Chapter 33: Biologic Therapies

Welcome to Last Minute Lecture.

This free chapter overview is designed to help students review and understand key concepts.

These summaries supplement not replaced the original textbook and may not be redistributed or resold.

For complete coverage, always consult the official text.

Welcome to the Deep Dive.

Today, you've asked us to get into a really foundational source,

a key chapter on biologic therapies from a big psychiatry textbook.

It's pretty dense stuff, technical, but absolutely critical for understanding how we treat the brain.

It really is.

And our goal here isn't just listing definitions.

We want to give you a clear framework for the core neurobiology, the history, the way drugs are classified now, and some really essential clinical principles in psychopharmacology.

We're aiming to pull out the connection so you see the whole picture, not just isolated facts.

Exactly.

So let's dive right in where the action happens down to the cellular level.

When we talk about drugs affecting the brain, we're fundamentally talking about receptors, the brain's sort of communication hubs.

The text highlights two main kinds of these intrinsic ion channels.

That's right.

First up, you've got the voltage gated channels.

These are the ones like sodium, potassium, calcium channels that respond to changes in electrical charge across the cell membrane.

And the source points out that mutations here, genetic changes, lead to conditions called

Channelopathies.

Like what specifically?

Things like familial migraine or certain types of dystonia.

Basically disorders where the fundamental electrical signaling machinery is flawed because of the channel structure.

Okay.

So if those are the electrical switches, then the G protein coupled receptors or GPCRs are more like the chemical signal receivers.

This cascade always seemed, well, pretty intricate.

Can you break that down a bit?

It is complex.

Yeah, but really fascinating.

So think of an agonist, maybe a drug, maybe a natural neurotransmitter binding to that GPCR.

It's like a key fitting into a lock on the outside of the cell.

Right.

Inside the cell, this triggers the associated G protein.

It swaps out a molecule called GDP for a higher energy one, GTP, specifically on its alpha subunit.

That swap essentially flips the on switch for the G protein.

Okay.

And that activated G protein then goes on trigger other downstream effects.

The next steps in the cell's response.

Now this next bit the source covers is where things get really interesting, almost counterintuitive.

Yeah.

How does the cell turn off this signal?

You mentioned something called biased agonism.

Exactly.

It's not just a simple off switch.

Termination involves these specific proteins,

GPCR kinases or GRKs, and then proteins called arrestins.

For a long time, people thought arrestins just, you know, arrested the signal, stopped it.

Which makes sense, given the name.

Right.

But what we now understand, and the text emphasizes this, is that arrestins can actually kick off their own separate signaling pathways inside the cell, like the ERK pathway, for example.

And they can do this without involving the G protein pathway at all.

Wait.

So the same receptor, when activated, could trigger the G protein path or this arrestin path, depending on what?

The drug.

Precisely.

That's a biased agonism.

A specific drug, an agonist, might have a bias.

It might preferentially activate the arrestin pathway over the G protein pathway or vice versa.

Another drug hitting the same receptor might have a different bias.

Wow.

So that could explain why two drugs targeting the same receptor have different effects or side effects.

Exactly.

It opens up huge possibilities for designing drugs with more specific effects and maybe fewer side effects by targeting these biased pathways.

And the cell itself adds another layer of control with its structure.

The text mentions lipid rafts.

What are those about?

Yeah, think of the cell membrane not as just a uniform C, but as having these organized little platforms.

The lipid rafts, some are flat, some are little indentations called caveole.

These rafts act like organizing centers.

They can cluster together the necessary signaling molecules, the receptor, the G protein, the downstream effectors to make signaling more efficient.

Or they can do the opposites.

They can separate these components, keeping them apart, which would effectively dampen or inhibit the signal.

So the local environment directly controls the signal strength.

Makes sense.

Okay, let's zoom out from the cell to the bigger picture.

The history of these biologic therapies, it's not exactly a straight line, is it?

We use plant extracts for centuries.

Alcohol, coffee, opium.

Right.

And then came electroconvulsive therapy, ECT.

From the 1930s to the 50s, despite its, let's say, challenging image, it was actually the most effective treatment available for severe psychiatric disorders.

Still very effective today, of course.

Absolutely.

But a key moment, often overlooked, was way back in 1931.

A report from India described the effects of raw wolfia serpentina.

This eventually led to the drug reserpine, and that discovery really kickstarted research into monoamines, dopamine, serotonin, norepinephrine, which became central to And then there's lithium,

reported effective in 1949, but it took decades to become a standard treatment for bipolar disorder.

Why the delay?

It's complex, part skepticism, part lack of commercial interest initially, perhaps, but it highlights a recurring theme.

The path from discovery to widespread clinical use can be surprisingly long and bumpy.

Which kind of leads into the problem with how we used to classify these drugs, right?

We tend to name them by what primarily treat antipsychotics, antidepressants, but the text argues this is problematic.

Deeply problematic.

Because very few psychotropic drugs are truly specific to one diagnosis.

Think about benzodiazepines.

They're great anxiolytics, but also effective hypnotics, muscle relaxants, or SSRIs.

We call them antidepressants, but they're first -line treatments for panic disorder, OCD, even some pain conditions.

The label often doesn't capture the

So what's the alternative?

The text pushes for this neuroscience -based nomenclature, the NBN.

Yes, and it's a much more logical approach.

Instead of naming a drug by the illness it treats,

NBN classifies it based on its mechanism.

It looks at the pharmacology domain, which neurotransmitter system is it primarily interacting with.

Dopamine, serotonin, dot GABA.

And then the mode of that action, what is it actually doing to that system?

Is it an antagonist, an agonist, a reuptake inhibitor?

So it focuses on the how rather than the what for.

Exactly.

It gives clinicians a much clearer, more rational way to think about how these drugs work and how they might be combined or substituted.

Okay, let's use that NBN thinking as we look at the major drug classes, starting with the one that arguably launched modern psychopharmacology,

the antipsychotics.

Or, as NBN might prefer, dopamine antagonists or dopamine serotonin antagonists.

It all started with chlorpromazine in 1950.

What made it so revolutionary?

It wasn't just sedation.

Before chlorpromazine, sedatives just knocked people out.

Chlorpromazine produced something different.

Patients became,

the descriptions were indifferent and tranquil.

It seemed to target the core psychotic symptoms, the agitation, the delusions in a way nothing had before.

And the basic mechanism we figured out later was.

The standard view is blocking the dopamine type two D two receptor.

That seems key for treating psychosis.

But then came the newer agents, the atypicals, which NBN calls dopamine serotonin antagonists, DSAs.

What makes them different and why do they often have fewer movement side effects?

The key pharmacological distinction is that besides blocking D two receptors, they also have a high affinity for blocking a specific serotonin receptor, the 5HT2A receptor.

Okay, D2 plus 5HT2A blockade.

Right.

And the leading hypothesis for why they generally cause less EPS, those Parkinson's like symptoms, the stiffness, the restlessness, is related to how they bind to the D2 receptor.

How so?

They seem to bind more loosely and transiently compared to the older conventional antipsychotics.

They block D2, but then they come off relatively quickly.

This kiss and run binding might allow for more normal pulsatile dopamine signaling to get through in pathways controlling movement, like the Negrostriatal pathway, reducing the risk of EPS.

Interesting.

Okay, let's get practical.

The chapter details several specific DSAs critical clinical points.

We absolutely have to talk about clozapine.

Yes, clozapine is sort of unique.

It's reserved specifically for treatment resistant schizophrenia.

That means you have to have tried and failed other antipsychotics first.

It can be remarkably effective when others aren't.

The risks are serious.

Extremely serious.

The biggest concern is a granulocytosis, a potentially fatal drop in white blood cells.

This mandates strict regular blood monitoring.

You literally cannot get the drug without the blood tests.

There's also a significant seizure risk.

But it has a unique benefit regarding movement disorders.

Yes.

Unlike most antipsychotics, which can cause tardive dyskinesia,

TD, clozapine seems to actually suppress it or treat it, which is quite remarkable.

Okay, moving on.

Metabolic side effects are a huge issue with some DSAs, like olanzapine.

A major issue.

Olanzapine is very effective, particularly for acute mania and agitation.

The IM form works fast, but it has a very high liability for significant weight gain and associated risks like diabetes and high cholesterol.

It's a serious trade -off.

And there's a black box warning, too.

Yes.

For increased mortality risk when used to create psychosis or agitation in elderly patients with dementia.

It's not approved for that use.

Another one with a specific warning is Zipracidone.

What's the key concern there?

Cardiovascular risk.

Zipracidone can cause dose -related QT prolongation on the EKG.

This increases the risk of a dangerous heart rhythm called torsades de pointes.

Caution and monitoring are needed, especially at higher doses or with other QT prolonging drugs.

And there's a crucial administration point for Zipracidone.

Absolutely critical.

It must be taken with food, ideally a meal of at least 500 calories.

Its absorption, its bioavailability basically doubles when taken with food compared to on an empty stomach.

If a patient takes it without food, they're likely getting a subtherapeutic dose.

Good to know.

Okay, let's shift gears to antidepressants and anxiolex.

SSRIs, selective serotonin reuptake inhibitors are everywhere.

Used for depression, anxiety, OCD, PTSD.

But the big question is always the delayed onset.

Why does it take two, four, even six weeks to work when the drug gets into the brain right away?

Yes, the paradox.

It's a fascinating piece of neurobiology.

The SSRI immediately blocks the serotonin transporter.

Serotonin levels in the synapse go up quickly.

But initially, this increased serotonin strongly activates the 5H21A autoreceptors.

These are like feedback breaks located on the serotonin neuron itself.

When they get hit with all that extra serotonin, they tell the neuron to slow down to fire less.

So paradoxically, the net effect early on can be decreased serotonin release in some brain regions.

So the drug's immediate effect puts the brakes on the system it's trying to boost.

Exactly.

The therapeutic benefit only really kicks in once those 5H21A autoreceptors gradually become less sensitive.

They desensitize over about 14 to 21 days.

Once the brakes are less sensitive, the increased serotonin from reuptake inhibition can finally lead to a sustained increase in serotonergic neurotransmission.

The delay is the time it takes for the brakes to wear down.

That makes so much sense.

Okay, safety points for SSRIs.

The black box warning.

Yes.

The FDA warning highlights the need to closely monitor both adult and pediatric patients for worsening depression or the emergence of suicidal thoughts or behaviors, particularly during the initial weeks of treatment or when the dose has changed.

It's a crucial period.

And a major drug interaction to avoid.

Absolutely never combine SSRIs with irreversible MAOIs, monoamine oxidase inhibitors.

The risk is serotonin syndrome, a potentially fatal condition caused by excessive serotonin activity symptoms include confusion, agitation, fever, sweating, tremor, muscle rigidity, and potentially cardiovascular collapse.

Needs a washout period between these drug classes.

Got it.

What about the SNRIs, the serotonin norepinephrine reuptake inhibitors?

What's their main edge over older drugs like the tricyclics, TCAs?

Primarily it's selectivity.

Like SSRIs, they hit the serotonin transporter, cert, but they also hit the norepinephrine transporter, net.

Unlike the older TCAs though, they have much less affinity for other receptors like muscarinic acetylcholine receptors, histamine H1 receptors, or alpha -adrenergic receptors, which means fewer of those troublesome side effects common with TCAs like dry mouth, constipation, sedation, dizziness, orthostatic hypotension.

SNRIs generally have a much cleaner, more tolerable side effect profile.

Makes sense.

Let's quickly touch on buspirone.

It's used for anxiety, but it's not a benzodiazepine.

Unique mechanism.

Yes, very different.

It's a full agonist at the presynaptic 5H21A autoreceptor, initially acts like the SSRIs, putting the brakes on serotonin release.

But it's a partial agonist at the postsynaptic 5H21A receptors.

Like SSRIs, it also has a delayed onset of action, usually taking at least two weeks.

And clinicians sometimes use it for?

It's sometimes used as an add -on strategy to help mitigate SSRI -induced sexual dysfunction, although the evidence for that is somewhat mixed.

It doesn't cause sexual side effects itself.

Okay, and briefly, psychostimulants for ADHD.

Right, drugs like methylphenidate and amphetamine salts, primarily used for ADHD and sometimes narcolepsy.

Their main mechanism is blocking or even reversing the dopamine transporter, DAD, and the norepinephrine transporter, NET, increasing levels of DA and NE in the synapse, particularly in the prefrontal cortex.

They're highly effective for core ADHD symptoms, restlessness, inattention, impulsivity, with response rates around 65 -75%.

Let's move to the mood stabilizers.

Starting with lithium.

It's unique, right?

An element, not a synthesized drug.

Exactly, just lithium salts.

Its mechanism is complex and still not fully nailed down, but it involves multiple intracellular signaling pathways, notably the inhibition of an enzyme called glycogen synthase kinase 3, GSK3.

The chapter mentions something interesting about thyroid function in lithium, TSH levels.

Yes, this is a really important clinical point.

It's quite common for patients on lithium to develop an elevated thyroid stimulating hormone or TSH level, but often their actual circulating thyroid hormones, T3 and T4, remain perfectly normal.

So the TSH is high, but the thyroid output is okay.

How does that work?

It's considered a compensated hypothyroidism.

The pituitary gland is shouting louder, high TSH, to get the thyroid to produce enough hormone, and the thyroid is managing to do it.

So the key is to check the T3 and T4 levels.

If they are normal, this TSH elevation alone is usually not a reason to stop lithium, especially if it's working well for the patient's mood you just monitor.

That's a critical distinction.

Okay, on to the anticonvulsants used as mood stabilizers, Valprod or Divalprox.

Very effective, especially for acute mania, particularly those mixed states or manias with irritability or dysphoria.

Interestingly, while it does enhance GABA activity, the textbook points out that this GABA effect is probably not the main reason it works for mania, because other GABAergic drugs like benzodiazepines aren't effective as primary antimanics.

The exact mechanism is still debated.

Then there's Lamotrigine, often described differently.

Yes, it's often thought of as stabilizing mood from below.

It seems to have stronger efficacy in preventing or treating bipolar depression compared to mania, although it has benefits for both.

And it has a major drug interaction warning.

Absolutely critical.

If a patient is taking Valprod, you must start Lamotrigine at a lower dose and titrate it much more slowly, typically reducing the starting dose and titration rate by 50%.

Why is that?

Because Valprod significantly inhibits the enzyme that metabolizes Lamotrigine.

So taking them together roughly doubles the blood level of Lamotrigine.

This dramatically increases the risk of developing a serious, potentially life -threatening rash like Stevens -Johnson syndrome, SJS, or toxic epidermal necrolysis, TEN.

Slow titration is essential for safety, especially with Valcroc co -administration.

That's a potentially dangerous interaction.

And carbamazepine also carries a significant rash risk linked to genetics.

Correct.

Carbamazepine's mood -stabilizing and anticonvulsant effects are thought to relate to blocking voltage -gated sodium channels.

It's effective for acute mania, comparable to lithium or older antipsychotics.

But yes, there's a known risk of severe rashes like SJS -TEN, particularly associated with specific HLA gene variants.

Which ones?

The HLA -B1502 allele, which is much more common in people of Asian descent,

significantly increases the risk.

Genetic screening for this allele is recommended before starting carbamazepine in these populations.

There's also an association, though perhaps less strong, with HLA -A3D101 and rash risk in some Northern European and Japanese populations.

Okay, stepping back from specific drugs, the chapter outlines some overarching clinical principles.

Given all these options and risks, what's key for successful treatment?

Well, first is acknowledging the heterogeneity of response.

People vary wildly in how they respond to medications due to genetics, environment, and other factors.

This means dosage often isn't fixed.

It's coming through careful trial and error, starting within usual ranges and adjusting based on response and side effects.

So patients and personalization are key.

Absolutely.

And underpinning all of that is the therapeutic alliance.

Building a strong, trusting relationship between the clinician and patient is crucial.

These medications often have side effects.

The response can be unpredictable.

Patients might need to try several agents.

Good adherence and weathering the ups and downs really depend on that strong alliance.

We should also quickly clarify two terms that often get mixed up.

Potency versus efficacy.

Good point.

Potency refers to the amount of drug needed to produce a given effect.

So drug A might be more potent than drug B if you need a smaller dose, say 5 mg versus 100 mg, to get the same effect.

Haloperidol, for example, is much more potent than chlorpromazine.

But potency isn't the whole story.

Not at all.

Efficacy refers to the maximum effect a drug is capable of producing, regardless of the dose.

So while haloperidol is more potent, you need less emuline.

It and chlorpromazine are generally considered to have equal maximum efficacy in treating psychosis.

One is an inherently stronger in its ultimate potential effect, just in the dose needed.

Excellent clarification.

Finally, let's quickly run through some major adverse event categories.

The movement disorders,

extrapyramidal syndromes, EPS, are a big one with older antipsychotics and still a risk with DSAs.

Right.

And it's important to differentiate them.

You have acute EPS, which includes things like acute dystonia, muscle spasms, often neck or eyes, akathisia, that awful inner restlessness, inability to sit still, and Parkinsonism, tremor, rigidity, slow movement.

These tend to happen early in treatment, often dose -related, and usually respond quickly to dose reduction or anti -cholinergic meds like benztropine or defenhydramine.

And then there's the delayed one.

Tardive dyskinesia, TDA.

This typically emerges after months or years of treatment.

It involves involuntary movements, often of the face, tongue, lips, chewing, puckering, grimacing, but can also affect limbs and trunk.

It's often persistent, even after stopping the offending drug, and the risk is higher in older adults, women, and patients with mood disorders.

Managing TD is much trickier, often involving switching to an agent with lower TD risk, like clozapine, or using specific VMAT2 inhibitor drugs.

And the really rare but life -threatening one.

Neuroleptic malignant syndrome, NMS.

It's uncommon, but a true medical emergency.

Key features are severe muscle rigidity, lead pipe rigidity, hyperthermia, high fever, autonomic instability, fluctuating blood pressure, heart rate sweating,

and altered mental status.

Confusion stupor.

You'll also see lab evidence of muscle breakdown, like a very high creatine kinase CK level, require immediate cessation of the antipsychotic and intensive supportive care.

And briefly, cardiovascular risks.

Yes, mainly the QTC prolongation we mentioned with the zeprosidone.

Some older, low -potency agents like chlorpromazine and especially theortazine also carry this risk.

Prolonging the QTC interval increases the risk of torsades de pointe, a potentially fatal ventricular arrhythmia, needs careful consideration, especially with interacting meds or pre -existing heart conditions.

Finally, a note on special populations, like children.

Yes, the chapter notes that while we use many of these drugs in children and adolescents, especially for things like ADHD or OCD, where there's good evidence, much of the broader use is based more on clinical experience and extrapolation than large -scale trials specifically in kids.

Dosing needs extra caution.

The principle is often, start low, go slow, because kids metabolize drugs differently than adults, and their developing brains might be more sensitive.

Wow.

That was a very thorough journey through a complex chapter.

If you had to boil down the message, the synthesis of all these mechanisms, risks, principles, what would it be?

I think it comes down to the absolute necessity of an individualized risk -benefit assessment for every single patient.

As we've seen, these agents are powerful, they often aren't diagnosis specific, hence the move towards mechanism -based naming like NBN, but every single one from lithium to the DSAs to the SSRIs carries potential risks, cardiac, metabolic, hematologic, neurologic.

The art and science of psychopharmacology is constantly weighing the potential benefits for that specific person against those very real risks.

That careful balancing act.

Which leads us to a final thought, something for you, the listener, to perhaps mull over after this deep dive.

We've discussed how these sophisticated biologic treatments primarily aim to control symptoms rather than cure the underlying disorders, many of which are chronic with high relapse rates.

So considering that, what are the broader societal,

ethical, maybe even personal implications of treatments often requiring long -term, potentially indefinite medication simply to manage symptoms and maintain function?

Yeah, it's a complex question with no easy answers, but definitely worth reflecting on as these treatments continue to evolve and shape how we approach mental health care.

Thank you so much for joining us today for this deep dive into the critical area of biologic therapies in psychiatry.