Depression is conventionally viewed as a state of chemical imbalance, and antidepressants are suggested to act through increasing monoaminergic neurotransmission. These views are currently considered simplistic. This article examines the animal and human literature on the neurohistological mechanisms underlying stress, depression and antidepressant treatment. Pathological stress and depression are associated with changes such as loss of dendritic spines, shrinkage of the dendritic tree and loss of synapses in the hippocampus and prefrontal cortex. There is also a levaquin online pharmacy decrease in glia. Apoptosis may occur under extreme circumstances. In contrast, there is increased dendritic arborization and synaptogenesis in the amygdala. Antidepressant treatment protects against and even reverses some but not all of these stress-induced neurohistological changes. Pathological stress results in an aberrant neuroplasticity risperdal 3 mg otc response characterized by abnormally increased activity in the amygdala and by impaired functioning of the hippocampus, prefrontal cortex and downstream structures. This aberrant neuroplasticity response directly singulair without prescription explains most of the clinical symptoms of depression. Antidepressant treatment protects against stress-induced pathoplastic neurohistological and neurocognitive changes. Antidepressant treatment also restores functional neuroplasticity in stressed organisms and, thereby, presumably, facilitates re-adaptation through learning and memory mechanisms. Thus, the stress–depression syndrome and the therapeutic and prophylactic efficacy of antidepressant treatments can be explained through a hardwiring analogy. In this context, glutamate is an important neurotransmitter.

Keywords: Depression, stress, antidepressant drugs, electroconvulsive therapy, hippocampus, amygdala, prefrontal cortex, neuroplasticity, mechanism of action
Go to:
INTRODUCTION
There is a very large body of evidence which, when put together, suggests that antidepressant treatments act by inducing neuroplastic changes in the brain. This article provides a simple (and very much simplified!) explanation of the neuroplasticity hypothesis of antidepressant action.

How do antidepressant drugs act?
Conventional answers are basically based on premises such as “depression is an insufficiency of neurotransmitters” and “depression is a state of chemical imbalance in the brain”; antidepressants act by “replenishing the neurotransmitters” or “correcting the chemical imbalance.” Such answers are incomplete and, in the light of present knowledge, possibly even obsolete.

Conventional explanations
The conventional explanations of antidepressant mechanisms merely describe a proximal action of antidepressant drugs; some examples follow:[1]

Antidepressant drugs inhibit the reuptake of monoamines (such as serotonin, noradrenaline and dopamine) into the presynaptic neuron; persistence of these monoamines in the synaptic cleft results in increased postsynaptic receptor stimulation and hence in increased postsynaptic neurotransmission. This effect, presumably, corrects or compensates for the neurophysiological deficits that underlie depression. Examples of drugs that inhibit monoamine reuptake are the tricyclic antidepressants (TCA), the selective serotonin reuptake inhibitors (SSRIs), the serotonin–norepinephrine reuptake inhibitors (SNRIs) and others.
Antidepressant drugs inhibit the breakdown of monoamines (such as serotonin, noradrenaline and dopamine) in the storage vesicles of the presynaptic neuron. Preservation of these monoamines presumably improves the efficiency of synaptic neurotransmission. This may correct or compensate for the neurophysiological deficits that underlie depression. Drugs that inhibit monoamine breakdown are the monoamine oxidase inhibitors (MAOIs).
Antidepressant drugs increase the reuptake of serotonin (tianeptine), increase the release of serotonin and norepinephrine (mirtazapine), act directly on serotonin and melatonin receptors (agomelatine) or otherwise influence synaptic neurotransmission. With the exception of agomelatine, the focus of explanatory mechanisms is on the great triumvirate: serotonin, norepinephrine and dopamine.
Mechanisms have also been proposed for somatic treatments with antidepressant action. These treatments include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), light therapy, sleep deprivation therapy and others. The focus of the present article is on the pharmacological and not on the somatic treatments.


8