This document discusses how antidepressants can sometimes cause mania in bipolar patients by blocking norepinephrine transporters, preventing the clearance of dopamine from the prefrontal cortex and leading to dopamine flooding this area. It explains that the prefrontal cortex normally has few dopamine transporters and high dopamine levels, contributing to human traits like creativity, but that excess dopamine causes mania and can damage neurons through excitotoxicity and calcium dysregulation.

1. WHAT HAPPENS IN MANIA STAYS IN MANIA
Psychiatrists know that many times when an antidepressant
is prescribed to a depressed patient, the patient becomes
manic. Drug induced mania or manic switch occurs in
approximately 20-40% of bipolar patients and in less than
5% of major depressive disorder patients.
With very few exceptions
antidepressants work by
blocking the transporter
proteins. They are the
presynaptic neuron pumps
that recycle the left-over
neurotransmitter by
bringing it back into the
presynaptic neuron
terminal.
It is not clear at the moment if patients with major
depressive disorder who switch to mania when on
antidepressants may have a latent bipolar disorder.

2. The manic switch happens because the human prefrontal
cortex has very few dopamine transporters. This is an
extremely important characteristic of human species. Our
prefrontal cortex is soaking with dopamine. This fact
contributes to humans’ creativity, energy and volition. In
fact it may be the very reason we have a human civilization.
This is also the reason why patients with schizophrenia
treated with dopamine blockers become blunted, avolitional
and amotivational. These medications (typical
antipsychotics) worsen negative symptoms of schizophrenia
because they block the dopamine in the prefrontal cortex.
This is what happens in a manic switch at the molecular
level:
1. The excess dopamine from the prefrontal cortex is
disposed of by norepinephrine transporters (which have a
lower affinity for dopamine).
2. Antidepressants especially tricyclic or SNRIs block the
norepinephrine transporters, thus preventing dopamine
clearance.
3. As a result dopamine floods the prefrontal cortex in
quantities much larger than normal, leading to mania.

3. As a result of blocking norepinephrine transporters,
dopamine floods the prefrontal cortex, leading to mania.
Mania causes the same damage to the brain as psychosis
does. Studies have shown that during psychotic episodes
excessive amounts of Calcium enter the neurons, leading to
the destruction of the organelles and the activation of cell
death cascade (apoptosis). This process is called
excitotoxicity.
During normal neurotransmission small amounts of
Calcium enter the neuron via NMDA receptors. This
Calcium entry into the neuron is beneficial, it is part of
glutamate neurotransmission and it forms the basis of long
term potentiation, which is essential for the memory.

4. Excessively high levels of Calcium in the neuron cause
damage by activating the cell death cascade (apoptosis). This
is what happens during psychotic episodes.
For this reason the neurons, developed diverse homeostatic
mechanisms to regulate intracellular Calcium level very
precisely. Thus extracellular Calcium level is approximately
2 mM, while the resting intracellular Calcium level is in the
range of 100nM (20,000 times less).
In order to keep tight control of the intracellular Calcium,
the neuron developed Calcium pumps (to eliminate it), and
Calcium proteins to sequestrate it. Thus it is estimated that
Calcium ion can only diffuse 0.5 micrometers and is free for

5. less than 50 microseconds before encountering a Calcium
binding protein to sequestrate it. This mechanism is
necessary due to the fact that free intacellular Calcium is
deadly for the cell because it activates apoptosis
(programmed cell death).
Excessive entry of Calcium in the neuron is toxic for the
neuron. For this reason Calcium is extremely regulated in
the cell.
ADONIS SFERA, MD