cause depression? Might treatment of the depression
with selective serotonin reuptake inhibitors compromise the foetus's
abilities to meet its ATP needs by inhibiting ATP production? Additionally
or alternatively in compromising the mother's ability to meet ATP needs
might selective serotonin reuptake inhibitors steal nutrients from the
foetus or even cannabalize the foetus to provide that nutrient, the heart
being especially vulnerable because of its workload?
In my electronic discussion of statin induced myopathy (3) I asked
whether statins might shift substrate dependence from glucose and fatty
acids to amino acids, my thesis being that in limiting the availablity of
fatty acids for ATP resynthesis statins might promote autophagy,
apoptosis and even necrosis of muscle cells to meet substrate needs for
ATP resynthesis. Might a similar process be implicated in the development
of congential abnormalities in the heart in babies born of mothers on
selective serotonin reuptake inhibitors?
The serotonin syndrome, seen in patients on selective serotonin
reuptake inhibitors, is charcterized by a combination of fever,
myoclonus, coma, seizures, cardiovascular collapse, and death. These
characteristics are reminiscent of those seen in malignant hyperthermia in
which muscular rigidity, tachycardia and hyperthermia develop.
Rhabdomyolysis may also develop. Acccording to Wikipedia the primary
biochemical abnormality in malignant hyperthermia is a greatly increased
Ca2+ release due to a lowered activation and heightened deactivation
threshold. The process of reabsorbing this excess Ca2+ is said to consume
large amounts of ATP and in so doing would presumably generate the
excessive heat from the increased rate of ATP hydrolysis. The muscle cell
is damaged by the depletion of ATP.
1. Kathryn Rost, Paul Nutting, Jeffrey L Smith, Carl E Elliott, and
Miriam Dickinson
Managing depression as a chronic disease: a randomised trial of ongoing
treatment in primary care
BMJ 2002; 325: 934.
2. D. Grahame Hardie *, Simon A. Hawley AMP-activated protein kinase:
the energy charge hypothesis revisited.
BioEssays. Volume 23 Issue 12, Pages 1112 - 1119
3. Sivakumar Sathasivam, Bryan Lecky. Statin induced myopathy. BMJ
2008;337:a2286
Competing interests:
None declared
Competing interests: No competing interests