Psychopharmacology of Antidepressants and Antipsychotics

[Petros Agapetos]

The Monoamine Theory of Depression

Neurons communicate with one another through neurotransmitter.When a presynaptic neuron fires [ex. Serotonin], the signal is passed along the receiving neuron by the binding of that neurotransmitter to receptors on the post-synaptic neuron. There are two ways a signal between two neurons ends after the neurotransmitter is delivered to the receptor; Either it is metabolized by Monoamine Oxidase , Or it is recycled back into the pre-synaptic/firing cell.

Antidepressants work by inhibiting the means by neurochemical signals are ended after firing a signal. Antidepressants work by elevating synaptic content of certain neurotransmitters, namely the monoamines: Serotonin, Dopamine, and Norepinephrine.

Monoamine Reputake inhibitors block reuptake channels, not permitting fired neurotransmitters to be recycled back into the firing nerve cell thereby letting the chemical signal go on longer.

Monoamine Oxidase Inhibitors work by blocking the enzyme which metabolize neurotransmitters, after they are fired, in order that the signal ends.

The Serotonin Theory of Depression states that depression is due to a lack of serotonergic neurotransmission. Hence, drugs are used which inhibit the reputake of serotonin, in order to raise its levels in the synaptic cleft.

For example, SSRI = Selective Serotonin Reuptake Inhibitors; selectively block serotonin transporter recycle channels; thereby increasing synaptic serotonin content; thereby turning up serotonin neuro-transmission. The Monoamine Theory of Depression is not born out of an understanding of what is wrong with the brain that is causing depression; but rather merely from the hypothesized activity of the anti-depressant.

[Petros Agapetos]

The Dopamine Hypothesis of Psychosis

There are two relevant dopaminergic neuron pathways in the brain;
I. The Mesolimbic - connects the midbrain to the Nucleus Accumbens/Pleasure Center, in the limbic system
II. The Mesocortical - connects the midbrain to the cortical frontal lobes.

High dopaminergic activity of the mesolimbic is associated with positive symptoms of psychosis/schizophrenia. Antipsychotics or Neuroleptics work by powerfully blocking dopamine receptors [on the post-synaptic/receiving neuron]. They block 70% - 90% of D2 type dopamine receptors. In response to the blockage of D2 doapmine receptors, the brain synthesizes 40% or more dopamine receptors - this is called "compensatory adaptation" This change is associated with both positive and negative symptoms of psychosis. D2 receptors are concentrated on the Mesolimbic pathway. Antagonism of D2 dopamine receptors in the brain causes this neuron pathway to cease functioning - the neurons no longer communicate with one-another, and thus nerve activity is shut down.

Psychotic symptoms can be put into three categories:
I. Positive (Hallucinations, Delusions, Disorganized Thought and Behaviour) - Antipsychotics only help with this category of symptoms
II Negative (Blunting of Affect. Emotional Indifference, Lack of Preoccupation, Motivation, and Initiative) - Antipsychotics worsen these symptoms
III. Cognitive (Ex. - ADHD type symptoms/ shortening of attention span; problems with concentration and focus) - Anti-Psychotics worsen these symptoms

[Petros Agapetos]

Dopaminergic pathways in the brain:

Mesolimbic - Connects the Ventral Tegmental Area to the Nucleus Accumbens/Reward Center in the Limbic Sytem (emotional regulation).
Mesocortical - Frontal lobe activity, Prefrontal Cortex,
Nigro-striatal - Kinetic disorders/disorders of movement; as in Parkinson's disease.
Tubero-Infundibular - Prolactin secretion due to tonic inhibition of dopamine

High synaptic dopamine content is associated with rewarding feelings, high mood, bright affect, motivation, initiative,. etc. Abrupt surges in dopaminergic activity is associated feelings of euphoria, confident state of mind, masculinity/manliness, etc. Dopaminergic transmission is associated with an increase in testosterone production. ADHD medicines are stimulants, which work by increasing dopaminergic neurotransmission in the brain.

However, Antipsychotics have the opposite effects, they block dopaminergic transmission; reduce the activity of the regions of the brain which need dopamine to communicate with one another. The nucleus accumbens cannot commicate with the midbrain; it this pathway is blocked; i.e. the receptors are plugged with with the antipsychotic molecules, so dopamine cannot activate them (as a key to a lock).

[Petros Agapetos]

The disease model of antipsychotic drug action asserts that taking neuroleptics for schizophrenia is like taking insulin for diabetes.
However, there is not enough evidence to conclude the hypothesis is even at the level of a theory. In fact, as early as the 1990's academic psychiatrists had abandoned this theory of schizophrena. Even Pierre Deniker himself, one of the founding father of modern Psychiatry abandoned this theory. "The dopamine theory of schizophrenia has no credibility among psychiatrists". Just because lowering dopamine activity has certain effects does NOT imply that the opposite activity - increasing dopamine - will have the opposite side effects. Drinking alcohol relieves social anxiety; this does not imply that social anxiety is caused by an alcohol deficiency. Giving someone a sleeping pill under the disease model of treatment would be to "treat sleeplessness", under this logic. The same can be applied to dopamine. Raising dopamine levels causes euphoria; this doesn't mean that dysphoria is due to lack of dopamine (it might be), but this former argument alone does not suffice to make that case. Evidence is required. The evidence base for the truth of the Dopamine Theory of Schizophrenia is not sufficient to deserve the title Theory; it is a working Hypothesis in Psychiatry.

Antipsychotics cause debilitating side effects due to their dopamine antagonism:

I. Lack of initiative, motivation, preoccupation
II. Blunting of Affect, Delay and Flattening of Emotional Responses
III. Sexual Side Effects affecting all phases of sexual function including Libido and Orgasm. D2 antagonism interferes with orgasm function of the brain.
IV. Lack of the Ability to Concentrate or Focus; shortening of attention span; slowing down of thought tempo/cognitive dysfunction; impairment of memory; degrades intelligence
V. Antipsychotics cause brain damage/shrinkage [the evidence for this is abundantly well-documented]

[Petros Agapetos]

There are three main dopaminergic pathways in the brain.

1.One involves the basal ganglia, which controls the initiation of motor movements. Nigro-striatal
2.The second involves the limbic system, which is the area of the brain that helps us mount emotional responses to the world. Mesolimbic
3.The third is in the frontal lobes, which is the part of the brain that gives rise to self-consciousness. Mesocortical


Antipsychotics work by blocking dopamine receptors along these three pathways, and over the long-term, these pathways become increasingly dysfunctional (at least in a high percentage of patients.) The dysfunction in the basal ganglia leads to tardive dyskinesia. The dysfunction in the limbic system and the frontal lobes leads to tardive psychosis and tardive dementia.

With the old standard neuroleptics, tardive dyskinesia was found to appear in five percent of patients within one year of treatment, with the percentage so afflicted increasing an additional five percent with each additional year of exposure. The new atypicals like Zyprexa and Risperidone may pose less of a tardive risk, although this isn’t yet entirely clear.

Researchers have compared tardive dyskinesia to “known neurological diseases, such as Huntington’s disease, dystonia musculorum deformans, and postencephalitic brain damage.” Here are a handful of the studies that have documented this drug-caused brain dysfunction.

Antipsychotics cause brain shrinkage/damage. And this damage is associated with the worsening of positive symptoms, which the drugs are supposed to treat.

Antipsychotics often create a condition called supersensitivity psychosis. The blockade of D2 type dopamine receptors leads to the brain synthesizing 40% or more dopamine receptors, in an effort to try to sensitize itself to dopamine. Then as the drug is withdrawn, the person ends up having extra dopamine receptors, and left more sensitive to dopamine; the very condition hypothesized to cause the illness. Antipsychotics are abnormalizing agents. They do not rectify an underlying chemical imbalance. The chemical imbalance theory re: Psychosis is not credible among academic psychiatrists ever since the early 90's.

[Petros Agapetos]

Most antipsychotics/neuroleptics are dopamine antagonists, they block dopamine receptors; Abilify is the only main neuroleptic used which is partial agonist - partially activates dopamine receptors (but with lower intrinsic activity than dopamine).

Abilify is a partial agonist :

On postynaptic D2 receptors Abilify partially agonizes them with 30% intrinsic activity. On presynaptic D2 receptors Abilify agonizes with 75% intrinsic activity (these receptors reduce dopamine firing when activated).Overall effect of Abilify on dopamine is controlled dampening down/modulation. Areas where dopamine activity is high, Abilify lowers it, and where dopamine activity is low, Abilify increases dopaminergic activity.

[Petros Agapetos]

An Alternative Theory of Psychosis - The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

Like the dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, NMDA antagonists mimic some positive and negative symptoms with less brain harm. Likely, both dopaminergic and glutaminergic abnormalities are implicated in schizophrenia, from a profound alteration in the function of the chemical synapses, as well as electrical synaptic irregularities. These form a portion of the complex constellation of factors, neurochemically, psychologically, psychosocially, and structurally, which result in schizophrenia.

[Petros Agapetos]

Antidepressants increase the amounts of serotonin, norepinephrine through reuptake inhibition or de-activation of mononamine oxidase enzymes which break down these neurotransmitters.One antidepressant called Welbutrin (Bupropion) increases dopamine content in dopaminergic neuron synapses; thereby increasing dopaminergic activity; treating depression and anhedonia.

Antipsychotics reduce dopaminergic activity by dopamine antagonism; they attach to dopamine receptors blocking them; not letting dopamine attach to them when fired; this results in the nerves that communicate via dopamine causing the signal transmission between dopamine neurons to reduce - the opposite effect of the antidepressant Welbutrin, which works by increasing dopaminergic neurotransmission. Antipsychotics also have been demonstrated to cause anhedonia (lack of pleasure), reduce libido and orgasm , reduce motivation , preoccupation and initiative

[Petros Agapetos]

Modafinil is a weak dopamine re-uptake inhibitor and orexin releaser (neuropeptide)
The R-enantiomer of Modafinil = Armodafinil, is a D2 dopamine receptor partial agonist (Ki = 16nm) intrinsic activity = 48%.

Dexedrine is an amphetamine enantiomer prescried for the treatment of ADHD.
- Cognitive Enhancer
- Aphrodisiac
- Performance Enhancer
- Euphoriant
- Treats Depression

Mesolimbic dopamine activity is associated with reward-related cognition, incentive salience (wanting), pleasure (liking), positive reinforcement, addiction, ADHD, and Psychosis/Schizophrenia.

Mesocortical dopamine activity is associated with executive functions, ADHD, addiction.

Nigrostriatal dopamine activity is associated with associated learning, reward associated cognition, addiction, Parkinsonism.

This is why increasing dopamine activity can create a mental state which treats ADHD symptoms, depression, anhedonia, and antipsychotic induced psychic dysfunctions; associated with low dopamine: anhedonia, lack of motivation, preoccupation , initiative, reduced and delayed response to external stimuli = blunting of affect and emotional dysfunction (indifference, apathy, etc.), docility, etc.

[Petros Agapetos]

Rotigotine is a medication prescribed for Parkinson's disease which can be used to treat antipsychotic induced impairment of attention motivation and drive, anhedonia, depression. Rotigotine is a non-ergoline non-selective dopamine agonist of D1, D2, D3, and to a lesser extent D4 and D5 receptors, whith the highest affinity on D3. Rotigotine is 100 fold more selective to D3 than D1 and 10 fold more selective for D3 than D2, D4, D5. It also has activity on serotonin receptor 5HT1A (Ki = 30 nM)