The Beauty behind the Antipsychotic Evolution

Ethan Smith
5 days ago
18 min read

I'll admit, "antipsychotic" is a bit of a scary word. The second half, "psychotic," refers to some of the most extreme and frightening experiences a human can have. I think the word evokes imagery of psychiatric wards, confusion, strait jackets, possibly violence, and overall distress. A treatment designed to suppress such a serious condition might suggest being powerful enough to match the strength of the condition, thus giving antipsychotics their own stigma—especially if one knows the history of lobotomies and some of the other early treatments.

That said, modern antipsychotics have come a long way in development and are now used to treat a variety of conditions that are not characterized by psychosis, including autism, OCD, sleep disorders, depression, bipolar disorder, and more. Today, it's estimated about 3.8 million people in America take antipsychotics. They're far from ideal. Many have mixed feelings on their usefulness. Namely, they may successfully treat an illness but can come with burdening side effects. Nonetheless, the newer generation medications have allowed even folks with severe conditions to return as functional members of society.

In this post, I want to talk about how antipsychotics have changed over time. Having read over the pharmacology and research surrounding the medications, I've come to admire what we've achieved, and I find it quite serendipitously elegant. This view may seem in contradiction to my previous post on psychiatry. Though my general stance remains. We still have a long way to go, and there's never been a better time to improve our tools.

Some History

For a long time in history, addressing those suffering with mental health issues had been somewhat of a voodoo practice almost universally across different cultures but with large variance in their specific implementations. It was often treated as originating from supernatural causes like possession of evil spirits that warranted exorcisms or labeling those with antisocial behaviors as witches. Moving forward, some societies attempted something of a "pre-science" working on means of classifying ailments such as the Greek's 4 biles, which were treated with methods like blood-letting and herbal remedies. Traditional Chinese medicine also had some validity, though these were typically insufficient for the more severe disorders like psychosis.

The 18th and 19th centuries saw the creation of asylums. The motivation aimed to be noble. At the time, those with severe mental disorders were put in jail or left on the streets. It was recognized that this both put civilians in danger for those in the street, and it didn't accomplish much to incarcerate them. It was intended to be a place to provide moral treatment and therapy to ease symptoms. However, these institutions quickly became overcrowded and underfunded leading to a decrease in the quality of treatment and ultimately the horror stories of asylums we know today. Staff were undertrained and often dealt with patients through cruel treatment, strait jackets, and restraints.

In 1935, the first lobotomy was performed. It was a calculated stab into the prefrontal cortex. It was a decently effective treatment for those under the most severe distress like delusional bipolar and schizophrenia. Though it was an extreme treatment to perform intentional brain damage to a patient. It quickly became an overprescribed method, where it was a chosen treatment to many at the first sign of deviant behavior, even done to young children at times.

We needed a better way to address mental suffering--a less extreme and destructive solution. The answer was the antipsychotic class of drugs.

Neurotransmission and Pharmacology

Before delving into the different generations of antipsychotics, it's worth detailing a bit on how neurotransmission works in the brain, and how medications affect this process.

Neurotransmitters

A brain is made up of atomic units called neurons (among many other things) which are responsible for the brain's function. Neurons communicate with each other by passing neurotransmitters to each other. We can call this neurotransmission

There are many different kinds of neurotransmitters, though the most popularly discussed ones are:

Dopamine - involved in focus, motivation, and rewards
Norepinephrine (noradrenaline) - attention, alertness, arousal, mood regulation, and stress response
Epinephrine (adrenaline) - stress response, arousal (less common in the brain and more involved in physiological components)
Serotonin - mood, sleep, appetite
GABA (gamma-aminobutyric acid) - the main excitatory neurotransmitter, involved in learning and memory
Glutamate - the main inhibitory neurotransmitter, reduces neuronal excitability

Neurotransmitters can have excitatory (increasing brain activity) or inhibitory (reducing brain activity) functions. GABA and Glutamate are almost strictly inhibitory and excitatory respectively. The other listed neurotransmitters have more nuanced effects and can play both roles.

We can think of there being a sender and a receiver. Between neurons exists a small gap. At this junction, the sender of neurotransmitters constitutes the pre-synapse and the receiver constitutes the post-synapse. When a neuron fires, it releases neurotransmitters which go and bind to receptors on the receiving neuron, yielding some kind of excitatory effect (increasing the chance that it will fire) or inhibitory effect (reducing the chance that it will fire)

Neurotransmission and Receptor Dynamics

When neurotransmitters bind to a receptor, they can play several kinds of roles.

Agonists - Full Agonists

Activate the receptor inducing the function this receptor plays in neurotransmission. Most endogenous, natural neurotransmitters are full agonists

Partial Agonists

Only partially activate the receptor

Antagonist

Effectively block or clog the receptor without activating it

Inverse Agonist

Reduce the receptors activity beyond its base rate level

Reversible vs Irreversible Binding - Receptor Affinity and Concentration

Often, neurotransmitters and drugs won't just bind to a receptor permanently but repeatedly bind and unbind. This is the case for reversible binding.

Irreversible binding occurs less commonly where a molecule binds to a receptor and simply doesn't leave. This might sound like it induces a permanent effect. However, receptors are regularly replaced and recycled. So we would say that this molecule binds for the rest of the receptors life until it is destroyed.

The rate at which we see binding is affected by a molecule's affinity, which can be thought of how nicely it fits with the receptor, and the concentration of the molecule. Higher concentrations, in other words, how much of it is present, leads to greater binding

Binding Sites

There are many different places a neurotransmitter or molecule can bind to a receptor, differing by what kind of receptor it is. Without going into too much detail, the important piece to understand here is that there are, in fact, multiple sites with different functions.

The main parts worth covering are:

Orthosteric Site (Primary Binding Site)
- The site that activates the receptor, where endogenous neurotransmitters typically bind
Allosteric Sites
- An alternate site than the orthosteric Site
- When something binds here, it changes the receptor's shape and modulates how the orthosteric site works.

Receptor Subtypes

There are many different kinds of receptors neurotransmitters can bind to, each with different effects. For instance, there are 5 known dopamine receptors and 14 known serotonin receptors.

With that out of the way, we can begin discussing the evolution of antipsychotics.

1st Generation Antipsychotics

The 1st generation antipsychotics were a treatment discovered by accident initially, which is a common backstory for many medications in the psychiatric world. In 1950, chlorpromazine was discovered as an anesthetic for surgery, though it didn't render patients unconscious like most modern anesthetics. The observation of something that could calm and numb patients while keeping them awake gave the idea that such a medication could be used to address mental suffering. Following, the drug discovery field was inspired to develop similar drugs. These were called the "typical" or 1st generation antipsychotics

These medications worked by blocking dopamine receptors. There are 5 unique dopamine receptors, D1-D5, each handling different aspects of cognition and biological function. Most antipsychotics have some level of activity at all of them. Though, the main target of interest is typically the D2 receptor. More simply put, dopamine neurotransmitters intrinsic to the brain would normally bind to these receptors as part of human cognition. The drugs would effectively clog these receptor sites without activating them, thus blocking and reducing dopamine neurotransmission. This led to the theory that psychosis could be attributed to excess dopamine activity, particularly in the prefrontal cortex. One caveat was that the drugs don't particularly discriminate which regions of the brain they target. This theory was later further supported by the evidence that dopamine-based stimulant drugs like amphetamines or meth could induce psychosis.

It's worth detailing the different functions of each dopamine receptor as the different ratios of activity that each drug has affects the corresponding experience a patient has. This will become particularly relevant as we discuss the 3rd generation antipsychotics.

D1 and D5 receptors are considered part of the same family due to their similar roles.

D1 receptors are the most abundant dopamine receptors in the brain. They're heavily involved in:

Reward processing and motivation
Cognitive functions like working memory and attention
Motor control and movement initiation
Regulating blood pressure in the kidneys

D5 receptors are less common but play roles in:

Working memory and decision-making (particularly in the prefrontal cortex)
Attention and cognitive flexibility
Regulating hippocampal function related to learning

Then there's the D2-like family (D2, D3, and D4 receptors)

D2 receptors are perhaps the most clinically significant and are involved in:

Motor control (their dysfunction is central to Parkinson's disease)
Reward and motivation
Prolactin regulation by inhibiting prolactin release from the pituitary. Thus, the blockage of these receptors causes a increase in prolactin, stimulating hormonal functions like breast growth and milk production
They're the primary target of most antipsychotic medications

D3 receptors are found mainly in limbic areas and contribute to:

Emotional regulation and reward processing
Motivation and drug-seeking behavior
Cognitive functions
Social behavior

D4 receptors have more limited distribution and are associated with:

Attention and impulse control
Novelty-seeking behavior
Frontal cortex cognitive functions
Some genetic variants are linked to ADHD

While this was a substantial improvement from the lobotomy, they carried significant side effects. They induced "extrapyramidal symptoms," side effects which impacted one's motor abilities, such as causing tremors, severely uncomfortable restlessness, and tics. The blocking of dopamine can actually be seen as drug-induced Parkinson's disease due to how the symptoms of Parkinson's involve an insufficiency of dopamine in parts of the brain corresponding to motor control. Additionally, there were other side effects around heart risks, prolactin buildup which could cause breast growth, anticholinergic effects which could increase the risk of dementia, and extreme weight gain.

The 1st generation antipsychotics can be thought of as "dirty" drugs. They had affinity for many different receptors of the brain beyond the main treatment target of D2 receptors, kind of like a shotgun approach of hitting anything and everything in neurotransmission and being lucky enough that we managed to hit the receptors that address psychotic symptoms. This is in stark contrast to the SSRI antidepressant (Selective Serotonin Reuptake Inhibitors) which have high affinity for one target and little to none for other receptors in the brain.

For instance, this is the binding profile of Haloperidol, a 1st generation antipsychotic. I like to think of it as the fingerprint of a molecule in it's pharmacology sense. The way to read it is to consider both its action and the Ki value. Lower Ki values indicate greater binding, basically needing less concentration for higher binding rates. In this case, we can see that D3 is the most prominent binding site and D2 being the second highest.

While D2 blocking/antagonism in itself carries side effects, there were many more problems patients had to deal with explained by all the other receptor sites that the drugs affected.

Because of this, non-adherence to medication was a problem. Patients often felt so zombified (given that dopamine plays a role in motivation and mood) and ill that at times it was preferable to live in their pre-medicated problematic state.

Some other 1st generation antipsychotics include:

Haloperidol (Haldol) - became one of the most widely used
Fluphenazine (Prolixin) - available in long-acting injectable form
Perphenazine (Trilafon)
Trifluoperazine (Stelazine)
Thioridazine (Mellaril)

The "happy accident" discovery of 1st generation antipsychotics was that antagonism of dopamine receptors could mitigate psychotic symptoms

2nd Generation Antipsychotics

The 2nd generation antipsychotics (also called the Atypical Antipsychotics), are where we see the first piece of beauty in antipsychotic drug development in my opinion. Namely, it was the discovery that, in addition to the main dopamine receptor blockage, antagonism at the 5ht2a receptor mitigates the significant movement-related side effects and may also have some benefits to depression and other "Negative" symptoms of schizophrenia. A few other notable observations about 5HT2A

It has been observed that patients with suicidal tendencies have high expression of 5HT2A receptors, corresponding to high activity. Thus, blocking them may be beneficial
5HT2A is one of the main targets of many psychedelics, which can be reminiscent of schizophrenic symptoms in hallucinations (however, it's been often said that schizophrenia is better compared to the effects of dissociative like PCP or deliriant like diphenhydramine). Regardless, it is possible that blocking activity here could be relevant to alleviating schizophrenic symptoms as well.

Positive symptoms are "additions" to normal experience while negative symptoms are thought of as absences or reductions of normal experience https://www.verywellhealth.com/schizophrenia-symptoms-8551091

2nd generation psychotics weren't really discovered until the 1990s. Though, the story actually begins earlier with clozapine, discovered in 1958 but not widely used until the 1990s. Clozapine was shelved for years after it caused fatal blood disorders in some patients in Finland in the 1970s. However, researchers noticed it was uniquely effective for treatment-resistant schizophrenia and had minimal movement side effects: a dramatically reduced risk of tardive dyskinesia and similar disorders.

While second-generation antipsychotics did largely deliver on reducing movement side effects, they introduced their own flavor of problems.

Quite notably is extreme metabolic side effects. It is quite common to observe patients gaining 20-50 pounds, suffer from diabetes or insulin resistance, develop high cholesterol and triglycerides, and have increased risk of heart disease and stroke

There are also a number of other side effects from intense sedation, increased prolactin levels which affect hormones, and QT prolongation (heart rhythm changes) with some medications.

A study was conducted known as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) which performed a comparisson of first and second-generation antipsychotics. The results were sobering:

Second-generation antipsychotics weren't clearly more effective than first-generation ones
Patients discontinued second-generation medications at similar rates due to side effects

While all of the 2nd generation antipsychotics share the main characteristics of

Vary in levels of benefits, experience, and side effects like sleepiness, movement issues, and metabolic issues based on its receptor binding fingerprint.

Clozapine (Clozaril) - the prototype, reserved for treatment-resistant cases
Risperidone (Risperdal) - first widely used atypical
Olanzapine (Zyprexa) - became very popular despite weight gain issues and intense sleepiness
Quetiapine (Seroquel) - also used for mood disorders
Ziprasidone (Geodon) - less weight gain than others
Aripiprazole (Abilify) - unique mechanism as a "partial agonist"
Paliperidone (Invega) - active metabolite of risperidone
Lurasidone (Latuda) - newer option with less metabolic effects

For instance, this is the binding profile of Olanzapine. I could imagine that its high inverse agonism activity at H1 (histamine, responsible for wakefulness) and high level of inverse agonism at 5HT2A could partially explain how it causes more fatigue than others.

Also notable, we see a D2L variant and a D2S variant, which correspond to D2 receptors located in Limbic system and Striatum respectively. The striatum is more involved in motor effects, so the effect at each region of the brain is worth considering in drug design.

In a way, it can be sent what we want is blocking D2 in the limbic system which reduces excessive dopamine signaling and corresponds to the reduction of schizophrenia symptoms. Blocking D2 in the striatum is mostly an unintended side effect causing drug-induced Parkinsons. It currently seems difficult to target one but not the other.

Studies have suggested that:

65-70% D2 Limbic occupancy is required for antipsychotic efficacy
>80% D2 Striatum occupancy starts causing significant Extrapyramidal symptoms

On the other hand, risperidone is less infamous for fatigue side effects, which may be explained by less activity at H1

Also really interesting to me is that Lurasidone is unique for being approved for bipolar depression, having possibly stronger antidepressant effects than the others. A very notable characteristic of this drug is that it has very high inverse agonism activity at 5HT7 which is implicated in depression, although research is still quite early here.

The "happy accident" discovery of 2nd generation antipsychotics was that antagonism of the serotonin 5ht2a receptor could mitigate movement side effects and possibly address mood disorders, as well as other activity at other serotonin sites.

3rd Generation Antipsychotics

It is debated whether 3rd generation antipsychotics should actually be recognized as "3rd generation antipsychotics" or if they should be classified as 2nd generation antipsychotics. Like the 2nd generation antipsychotics, they include activity at serotonin receptors, particularly the 5HT2A antagonism. However, what makes them distinct from previous generations is that instead of outright antagonizing/blocking dopamine receptors, they "partially agonize" them. To me, this is particularly fascinating and warrants the novel label.

Partial agonism as a purposefully desired therapeutic mechanism is particularly rare in our medical toolbox, and often, if it does appear, it may not necessarily be a significant component of what is responsible for an overall therapeutic effect.

The result is theorized to be a "stabilizing" effect as opposed to a pure reduction of activity. In other words, when dopamine is low, it can actually raise net dopamine activity. However, when dopamine is high, it reduces dopamine activity. Hence the stabilizing effect of creating a floor to prevent activity from becoming too low and a ceiling to prevent activity from going too high. We can think of this drug acting like a weakened version of dopamine itself, that by competitively taking endogenous dopamine's seat in receptors, can create this regulating effect.

First let's visualize what a post-synaptic neuron might look like in both the cases of low dopamine and high dopamine without the drug in the picture. We'll say that each dopamine molecule contributes an effect of 1.0 while the drug only contributes an effect of 0.6.

Low Dopamine without drug

High Dopamine without drug

Now we'll introduce the drug into the picture

Low Dopamine with Drug

High Dopamine with Drug

Through this mechanism, we could imagine some benefits being:

Lack of loss of motivation, zombification induced by dopamine supression
Reduction of movement problems induced by dopamine supression
Effectiveness against both positive and negative symptoms
Lower risk of weight gain and metabolic problems
Less sedation than many second-generation antipsychotics

While some of these benefits are in fact reported, it is somewhat of a theoretical perspective. Additionally, molecules that act as dopamine agonists are known to have a handful of undesirable effects, my hypothesis being that they activate dopamine receptors without actually having a firing from the presynaptic neuron. In a way, inducing dopamine activity without a corresponding stimuli to warrant it. Not to mention, while dopamine pathways carefully signal and fire in some parts of the brain, these agonists increase activity everywhere. Some Parkinson's disease medications are dopamine agonists, and these effects have been observed in a fairly large percentage of patients. Some of these effects include:

Impulse control disorders - Typically hedonistc behaviors like pathological gambling, compulsive shopping, hypersexuality, or craving more dopaminergic drugs like stimulants. However, we may also see "punding" which describes repetitive purposeless behaviors like sorting objects for hours
Induced schizophrenic symptoms - hallucinations, delirium, confusion, psychosis
Sleep Attacks - Sudden uncontrollable sleep episodes
Mood Issues - Mania, depression, anxiety
Orthostatic hypotension - sudden drop in blood pressure when standing which can cause fainting
Heart Complications
Severe restlessness/akathisia - while antagonists induce extrapyramidal symptoms like tics or tardive dyskinesial, agonists may instead induce restlessness.

Partial agonists may also have these effects, though to lesser degree.

The prototype and most well-known example is aripiprazole (Abilify), introduced in 2002.

Other medications sometimes included in this category are:

Brexpiprazole (Rexulti) - may have less issues of restlessness compared to abilify
Cariprazine (Vraylar) - notable for preferring D3 receptors over D2 receptors, helping with negative symptoms of schizophrenia and possibly less issues we see with D2 antagonism like movement effects. Partially due to the fact that D3 receptors are more present in the limbic system than the striatum.

This is the binding profile of Abilify. We observe relatively low activity at 5HT2A compared to dopaminergic targets, not to mention it is also a partial agonist instead of a full agonist. This lack of typical high levels of antagonism may partially explain restlessness issues. Desirably, we do see higher preference for D2L than D2S.

This is the binding profile of Vraylar. Differing from Abilify, it has inverse agonism at 5HT2A. It has relatively balanced preference for D2L and D2S though it significantly prefers D3 compared to D2.

Where we are in patient tolerability and use cases.

Looking across online reviews, it does seem that patient experience has improved since the 1st generation antipsychotics. However, the reviews between 2nd generation and 3rd generation doesn't appear to show a significant difference. Some of this may be a "pick your poison" in terms of which side effects you can better tolerate. Regardless, this should be taken with a MASSIVE grain of salt given that the demographics of each sample might differ substantially. In other words, the kinds of people and illnesses that are given each drug differ substantially. i.e. Haldol is given to more extreme treatment-resistant cases rarely ever as a first-resort, or how abilify is now often used for autism, ocd, depression, etc.

A 1st generation antipsychotic

A 2nd generation antipsychotic

A 3rd generation antipsychotic

No matter how you slice it though, it looks like we have good headroom for building better experiences for patients.

The Future

There appears to be a few promising directions based on observed pitfalls of each generation's antipsychotics and what we have learned is responsible for therapeutic vs undesirable effects.

Brain region-specific targeting

As mentioned previously, drugs are blind to which part of the brain they have an effect over. That is unless different regions of the brain have different receptors, as is the case with D2S and D2L which are different enough that different molecules may have different affinities for each.

So a few thoughts.

D2L vs D2S balance: Abilify has a fairly stronger preference for D2L than D2S. Is it possible to develop a drug that can target D2L completely with little to no activity in D2L?
Better selectivity more generally, Better Understanding D1-5 effects: Vraylar is interesting for its preference for D3 receptors though it's unclear if this is a valid therapeutic target for reducing schizophrenia symptoms. Regardless, it is recognized as having capable antidepressant activity for reasons I believe are mostly unexplained. What kinds of affinities and agonism vs antagonism might be beneficial at each of the D1-D5 receptors?
Targeted Delivery: It may be desirable to somehow target certain areas like limbic system, striatum, prefrontal cortex, etc. in cases where we do not have different receptor subtypes, meaning that relying on varying receptor affinities will not benefit us here. Is it possible to one day deliver medication locally to a region of the brain that will constitute a benefit while avoiding hitting other regions? As far as I know, this is currently not possible from oral route medication, an "all or nothing" kind of principle.
Better Serotonergic Understanding: While 5HT2A is the primary target for reducing movement symptoms and some antidepressant effects, these drugs typically hit many other serotonin subtypes, some of which have substantial therapeutic effects like 5HT7. What else might we discover here?
Factorized Selectivity: All generations of antipsychotic drugs have been "dirty" in regards to their affinities for many kinds of receptors beyond those of interest. Currently, we generally aim to hit both 5HT2A and D2 primarily. Though a single drug for both of these targets may lend itself to having many more targets? Similar to SSRIs, can we develop several drugs intended to be taken together for high levels of specificity or only single target? One benefit of this is that customized treatment plans could be developed by balancing the doses of, say, the drug responsible for dopamine antagonism and the drug responsible for 5HT2A antagonism. On the other hand, this could create more complexity in figuring out the optimal balancing act of doses. Not to mention, different drugs may each have different half life's, or durations of effect, requiring different frequencies at which each drug is taken.

However, this all hardly scratches the surface of what's possible when we get tunnel vision on the typical D2 and 5HT2A blockade that has been in place for 70 years.

Some other researched directions include:

Muscarinic receptor agonists (M1/M4) - Xanomeline-trospium (KarXT/Cobenfy) - just FDA approved in 2024, this is the first truly novel mechanism in decades
- Activates M1 and M4 muscarinic acetylcholine receptors
- Early trials show efficacy for positive AND negative symptoms without the typical D2-related side effects (no EPS, no prolactin elevation, no weight gain)
- Trospium is added to block peripheral muscarinic side effects (nausea, etc.)
TAAR1 (Trace Amine-Associated Receptor 1) agonists:
- Ulotaront (in Phase 3 trials)
- Modulates dopamine and glutamate systems indirectly
- Potential for efficacy without direct D2 blockade
- May help with negative and cognitive symptoms
Glutamate-Based Approaches
1. NMDA receptor modulators
  - Rather than blocking receptors, these aim to enhance NMDA function (which may be deficient in schizophrenia)
  - Glycine site agonists - enhance NMDA function at the glycine co-agonist site
  - D-serine - a co-agonist at NMDA receptors being tested as an add-on therapy
  - Potential to address negative and cognitive symptoms that D2 blockers don't help
2. mGluR2/3 agonists:
  - Target metabotropic glutamate receptors
  - Could modulate glutamate release presynaptically
Imaging techniques to better classify subtypes of schizophrenia and the exact kinds of needs
1. Subtyping schizophrenia:
  - Using neuroimaging, genetics, and biomarkers to identify distinct subtypes
  - Some patients may have primarily dopamine dysregulation, others glutamate dysfunction, others inflammation
2. Predicting treatment response:
  - PET imaging to measure D2 occupancy and predict response
  - Genetic markers (like variants in dopamine or serotonin genes) to guide drug selection
  - EEG/MEG patterns to identify who will respond to which medication
Inflammation and Immune Approaches - Growing evidence links immune dysfunction to psychosis
1. Anti-inflammatory strategies:
  - Minocycline - antibiotic with anti-inflammatory properties, showing promise in early psychosis
  - COX-2 inhibitors - celecoxib as add-on showing modest benefits
  - Monoclonal antibodies targeting specific cytokines in inflammation-related psychosis
2. Autoimmune psychosis:
  - Better recognition of NMDA receptor encephalitis and other autoimmune causes
  - Immunotherapy (steroids, IVIG, rituximab) for appropriate cases
  - May help identify a subset of "schizophrenia" that's actually autoimmune
Circuit-Based and Neuromodulation Approaches
1. Targeted brain stimulation:
  - Transcranial magnetic stimulation (TMS) for auditory hallucinations (targeting specific cortical areas)
  - Transcranial direct current stimulation (tDCS) for negative symptoms
  - Deep brain stimulation (DBS) for treatment-resistant cases (experimental)
  - These can target specific dysfunctional circuits without systemic drug effects
2. Closed-loop systems:
  - Devices that detect aberrant brain activity and deliver stimulation only when needed
  - Like a "pacemaker for the brain" but for psychosis
6. Cannabinoid System Modulation
1. CBD (cannabidiol):
  - Some evidence for antipsychotic properties with adifferent mechanism than typical antipsychotics
  - May be particularly useful in cannabis-induced psychosis
2. CB2 receptor modulation:
  - Avoiding the psychoactive CB1 receptors
  - Targeting inflammation and neuroprotection
Neuroplasticity and Cognitive Enhancement - Recognizing that cognitive deficits are core to schizophrenia:
1. Cognitive remediation + pharmacology:
  - Combining cognitive training with medications that enhance plasticity
  - Nicotinic α7 receptor agonists for cognition
  - Phosphodiesterase inhibitors to enhance learning
2. Brain-derived neurotrophic factor (BDNF) enhancement:
  - Approaches to increase neuroplasticity and neurogenesis
  - May help reverse some structural brain changes
Biased Agonism and Functional Selectivity - More sophisticated pharmacology:
1. Biased D2 ligands:
  - Drugs that activate only certain downstream signaling pathways from D2 receptors. While the drug still binds to the same receptor, it might be able to be biased towards activating one pathway more than another.
  - Could get therapeutic benefits of D2 modulation without all the side effects
  - Effectively we may want to have β-arrestin pathway weakly activated while G-protein pathway to be more strongly activated

As mentioned in my other post, we are still in the stone age of psychiatric treatments and there has never been a better time to contribute to future developments.