Why is Clozapine So Unique? – Psychopharmacology Explained – Non D2 Receptor Actions

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Clozapine has a mechanism of action that is unique to other second-generation antipsychotics. (SGAs)

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Clozapine is a dopamine and serotonin antagonist (5HT2A) with a few unique differences compared to other SGAs.
Clozapine has a high dissociation constant for D₂, which is even higher than dopamine.
Clozapine has much higher antagonistic activity on cortical and limbic dopamine D₄ than D₂ receptors.
It also antagonises 5HT2 serotonergic receptor subtypes (5HT2A & 5HT_2C) and adrenergic (α1), histamine (H₁), and muscarinic receptors (M₁).

Effect on Muscarinic Receptors:

While Clozapine is an M1 antagonist, N-desmethylclozapine (NDMC), the main metabolite of Clozapine, acts as a potent allosteric M1 receptor agonist, unlike other antipsychotics. This M1 receptor activation by NDMC leads to the release of acetylcholine and dopamine in the cortex. This property suggests that NDMC might be more effective than Clozapine in addressing the cognitive deficits seen in schizophrenia.
N-desmethylclozapine (NDMC), via its allosteric M1 agonist activity, enhances NMDA receptor currents in the hippocampus. Sur et al., 2003]

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Clozapine is considered a potent inverse agonist at the 5-HT2AR, similar to pimavanserin which is an atypical antipsychotic with predominant 5-HT2A antagonist or inverse agonist effects which has received FDA approval in 2016 for hallucinations and delusions associated with Parkinson’s disease. [Stępnicki et al, 2018]
Clozapine has 5HT1A partial agonist activity, which increases DA in PFC and is thought to be beneficial in reducing negative and cognitive symptoms.
The combination of relatively high D₁, low D₂, and very high 5-HT2 receptor occupancy rates is unique to Clozapine and may explain its lower propensity for Extrapyramidal side effects.

D1 vs D2 binding for Clozapine: [Lidow et al., 1998]

Clozapine demonstrates binding affinity towards receptors affiliated with the dopamine D1 and D2 receptor families. Its binding affinity for the D2 receptor is significantly lower than conventional antipsychotic agents.

Clozapine achieves its therapeutic outcomes at substantially lower dosages than anticipated based on its comparatively modest D2 receptor binding affinity. Within the striatum, the occupancy of D2 receptors by Clozapine is merely within the range of 50–66% compared to that attained by other antipsychotic compounds. Importantly, Clozapine does not evoke an upregulation of D2 receptors in the striatal region.

Thus, due to the low level of st iatal D2 occupancy at therapeutic doses, chronic treatment with Clozapine does not affect striatal D2 receptors, thus having a low risk of EPSE.

This divergence in binding affinity is mirrored in positron emission tomography (PET) investigations, which reveal comparatively subdued receptor occupancy even at dosages yielding therapeutic efficacy.

This is clinically relevant as antagonism of dopamine D2 receptors precipitates a compensatory phenomenon characterised by escalated neuronal excitability, augmented dopamine synthesis, and heightened DA release. This dopamine supersensitivity is associated with side effects and treatment resistance. [Nair et al., 2022]

Long-term administration of dopamine D2-receptor-blocking medications is the risk of dopamine supersensitivity psychosis due to dopamine D2-receptor upregulation.

The potential clinical consequence of dopamine supersensitivity psychosis is that antipsychotic medication may progressively lose effectiveness in treating the schizophrenia, necessitating increasingly higher antipsychotic doses over time, with attendant increased side-effect burden.

Ultimately, dopamine supersensitivity psychosis may progress to treatment-resistant schizophrenia.

Medications that do not lead to dopamine supersensitivity psychosis may lead to better long-term clinical outcomes and reduced rates of TRS.

In contrast, Clozapine is a more potent D1 receptor agonist. Evidence for the D1 action comes from the following observations: [Ahlenius,1999]

Stimulation of DA D1 receptors in the prefrontal cortex enhances cognition and may have nootropic effects.
Clozapine effectively addresses L-DOPA-induced psychosis and dyskinesias in Parkinson’s disease treatment, unlike traditional antipsychotics, which worsen Parkinsonian symptoms.
Clozapine shows promise in treating tremors and movement disorders in Parkinson’s disease.
Untreated patients display decreased DA D1 receptor density in the prefrontal cortex.
Clozapine’s distinct pharmacodynamic profile as an antipsychotic is notable:
Unlike DA D1 receptor antagonists, which can worsen patients, Clozapine yields favourable clinical outcomes.
Selective DA D2 receptor benzamide antagonists like sulpiride and remoxipride, effective as antipsychotics, potentially spare DA D1 receptors. This could lead to DA D1 receptor activation through heightened dopamine synthesis and release facilitated by concurrent DA D2 receptor blockade.
Parallels between Clozapine and DA D1 receptor agonists are evident:
Both Clozapine and DA D1 receptor agonists can evoke myoclonic seizure activity.
Conversely, DA D2 receptor agonists possess anticonvulsant properties.

Clozapine in conventional doses occupied D2-receptors to a smaller extent (40%, 40%, 65%) than classical neuroleptics. The occupation of D1-receptors was higher (40%, 42%) than that of classical compounds (0-36%). The unique clinical profile of Clozapine may be related to its potency on both D1- and D2-receptors. [Wiesel et al., 1990]

Evidence suggests that optimal antipsychotic efficacy requires both D1 and D2 receptor affinity. [Ünal et al., 2019]

A recent study showed that antipsychotic efficacy correlated with the selective inhibition of D1Rs only under hyperdopaminergic conditions—a dopamine-state dependence exhibited by D1R partial agonism but not non-antipsychotic D1R antagonists. [Yun et al., 2023]

As the cerebral cortex expresses much higher levels of D1 than D2 receptors, D1R modulation is essential due to the prefrontal cortex’s top-down inhibition (modulation) of mesolimbic dopamine, contributing to antipsychotic efficacy.

Clozapine’s binding dynamics to dopamine receptors show an intriguing pattern: it strongly binds to D1 receptors when dopamine levels are low and to D2 receptors in higher dopamine concentrations, e.g. in schizophrenia. This distinctive property sets Clozapine apart from other antipsychotics in line with the dopamine hypothesis of schizophrenia.

Thus, Clozapine’s interaction with D2 receptors reduces positive symptoms. In contrast, its interaction with D1 receptors contributes to its efficacy in addressing cognitive symptoms and likely enhanced prefrontal cortex inhibition of the mesolimbic pathway. [Ünal et al., 2019]

Other Properties:

Clozapine is hypothesised to have some anti-inflammatory properties, as demonstrated in rats exposed to an inflammatory challenge, with response measured through activated microglia. Clozapine administration reversed microglial activation and iNOS increase, but not the alterations of oxidative stress parameters. [Ribeiro B et al.,2013 ]
Clozapine also increases Noradrenaline (NA) levels in the plasma and CSF via ɑ-2 receptor antagonism and noradrenaline reuptake inhibition. [Khokhar et al., 2018]
Clozapine and its primary major metabolites, clozapine-N-oxide (CNO) and N-desmethylclozapine (NDC), exhibit neuroprotective and anti-inflammatory properties. [Regen F et al., 2020]
Endogenous retinoid acid (RA) signalling is involved in the pathophysiology of schizophrenia. Patients with schizophrenia have lower levels of all-trans RA; at-RA (The biologically most active metabolite of vitamin A). Clozapine and its metabolites potently inhibit RA catabolism, thus increasing levels of at-RA. [Regen F et al., 2020]
Clozapine is also postulated to increase the GABAergic neuroactive steroid (NS) allopregnanolone which has anxiolytic and antidepressant properties.[Marx C et al., 2006]; [Zorumski C et al., 2013]