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PSYCH 148: Endocrine and Metabolic Disorders · Clinical Deep Dives

• 0:00
  SPEAKER_00: So I want to start today's deep dive with a story about a 42-year-old woman.
• 0:03
  SPEAKER_00: Let's just call her Ms. A.
• 0:04
  SPEAKER_01: Okay.
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  SPEAKER_00: And she is this incredibly dedicated marathon runner,
• 0:09
  SPEAKER_00: you know, totally disciplined and fantastic physical health.
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  SPEAKER_00: And she has absolutely zero history of any psychiatric illness.
• 0:17
  SPEAKER_00: I mean, not even a mild depressive episode in her past.
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  SPEAKER_01: Right.
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  SPEAKER_01: A completely clean slate.
• 0:21
  SPEAKER_00: Exactly.
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  SPEAKER_00: But a few weeks before a major race, she develops this really severe tendinitis in her knee.
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  SPEAKER_00: So she goes to her sports medicine doctor and they want to aggressively reduce
• 0:31
  SPEAKER_00: the inflammation so she can compete.
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  SPEAKER_01: Which makes sense.
• 0:34
  SPEAKER_00: Yeah.
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  SPEAKER_00: So the doctor prescribes her 60 milligrams a day of prednisone,
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  SPEAKER_00: which, you know, is a really potent synthetic corticosteroid.
• 0:42
  SPEAKER_01: Yeah.
• 0:43
  SPEAKER_01: And I should add that is a fairly standard,
• 0:45
  SPEAKER_01: albeit high dose medical intervention for that kind of acute severe inflammation.
• 0:50
  SPEAKER_00: Right.
• 0:50
  SPEAKER_00: It makes perfect orthopedic sense.
• 0:52
  SPEAKER_00: But within 24 hours of taking that very first dose,
• 0:55
  SPEAKER_00: Mrs. A's husband notices something is deeply, deeply wrong.
• 1:00
  SPEAKER_01: Oh, wow.
• 1:00
  SPEAKER_01: That fast.
• 1:01
  SPEAKER_00: Yeah, that fast.
• 1:02
  SPEAKER_00: She stops sleeping entirely.
• 1:04
  SPEAKER_00: But the weird thing is she isn't tired.
• 1:06
  SPEAKER_00: In fact, her energy is completely off the charts.
• 1:09
  SPEAKER_01: Right.
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  SPEAKER_01: She's hyper aroused.
• 1:11
  SPEAKER_00: Exactly.
• 1:12
  SPEAKER_00: Her speech becomes heavily pressured,
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  SPEAKER_00: just tumbling out of her mouth so fast her husband can barely understand
• 1:17
  SPEAKER_00: a word she's saying.
• 1:19
  SPEAKER_00: She knows she is supposed to be resting her injured knee,
• 1:22
  SPEAKER_00: but instead she is frantically compulsively cleaning their house from top to bottom
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  SPEAKER_00: at three in the morning.
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  SPEAKER_01: Wow.
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  SPEAKER_00: And when her husband tries to get her to stop she becomes intensely irritable
• 1:34
  SPEAKER_00: and profoundly anxious.
• 1:35
  SPEAKER_01: You know if a patient like that presented in a psychiatric emergency room
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  SPEAKER_01: The clinical picture looks absolutely identical to an acute manic episode.
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  SPEAKER_00: Spot on.
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  SPEAKER_01: Yeah, I mean,
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  SPEAKER_01: you would be completely forgiven for immediately thinking about
• 1:48
  SPEAKER_01: a new onset bipolar disorder.
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  SPEAKER_00: But it isn't bipolar disorder.
• 1:52
  SPEAKER_00: It's the prednisone.
• 1:53
  SPEAKER_00: Her psychiatric symptoms are a direct,
• 1:55
  SPEAKER_00: immediate consequence of a chemical that was introduced just to treat her knee.
• 2:00
  SPEAKER_00: And this scenario cuts right to the heart of what we are exploring today in this deep dive.
• 2:06
  SPEAKER_00: We're using Chapter 27.7 of Kaplan and Sadoc's Comprehensive Textbook of Psychiatry
• 2:12
  SPEAKER_00: as our foundation.
• 2:12
  SPEAKER_01: Which covers endocrine and metabolic disorders.
• 2:15
  SPEAKER_00: Exactly.
• 2:16
  SPEAKER_00: And our goal here for you,
• 2:18
  SPEAKER_00: the listener,
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  SPEAKER_00: whether you are a psychiatry trainee,
• 2:21
  SPEAKER_00: a seasoned clinician,
• 2:22
  SPEAKER_00: or just someone fascinated by the human body,
• 2:25
  SPEAKER_00: is to completely dismantle the idea that the brain operates in isolation.
• 2:30
  SPEAKER_01: Because it absolutely does not.
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  SPEAKER_01: I mean, the central thesis of this chapter and really the foundational principle
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  SPEAKER_01: of modern neuropsychiatry is that the line we draw between medical conditions
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  SPEAKER_01: and psychiatric conditions is largely an artificial construct.
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  SPEAKER_00: It's just a category we made up.
• 2:45
  SPEAKER_01: Yes, exactly.
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  SPEAKER_01: It is a boundary we invented for administrative convenience and,
• 2:49
  SPEAKER_01: you know, medical specialization.
• 2:51
  SPEAKER_01: Your patient's body certainly does not recognize that boundary.
• 2:54
  SPEAKER_00: Right.
• 2:54
  SPEAKER_00: So for this deep dive, we really need to establish a solid working definition of psychiatry.
• 3:00
  SPEAKER_00: We aren't just talking about ticking off a checklist of symptoms in a manual.
• 3:03
  SPEAKER_01: No, definitely not.
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  SPEAKER_00: We are defining psychiatry as the rigorous study of how the brain,
• 3:09
  SPEAKER_00: the mind, and a person's lived experience interact in real time.
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  SPEAKER_00: And crucially, how that intricate, delicate process can go wrong.
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  SPEAKER_01: And to understand how it
• 3:38
  SPEAKER_01: Exactly.
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  SPEAKER_01: This vast network of chemical messengers just traveling through the bloodstream.
• 3:42
  SPEAKER_00: Let's visualize this.
• 3:44
  SPEAKER_00: Instead of thinking of the body as a machine made of distinct separate parts,
• 3:48
  SPEAKER_00: I want you to think of it like
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  SPEAKER_00: a highly advanced modern smart home climate control system.
• 3:52
  SPEAKER_01: Oh, I like that.
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  SPEAKER_01: That is a much more functional analogy.
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  SPEAKER_00: Right.
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  SPEAKER_00: So in your house, you have the main thermostat on the wall in the hallway.
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  SPEAKER_00: That thermostat is the hypothalamus in the brain.
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  SPEAKER_00: It is constantly reading the ambient environment.
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  SPEAKER_01: Taking the temperature, so to speak.
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  SPEAKER_00: Exactly.
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  SPEAKER_00: Is it too hot?
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  SPEAKER_00: Is it too cold?
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  SPEAKER_00: Are we stressed?
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  SPEAKER_00: Do we have enough energy?
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  SPEAKER_01: And when the hypothalamus senses a shift,
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  SPEAKER_01: it doesn't directly turn on the furnace or the air conditioning.
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  SPEAKER_01: It sends a short-range wireless signal to the main control board located down in the basement.
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  SPEAKER_00: And that control board is the pituitary gland.
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  SPEAKER_00: We often call it the master relay station.
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  SPEAKER_01: Right.
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  SPEAKER_01: So the pituitary gland receives that signal.
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  SPEAKER_01: Interprets it and then sends its own hardwired signals out to
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  SPEAKER_01: the actual heavy machinery located throughout the house.
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  SPEAKER_00: So it signals the furnace,
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  SPEAKER_00: which we can think of as a thyroid gland regulating the baseline heat and energy.
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  SPEAKER_00: Yeah.
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  SPEAKER_00: It signals the emergency backup generators,
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  SPEAKER_00: which are the adrenal glands, managing our response to sudden stress.
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  SPEAKER_00: It signals the complex ductwork and energy storage systems like the pancreas and
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  SPEAKER_00: the metabolic system.
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  SPEAKER_01: It signals the reproductive systems, the gonads.
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  SPEAKER_00: Right.
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  SPEAKER_00: But the true genius of this system and the place
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  SPEAKER_00: where it most frequently breaks down is the feedback loop.
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  SPEAKER_00: This is crucial.
• 5:05
  SPEAKER_00: Yeah.
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  SPEAKER_00: When the furnace,
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  SPEAKER_00: the thyroid,
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  SPEAKER_00: turns on and starts pumping heat into the house,
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  SPEAKER_00: that heat eventually reaches the thermostat in the hallway.
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  SPEAKER_00: The hypothalamus senses the rising temperature and says, OK, we have enough heat.
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  SPEAKER_01: So it stops sending the signal to the basement control board.
• 5:21
  SPEAKER_00: Exactly.
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  SPEAKER_00: The control board stops signaling the furnace and the furnace shuts down.
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  SPEAKER_00: This is what we call a negative feedback loop.
• 5:27
  SPEAKER_01: And as we journey through this physiological smart home today,
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  SPEAKER_01: you are going to see one central unbreakable rule governing everything.
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  SPEAKER_01: It is a continuous multidirectional flow.
• 5:38
  SPEAKER_00: Hormones to brain to behavior.
• 5:39
  SPEAKER_01: Yes.
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  SPEAKER_01: Hormones alter the physical state of the brain.
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  SPEAKER_01: The altered brain dictates a change in behavior and that behavior in turn influences
• 5:47
  SPEAKER_01: the production of hormones.
• 5:49
  SPEAKER_01: Hormones interacting with the brain dictating behavior.
• 5:52
  SPEAKER_00: The clinical pearl here for you listening is profound.
• 5:55
  SPEAKER_00: Endocrine disorders these malfunctions in
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  SPEAKER_00: the smart home system frequently produce psychiatric symptoms incredibly early
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  SPEAKER_00: in their disease course.
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  SPEAKER_01: Absolutely.
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  SPEAKER_01: A malfunctioning thyroid or
• 6:05
  SPEAKER_01: a struggling pancreas will often throw off psychiatric sparks weeks,
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  SPEAKER_01: months, or even years before you see the classic physical stigmata of the disease.
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  SPEAKER_00: So that patient sitting in your clinic
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  SPEAKER_00: with what looks like treatment resistant depression or that patient
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  SPEAKER_00: who suddenly develops severe panic attacks out of nowhere in their 40s.
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  SPEAKER_00: Right.
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  SPEAKER_00: They might not have a primary psychiatric illness at all.
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  SPEAKER_00: Their symptoms might be a distress signal coming straight from
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  SPEAKER_00: a broken hormonal feedback loop in the basement.
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  SPEAKER_01: Which makes a rigorous understanding of the endocrine system a non-negotiable part
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  SPEAKER_01: of your differential diagnosis.
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  SPEAKER_01: You really cannot responsibly treat psychiatric distress without verifying that
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  SPEAKER_01: the underlying chemical infrastructure is actually intact.
• 6:49
  SPEAKER_00: Let's dive deeper into the architecture of this control system,
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  SPEAKER_00: starting with that master relay station, the pituitary gland.
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  SPEAKER_01: Right, because to understand the clinical manifestations we see in patients,
• 6:59
  SPEAKER_01: we have to understand the specific language these organs are using to speak
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  SPEAKER_01: to one another.
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  SPEAKER_00: So endocrinology fundamentally studies hormones.
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  SPEAKER_00: These are biochemical mediators.
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  SPEAKER_00: And they come in a few different structural forms, right?
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  SPEAKER_01: Yeah, some are peptides,
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  SPEAKER_01: some are steroids derived from cholesterol,
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  SPEAKER_01: and some are amines derived from amino acids.
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  SPEAKER_01: But their defining characteristics The characteristic is that they are secreted
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  SPEAKER_01: by one tissue,
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  SPEAKER_01: they travel through the general circulation,
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  SPEAKER_01: and they exert a specific physiological effect on a distant target tissue.
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  SPEAKER_00: And the cascade of communication usually follows a three-step process.
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  SPEAKER_00: First, the hypothalamus or thermostat produces what we call releasing factors.
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  SPEAKER_01: Right.
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  SPEAKER_01: For example, thyrotropin-releasing hormone or TRH and corticotropin-releasing hormone, CRH.
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  SPEAKER_00: And these releasing factors have a very short commute.
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  SPEAKER_00: They just travel down tiny vascular network directly into the anterior lobe of
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  SPEAKER_00: the pituitary gland.
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  SPEAKER_01: Yes, and the anterior pituitary then responds by manufacturing
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  SPEAKER_01: and releasing stimulating hormones.
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  SPEAKER_00: So the TRH from the hypothalamus prompts the pituitary
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  SPEAKER_00: to release thyroid-stimulating hormone, TSH.
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  SPEAKER_00: The CRH prompts the release of adrenocorticotropic hormone, ACTH.
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  SPEAKER_01: Precisely.
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  SPEAKER_01: And then these stimulating hormones are dumped into the massive superhighway of
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  SPEAKER_01: the systemic bloodstream.
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  SPEAKER_01: They travel all the way to the target organs,
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  SPEAKER_01: the thyroid in your neck, the adrenals sitting on top of your kidneys.
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  SPEAKER_00: And those target organs then produce the final...
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  SPEAKER_00: And
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  SPEAKER_01: it is those final hormones that act on the body's cells,
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  SPEAKER_01: including the neurons in the brain, to change how we actually feel and function.
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  SPEAKER_00: And just to fully map out this master relay board,
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  SPEAKER_00: the interior pituitary is responsible for churning out six key stimulating hormones.
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  SPEAKER_01: Right.
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  SPEAKER_01: Let's list them.
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  SPEAKER_00: We have TSH for the thyroid.
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  SPEAKER_00: We have growth hormone or GH.
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  SPEAKER_00: We have prolactin, which we will definitely discuss later regarding antipsychotics.
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  SPEAKER_00: We have luteinizing hormone and follicle stimulating hormone LH and FSH,
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  SPEAKER_00: which control the gonads.
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  SPEAKER_00: And we have ACTH for the adrenals.
• 8:59
  SPEAKER_01: Spot on.
• 9:00
  SPEAKER_01: And it is also worth noting the posterior pituitary,
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  SPEAKER_01: the back half of the gland, operates a bit differently.
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  SPEAKER_01: It doesn't manufacture its own hormone.
• 9:07
  SPEAKER_00: Oh, right.
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  SPEAKER_00: It's just a storage unit.
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  SPEAKER_01: Essentially, yes.
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  SPEAKER_01: It stores two hormones that are actually synthesized up in the hypothalamus,
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  SPEAKER_01: vasopressin,
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  SPEAKER_01: which regulates water balance and blood pressure,
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  SPEAKER_01: and oxytocin, which is heavily involved in social bonding and reproduction.
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  SPEAKER_00: Okay.
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  SPEAKER_00: So if I'm a psychiatrist listening to this, why do I need to know this intricate cascade?
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  SPEAKER_01: Because endocrinopathies,
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  SPEAKER_01: the diseases of this chemical network,
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  SPEAKER_01: essentially boil down to three mechanical failures.
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  SPEAKER_01: Number one, excessive production.
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  SPEAKER_00: The valve is stuck open.
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  SPEAKER_01: Right.
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  SPEAKER_01: And too much hormone is flooding the system.
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  SPEAKER_01: Number two, deficient production.
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  SPEAKER_01: The factory has shut down and there isn't enough hormone to meet the body's demands.
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  SPEAKER_01: Or number three, receptor resistance.
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  SPEAKER_00: Receptor resistance meaning the hormone is floating around in the blood,
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  SPEAKER_00: maybe even in massive quantities.
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  SPEAKER_00: The target cells have essentially put their hands over their ears.
• 10:02
  SPEAKER_01: Exactly.
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  SPEAKER_01: They are completely deaf to the signal.
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  SPEAKER_01: And because the brain is the most metabolically demanding organ in the body,
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  SPEAKER_01: and because its neurons are heavily studded with receptors for all
• 10:11
  SPEAKER_01: of these hormones,
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  SPEAKER_01: the brain often reacts to these mechanical failures before the rest of
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  SPEAKER_01: the body does.
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  SPEAKER_01: Yeah, the earliest stage of an endocrine disease frequently presents purely as
• 10:20
  SPEAKER_01: a psychiatric syndrome.
• 10:21
  SPEAKER_00: Okay.
• 10:22
  SPEAKER_00: Let's unpack this with a clinical scenario to really ground it.
• 10:24
  SPEAKER_00: Sure.
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  SPEAKER_00: A patient walks into your clinic.
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  SPEAKER_00: They meet all the DSMV criteria for major depressive disorder.
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  SPEAKER_00: They are lethargic.
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  SPEAKER_00: Their mood is profoundly low.
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  SPEAKER_00: They can't concentrate at work and they've lost interest in their hobbies.
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  SPEAKER_01: A very standard presentation.
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  SPEAKER_00: Right.
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  SPEAKER_00: You diagnose them and you prescribe a standard SSRI,
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  SPEAKER_00: a selective serotonin reuptake inhibitor like sertraline or citalafram.
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  SPEAKER_00: But unbeknownst to you, their actual underlying pathology is a deficient thyroid gland.
• 10:54
  SPEAKER_00: Are we basically just trying to fix a hardware problem with a software patch?
• 10:58
  SPEAKER_01: That is a brilliant way to phrase it.
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  SPEAKER_01: And the answer is yes.
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  SPEAKER_01: You are giving a serotonin reuptake inhibitor to a brain
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  SPEAKER_01: that is fundamentally lacking the metabolic energy to even function.
• 11:07
  SPEAKER_00: Wow.
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  SPEAKER_01: And here is the brutal clinical reality.
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  SPEAKER_01: Those psychiatric symptoms will absolutely not resolve until
• 11:14
  SPEAKER_01: the underlying endocrine disturbance is corrected.
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  SPEAKER_00: So they come back a month later and they say, Doc, I don't feel any better.
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  SPEAKER_01: And the standard psychiatric response is often, well,
• 11:24
  SPEAKER_01: let's increase the dose or let's switch to an SNRI or let's augment with
• 11:29
  SPEAKER_01: an atypical antipsychotic.
• 11:30
  SPEAKER_00: Or you end up labeling the patient as having treatment resistant depression.
• 11:33
  SPEAKER_01: Exactly.
• 11:34
  SPEAKER_01: And you subject them to polypharmacy, side effects and months of ongoing suffering.
• 11:39
  SPEAKER_01: But you can increase that SSRI to the absolute maximum legal limit and
• 11:43
  SPEAKER_01: the patient will not achieve remission because you are ignoring the broken pipe in
• 11:47
  SPEAKER_01: the basement.
• 11:48
  SPEAKER_00: Which is why the DSMV, to its credit, has a specific diagnostic category for this.
• 11:53
  SPEAKER_00: It classifies these presentations as a depressive disorder due to another medical condition.
• 11:58
  SPEAKER_01: Yes.
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  SPEAKER_01: It is forcing us to acknowledge that the mood disturbance is
• 12:02
  SPEAKER_01: the direct pathophysiological consequence of a general medical condition.
• 12:06
  SPEAKER_00: This demands a shift in clinical behavior.
• 12:08
  SPEAKER_00: A rigorous evaluation of endocrine function is a mandatory part
• 12:12
  SPEAKER_00: of any initial psychiatric workup.
• 12:14
  SPEAKER_00: You cannot just listen to the psychological narrative.
• 12:17
  SPEAKER_01: You must check the physical dials.
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  SPEAKER_01: That means ordering baseline blood work,
• 12:22
  SPEAKER_01: serum electrolytes,
• 12:23
  SPEAKER_01: fasting blood glucose, TSH for the thyroid, and calcium concentrations.
• 12:28
  SPEAKER_01: You have to verify the integrity of the smart home network before you start trying to rewire it.
• 12:33
  SPEAKER_00: Right.
• 12:33
  SPEAKER_00: So let's follow the first major wire out from the pituitary control board.
• 12:37
  SPEAKER_00: Let's look at the furnace of the house.
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  SPEAKER_00: We're moving into the thyroid system.
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  SPEAKER_01: The thyroid gland, located in the anterior neck, produces two primary hormones.
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  SPEAKER_01: Thyroxine, known as T4, and triodothyronine, known as T3.
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  SPEAKER_01: These are the master regulators of metabolic activity,
• 12:53
  SPEAKER_01: heat production, and protein synthesis for virtually every cell in the human body.
• 12:57
  SPEAKER_00: And T4 is generally considered a pro-hormone, right?
• 12:59
  SPEAKER_00: It's the stable transport version that circulates in the blood,
• 13:03
  SPEAKER_00: and then local tissues convert it into T3, which is the highly active version.
• 13:06
  SPEAKER_01: Yes.
• 13:07
  SPEAKER_01: Interestingly,
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  SPEAKER_01: T4 is the primary hormone available to the brain crossing the blood-brain barrier.
• 13:12
  SPEAKER_01: But once inside, the glial cells convert it into T3 for the neurons to actually use.
• 13:17
  SPEAKER_00: Let's look at what happens when this furnace breaks down.
• 13:20
  SPEAKER_00: The first major malfunction is hypothyroidism.
• 13:22
  SPEAKER_00: The mechanism is simple enough, you know, inadequate thyroid hormone production.
• 13:26
  SPEAKER_00: But in the clinic, this presents on a spectrum.
• 13:29
  SPEAKER_01: Correct.
• 13:29
  SPEAKER_01: You have overt hypothyroidism, which is clear cut.
• 13:33
  SPEAKER_01: The TSH level from the pituitary is screaming high.
• 13:37
  SPEAKER_01: The thermostat is desperately calling for heat,
• 13:39
  SPEAKER_01: but the actual T4 levels in the blood are abnormally low.
• 13:43
  SPEAKER_01: The furnace is completely broken.
• 13:45
  SPEAKER_01: But then you have subclinical hypothyroidism.
• 13:47
  SPEAKER_00: And this is where things get really sneaky.
• 13:50
  SPEAKER_00: In subclinical hypothyroidism,
• 13:51
  SPEAKER_00: the TSH is elevated,
• 13:53
  SPEAKER_00: indicating the pituitary is working overtime to stimulate the thyroid.
• 13:57
  SPEAKER_00: But the T4 levels are still technically clinging to the normal range.
• 14:01
  SPEAKER_01: And despite the T4 being technically normal,
• 14:03
  SPEAKER_01: patients with subclinical hypothyroidism frequently suffer
• 14:06
  SPEAKER_01: from significant psychiatric and cognitive symptoms.
• 14:09
  SPEAKER_00: What causes this failure?
• 14:11
  SPEAKER_01: Well, the etiology varies globally.
• 14:13
  SPEAKER_01: In developing nations,
• 14:14
  SPEAKER_01: dietary iodine deficiency is the primary cause,
• 14:17
  SPEAKER_01: as iodine is a necessary building block for thyroid hormones.
• 14:20
  SPEAKER_01: But in nations where iodine is routinely added to table salt,
• 14:24
  SPEAKER_01: the most common cause is Hashimoto's thyroiditis.
• 14:27
  SPEAKER_00: Which is an autoimmune condition.
• 14:28
  SPEAKER_00: The patient's own immune system produces antithyroid antibodies
• 14:32
  SPEAKER_00: that systematically attack and destroy the enzyme systems within the thyroid gland.
• 14:36
  SPEAKER_01: Right.
• 14:37
  SPEAKER_00: But for psychiatrists,
• 14:38
  SPEAKER_00: there is another cause that should immediately set off alarm bells,
• 14:41
  SPEAKER_00: and that is medication-induced hypothyroidism, specifically lithium.
• 14:46
  SPEAKER_01: Yes, and we will explore the lithium connection in depth shortly, as it is a critical trap.
• 14:52
  SPEAKER_01: But first, let's paint the clinical picture.
• 14:54
  SPEAKER_01: What happens to a human being when their thyroid hormone plummets?
• 14:57
  SPEAKER_00: When the furnace dies, the whole house freezes.
• 15:00
  SPEAKER_00: The machinery of the patient's body and mind appears to grind to a halt.
• 15:04
  SPEAKER_00: The core manifestation is profound deceleration.
• 15:07
  SPEAKER_00: If we're building a mental model, it is simply this.
• 15:10
  SPEAKER_00: Hypothyroidism equals slow.
• 15:12
  SPEAKER_01: The psychiatric overlap with major depression is nearly indistinguishable on a surface level.
• 15:17
  SPEAKER_01: The patient reports a pervasive lack of energy, profound apathy, and a heavily depressed mood.
• 15:23
  SPEAKER_01: But you also see significant psychomotor slowing.
• 15:27
  SPEAKER_00: They physically move more deliberately.
• 15:28
  SPEAKER_01: Yes, their speech is slow, perhaps slightly slurred or hoarse.
• 15:33
  SPEAKER_00: And the cognitive impact is severe.
• 15:35
  SPEAKER_00: They come in complaining that their memory is failing,
• 15:37
  SPEAKER_00: that they can't concentrate on a book or a television program.
• 15:40
  SPEAKER_00: If you run neuropsychological testing,
• 15:42
  SPEAKER_00: their complex attention and information processing speeds have just plummeted.
• 15:47
  SPEAKER_01: But this is where the physical clues,
• 15:48
  SPEAKER_01: the medical examination become absolutely vital because
• 15:52
  SPEAKER_01: the whole metabolism is slow.
• 15:53
  SPEAKER_01: They frequently experience unexplained weight gain despite poor appetite.
• 15:57
  SPEAKER_01: They complain of severe cold intolerance.
• 15:59
  SPEAKER_01: I mean, they might be wearing a heavy sweater in the middle of summer.
• 16:02
  SPEAKER_01: Their gut motility slows down, leading to chronic constipation.
• 16:06
  SPEAKER_01: Their skin becomes dry and coarse.
• 16:08
  SPEAKER_01: And if you test their reflexes,
• 16:10
  SPEAKER_01: particularly the Achilles tendon reflex, the relaxation phase is noticeably delayed.
• 16:15
  SPEAKER_00: And the tragic part is,
• 16:16
  SPEAKER_00: because the symptoms develop so gradually,
• 16:19
  SPEAKER_00: patients and doctors often attribute this slowing down to other life events.
• 16:23
  SPEAKER_00: The textbook provides a perfect real-world case study of this exact phenomenon.
• 16:28
  SPEAKER_01: Oh, yes.
• 16:28
  SPEAKER_01: Let's go through that.
• 16:29
  SPEAKER_00: Let's look at Mrs. A.
• 16:31
  SPEAKER_00: Different Ms. A from our marathon runner earlier.
• 16:34
  SPEAKER_00: This Ms. A is a 54-year-old woman with no previous psychiatric history.
• 16:38
  SPEAKER_00: She goes to her primary care doctor complaining of depressed mood, fever,
• 16:42
  SPEAKER_00: lethargy, apathy,
• 16:43
  SPEAKER_00: weight gain, and she's particularly distressed by how poor her memory has become.
• 16:48
  SPEAKER_01: Now, consider the context here.
• 16:50
  SPEAKER_01: She is a 54-year-old woman.
• 16:51
  SPEAKER_01: What is the immediate reflective diagnostic assumption many clinicians will make?
• 16:55
  SPEAKER_00: Menopause.
• 16:56
  SPEAKER_00: They assume this is a natural hormonal transition causing mood and cognitive changes.
• 17:01
  SPEAKER_00: It seems entirely logical on the surface.
• 17:03
  SPEAKER_01: And so her doctors prescribed hormone replacement therapy,
• 17:06
  SPEAKER_01: estrogen and progesterone, and she remained on this therapy for six whole months.
• 17:11
  SPEAKER_00: But absolutely nothing happened.
• 17:13
  SPEAKER_00: Her symptoms didn't improve at all.
• 17:14
  SPEAKER_00: In fact, she continued to decline.
• 17:17
  SPEAKER_00: Finally, after half a year of suffering, a clinician decides to order a simple thyroid panel.
• 17:22
  SPEAKER_00: They check her TSH.
• 17:23
  SPEAKER_01: And her TSH level came back at 14 MIUL.
• 17:26
  SPEAKER_00: Which is high.
• 17:27
  SPEAKER_01: Very high.
• 17:27
  SPEAKER_01: To put that in clinical context,
• 17:29
  SPEAKER_01: a normal TSH generally caps out around 4.0 or 5.0, depending on the lab assay.
• 17:34
  SPEAKER_01: A TSH of 14 means the pituitary gland is screaming at the top of its lungs,
• 17:39
  SPEAKER_01: begging the thyroid for more hormone, and the thyroid is just unresponsive.
• 17:43
  SPEAKER_00: So the intervention was incredibly straightforward.
• 17:46
  SPEAKER_00: They didn't send her to a psychiatrist.
• 17:47
  SPEAKER_00: They didn't start her on an SSRI.
• 17:50
  SPEAKER_00: They simply prescribed 0.05 milligrams a day of levothyroxine, which is synthetic T4.
• 17:56
  SPEAKER_01: And within eight weeks of initiating that simple daily pill,
• 17:59
  SPEAKER_01: her energy level surged back to normal.
• 18:01
  SPEAKER_01: Her interest in daily activities returned.
• 18:03
  SPEAKER_01: Her depressive symptoms lifted entirely
• 18:05
  SPEAKER_01: and her subjective memory complaints completely resolved.
• 18:08
  SPEAKER_01: Follow-up blood work showed her TSH had dropped to a perfectly normal 3.3.
• 18:13
  SPEAKER_01: By fixing the furnace, the mind was restored.
• 18:15
  SPEAKER_00: It's a beautiful, clean resolution.
• 18:18
  SPEAKER_00: But the textbook also provides a second case study,
• 18:21
  SPEAKER_00: it's Kay,
• 18:22
  SPEAKER_00: which illustrates how incredibly dangerous it can be when we view a patient strictly
• 18:26
  SPEAKER_00: through a psychiatric lens and ignore the endocrine system entirely.
• 18:30
  SPEAKER_01: This is a crucial case.
• 18:31
  SPEAKER_00: So Ms. K is 32 years old.
• 18:33
  SPEAKER_00: Unlike Mrs. A, she has a long documented history of recurrent major depressive disorder.
• 18:38
  SPEAKER_00: She presents to the emergency room at 14 weeks postpartum.
• 18:43
  SPEAKER_00: And she is in absolute crisis.
• 18:45
  SPEAKER_00: She is severely depressed and is experiencing passive suicidal ideation.
• 18:50
  SPEAKER_00: Her history notes that she stopped taking her SSRI
• 18:52
  SPEAKER_00: when she found out she was pregnant,
• 18:54
  SPEAKER_00: and she restarted it immediately after delivery,
• 18:56
  SPEAKER_00: but her mood just kept deteriorating.
• 18:58
  SPEAKER_01: And if you look closely at the evolution of her symptoms,
• 19:00
  SPEAKER_01: there was a distinct shift that really should have been a red flag.
• 19:03
  SPEAKER_01: Initially postpartum,
• 19:05
  SPEAKER_01: she developed tachycardia,
• 19:06
  SPEAKER_01: a racing heart worsening insomnia, extreme agitation and severe panic attacks.
• 19:10
  SPEAKER_00: But then after about a month,
• 19:12
  SPEAKER_00: that anxious hyper aroused state just vanished and it morphed
• 19:15
  SPEAKER_00: into severe heavy depression, lethargy and profound apathy.
• 19:19
  SPEAKER_01: Right.
• 19:20
  SPEAKER_01: And this biphasic pattern,
• 19:21
  SPEAKER_01: a period of rapid hyperfunctioning,
• 19:23
  SPEAKER_01: Followed by a crash into sluggishness is a classic hallmark
• 19:27
  SPEAKER_01: of postpartum thyroiditis.
• 19:29
  SPEAKER_00: Can you explain the mechanism there?
• 19:30
  SPEAKER_01: Sure.
• 19:31
  SPEAKER_01: The immune system temporarily attacks the thyroid,
• 19:34
  SPEAKER_01: causing it to leak all its stored hormones into the blood,
• 19:37
  SPEAKER_01: which causes the anxiety and tachycardia.
• 19:40
  SPEAKER_01: Then, once the stores are totally depleted,
• 19:43
  SPEAKER_01: the gland fails,
• 19:45
  SPEAKER_01: and the patient crashes into profound hypothyroidism, causing the heavy depression.
• 19:49
  SPEAKER_00: But the psychiatric team in the emergency room didn't see it that way.
• 19:53
  SPEAKER_00: They saw a woman with a known history of depression who wasn't responding to her SSRI.
• 19:58
  SPEAKER_00: They fell into the clinical trap of confirmation bias.
• 20:02
  SPEAKER_00: They labeled her presentation as treatment resistant depression and they decided
• 20:06
  SPEAKER_00: to aggressively augment her therapy.
• 20:08
  SPEAKER_01: Which is where they made a huge error.
• 20:10
  SPEAKER_00: Yeah, they added 600 milligrams of lithium.
• 20:12
  SPEAKER_01: Which is where this case becomes a real cautionary tale.
• 20:14
  SPEAKER_01: We touched on this earlier.
• 20:16
  SPEAKER_01: Lithium is heavily implicated in causing hypothyroidism.
• 20:19
  SPEAKER_01: It directly interferes with the thyroid gland's ability to release hormones.
• 20:23
  SPEAKER_00: So by giving lithium to a woman who was already crashing into a hypothyroid state,
• 20:27
  SPEAKER_01: they were essentially pouring water onto a drowning engine.
• 20:30
  SPEAKER_00: Her symptoms worsened dramatically.
• 20:32
  SPEAKER_00: She developed severe memory deficits.
• 20:35
  SPEAKER_00: Crucially,
• 20:36
  SPEAKER_00: her breast milk supply dried up,
• 20:38
  SPEAKER_00: which only compounded her psychological distress as she felt she couldn't care
• 20:41
  SPEAKER_00: for her newborn.
• 20:43
  SPEAKER_00: Her suicidal ideation shifted from passive to active.
• 20:47
  SPEAKER_01: It was only at this point of near catastrophe that routine laboratory tests revealed the truth.
• 20:52
  SPEAKER_01: Her TSH was highly elevated at eight.
• 20:54
  SPEAKER_01: Her free T4 was exceptionally low.
• 20:57
  SPEAKER_01: Furthermore, a deeper dive showed highly elevated levels of antithyroid antibodies.
• 21:02
  SPEAKER_00: And a physical examination,
• 21:03
  SPEAKER_00: which arguably should have been done much earlier,
• 21:06
  SPEAKER_00: finally revealed a small, painless goiter, an enlarged thyroid gland in her neck.
• 21:11
  SPEAKER_01: Right.
• 21:11
  SPEAKER_01: So the true diagnosis was postpartum thyroiditis,
• 21:13
  SPEAKER_01: severely exacerbated by iatrogenic lithium administration.
• 21:17
  SPEAKER_01: The treatment plan was immediately overhauled.
• 21:19
  SPEAKER_01: They stopped the lithium, halting the active damage to her thyroid.
• 21:23
  SPEAKER_01: They initiated Synthroid, the synthetic thyroid replacement.
• 21:26
  SPEAKER_01: They tweaked her antidepressant to bupropium.
• 21:28
  SPEAKER_00: And the result.
• 21:30
  SPEAKER_00: Within four weeks, she experienced a massive improvement in her mood and cognitive function.
• 21:35
  SPEAKER_00: By six weeks, her thyroid levels had normalized completely.
• 21:39
  SPEAKER_01: This case perfectly illustrates the absolute danger of diagnostic siloing.
• 21:44
  SPEAKER_01: If you only look for psychiatric causes,
• 21:46
  SPEAKER_01: you will only find psychiatric solutions even
• 21:49
  SPEAKER_01: when those solutions are actively harming the patient.
• 21:51
  SPEAKER_00: Which brings up a question I think a lot of you listening might have.
• 21:54
  SPEAKER_00: We know what it looks like from the outside, the slowing down, the apathy.
• 21:58
  SPEAKER_00: But what is actually happening inside the brain?
• 22:01
  SPEAKER_00: How does a lack of thyroid hormone in the blood physically alter
• 22:05
  SPEAKER_00: the emotional processing centers of the brain?
• 22:07
  SPEAKER_01: It is a deeply complex, multilayered physiological breakdown.
• 22:11
  SPEAKER_01: We have to look at both neurotransmitter systems and gross cerebral blood flow.
• 22:16
  SPEAKER_01: Let's start with the neurotransmitter,
• 22:18
  SPEAKER_01: specifically serotonin, which we know is intimately involved in mood regulation.
• 22:22
  SPEAKER_00: Right, the exact target of our SSRIs.
• 22:24
  SPEAKER_01: Exactly.
• 22:26
  SPEAKER_01: Thyroid hormones exert both genomic and non-genomic effects on the central nervous system.
• 22:32
  SPEAKER_01: Genomic,
• 22:32
  SPEAKER_01: meaning they actually enter the nucleus of the neuron
• 22:34
  SPEAKER_01: and alter how genes are expressed.
• 22:37
  SPEAKER_01: In a hycothyroid state, the brain's actual synthesis of serotonin is fundamentally reduced.
• 22:43
  SPEAKER_00: Really?
• 22:43
  SPEAKER_01: Yes.
• 22:44
  SPEAKER_01: Research has clearly demonstrated that serum serotonin levels correlate directly
• 22:48
  SPEAKER_01: with serum T3 levels.
• 22:50
  SPEAKER_01: If T3 drops, serotonin production drops.
• 22:53
  SPEAKER_00: So the SSRI isn't working because there isn't enough raw serotonin being produced
• 22:57
  SPEAKER_00: for the drug to even keep in the synaptic cleft.
• 22:59
  SPEAKER_01: Spot on.
• 23:00
  SPEAKER_01: But it goes beyond just the total amount of serotonin.
• 23:03
  SPEAKER_01: The actual receptor architecture changes.
• 23:06
  SPEAKER_01: In hypothyroidism,
• 23:06
  SPEAKER_01: we see a decreased number and function of postsynaptic beta adrenergic receptors.
• 23:11
  SPEAKER_01: And what about the blood flow?
• 23:12
  SPEAKER_01: The brain requires an enormous amount of oxygen and glucose just to maintain baseline function.
• 23:25
  SPEAKER_01: This is where neuroimaging provides stunning visual evidence.
• 23:29
  SPEAKER_01: Studies measuring regional cerebral blood flow show significant quantifiable
• 23:33
  SPEAKER_01: decreases in blood flow to specific areas of the brain in hypothyroid patients.
• 23:38
  SPEAKER_00: Which areas?
• 23:38
  SPEAKER_01: Specifically,
• 23:39
  SPEAKER_01: we see reduced perfusion in the bilateral amygdala,
• 23:42
  SPEAKER_01: the hippocampus, and the anterior cingulate cortex.
• 23:45
  SPEAKER_00: And those aren't just random areas.
• 23:47
  SPEAKER_00: The amygdala processes fear and emotion.
• 23:50
  SPEAKER_00: The hippocampus encodes memory.
• 23:53
  SPEAKER_00: The anterior cingulate cortex is crucial for attention and motivation.
• 23:57
  SPEAKER_01: Precisely.
• 23:58
  SPEAKER_01: The core emotional and memory processing centers of
• 24:01
  SPEAKER_01: the brain are quite literally being starved of resources.
• 24:04
  SPEAKER_01: They are operating in a low power energy conservation mode.
• 24:07
  SPEAKER_01: When you administer thyroid hormone replacement to these patients,
• 24:10
  SPEAKER_01: subsequent imaging shows the regional blood flow is completely restored
• 24:14
  SPEAKER_01: and concurrently the neuropsychiatric complaints just vanish.
• 24:17
  SPEAKER_00: It is a stark reminder that the brain is just another organ.
• 24:22
  SPEAKER_00: It requires a highly specific metabolic environment to function.
• 24:26
  SPEAKER_00: Okay, now let's take our hands off the brake and slam the accelerator.
• 24:30
  SPEAKER_00: Let's turn the dial in the thyroid system in the completely opposite direction.
• 24:34
  SPEAKER_00: We go from a shortage of fuel to an absolute flood.
• 24:37
  SPEAKER_00: Let's discuss hyperthyroidism.
• 24:39
  SPEAKER_01: Here, the mechanism is the rampant overproduction of thyroid hormone.
• 24:43
  SPEAKER_01: The most common cause globally is Graves' disease.
• 24:46
  SPEAKER_01: This is another autoimmune condition,
• 24:48
  SPEAKER_01: but instead of the antibodies destroying the gland,
• 24:50
  SPEAKER_01: these specific antibodies actually mimic TSH.
• 24:53
  SPEAKER_00: Oh, wow.
• 24:53
  SPEAKER_01: Yeah,
• 24:54
  SPEAKER_01: they bind to the TSH receptors on the thyroid gland and constantly stimulate it,
• 24:58
  SPEAKER_01: forcing the thyroid to overproduce T3 and T4.
• 25:01
  SPEAKER_00: You can also see this overproduction with toxic multinodular goiters,
• 25:04
  SPEAKER_00: where independent nodules on the gland just start churning out hormone autonomously.
• 25:09
  SPEAKER_00: If we look at the lab work for these patients, we see the exact inverse of hypothyroidism.
• 25:13
  SPEAKER_01: Yes.
• 25:14
  SPEAKER_01: The TSH level will be profoundly suppressed,
• 25:17
  SPEAKER_01: often practically undetectable,
• 25:19
  SPEAKER_01: because the pituitary gland is screaming, stop, it's too hot.
• 25:22
  SPEAKER_01: But the T4 and T3 levels in the blood are skyrocketing because
• 25:26
  SPEAKER_01: the thyroid is ignoring the pituitary and responding to the rogue antibodies or
• 25:31
  SPEAKER_01: the autonomous nodules.
• 25:32
  SPEAKER_00: The physical and psychiatric manifestation here is best remembered with our second core model.
• 25:38
  SPEAKER_00: Hyperthyroidism equals fast.
• 25:40
  SPEAKER_00: The physiological machinery is accelerating wildly out of control.
• 25:43
  SPEAKER_01: The physical signs are really dramatic.
• 25:45
  SPEAKER_01: The patient experiences marked tachycardia.
• 25:48
  SPEAKER_01: Their resting heart rate might be over 100 beats per minute.
• 25:51
  SPEAKER_01: They develop a fine, rapid tremor in their hands.
• 25:53
  SPEAKER_01: Their basal metabolic rate is so high they are constantly sweating.
• 25:57
  SPEAKER_01: They experience severe heat intolerance,
• 25:59
  SPEAKER_01: and they often lose a significant amount of weight despite having
• 26:02
  SPEAKER_01: a ravenous appetite.
• 26:03
  SPEAKER_00: And psychiatrically.
• 26:04
  SPEAKER_00: How does this flooded brain present in the clinic?
• 26:07
  SPEAKER_01: They experience profound vibrating anxiety,
• 26:10
  SPEAKER_01: severe irritability,
• 26:12
  SPEAKER_01: where the slightest annoyance provokes an explosive reaction,
• 26:15
  SPEAKER_01: relentless insomnia, which rapidly deteriorates their cognitive state.
• 26:19
  SPEAKER_01: They experience intense mood instability and emotional ability,
• 26:23
  SPEAKER_01: bursting into tears or rage unpredictably.
• 26:25
  SPEAKER_01: Their thoughts race,
• 26:27
  SPEAKER_01: their speech becomes pressured,
• 26:29
  SPEAKER_01: and they are physically hyperactive, just unable to sit still.
• 26:32
  SPEAKER_00: So if a patient walks into my office shaking,
• 26:35
  SPEAKER_00: sweating, heart racing, terrified that they are losing their mind.
• 26:39
  SPEAKER_01: The primary diagnostic differential you must wrestle with is this.
• 26:42
  SPEAKER_01: Is this a severe panic disorder?
• 26:44
  SPEAKER_01: Is it generalized anxiety disorder?
• 26:46
  SPEAKER_01: Or is this hyperthyroidism mimicking a psychiatric crisis?
• 26:49
  SPEAKER_00: And the textbook points out that it can also mimic a manic episode.
• 26:53
  SPEAKER_01: It can, but there is a crucial clinical nuance here.
• 26:56
  SPEAKER_01: While a hyperthyroid patient may appear manic,
• 26:58
  SPEAKER_01: they are talking fast, they aren't sleeping, they are hyperactive.
• 27:01
  SPEAKER_01: True bipolar mania is rarely caused solely by hyperthyroidism.
• 27:05
  SPEAKER_00: How do you tell the difference?
• 27:06
  SPEAKER_01: A truly manic patient is typically euphoric, grandiose, and feels powerful.
• 27:11
  SPEAKER_01: The hyperthyroid patient, on the other hand, is generally miserable.
• 27:15
  SPEAKER_01: They are agitated, deeply anxious, and utterly exhausted by their inability to sleep.
• 27:20
  SPEAKER_01: They desperately want to rest, but their body refuses to let them.
• 27:24
  SPEAKER_00: And if the hyperthyroidism is left untreated and progresses to a severe state?
• 27:28
  SPEAKER_01: The hyperaroused state can cross the threshold into full-blown psychosis.
• 27:33
  SPEAKER_01: Patients can develop paranoid delusions, vivid visual hallucinations, and acute delirium.
• 27:39
  SPEAKER_01: The most severe,
• 27:40
  SPEAKER_01: life-threatening exacerbation is known as a thyroid storm,
• 27:43
  SPEAKER_01: which is a medical emergency presenting with massive tachycardia,
• 27:46
  SPEAKER_01: high fever,
• 27:47
  SPEAKER_01: and severely altered mental status,
• 27:49
  SPEAKER_01: often progressing to coma or death if not aggressively managed.
• 27:53
  SPEAKER_00: So how do we approach treating the psychiatric symptoms of
• 27:56
  SPEAKER_00: a patient running this fast thyroid program?
• 27:58
  SPEAKER_01: The golden rule applies.
• 28:00
  SPEAKER_01: You treat the underlying endocrine cause.
• 28:02
  SPEAKER_01: For hyperthyroidism,
• 28:03
  SPEAKER_01: that means using antithyroid drugs like methamazole or propilthiracil,
• 28:07
  SPEAKER_01: which directly inhibit the synthesis of thyroid hormones within the gland.
• 28:11
  SPEAKER_00: But those drugs take time to work.
• 28:13
  SPEAKER_00: What do we do about the patient who is practically vibrating out of their chair right now?
• 28:17
  SPEAKER_01: For immediate symptomatic relief, we rely heavily on beta blockers, most commonly propranolol.
• 28:23
  SPEAKER_01: The beta blocker doesn't fix the thyroid,
• 28:25
  SPEAKER_01: but it immediately blocks the downstream effect of the hormones on
• 28:28
  SPEAKER_01: the sympathetic nervous system.
• 28:30
  SPEAKER_01: It slows the racing heart,
• 28:32
  SPEAKER_01: stops the tremors,
• 28:33
  SPEAKER_01: and dramatically reduces the physical sensation of anxiety,
• 28:37
  SPEAKER_01: which helps calm the patient psychologically.
• 28:39
  SPEAKER_00: What if they have crossed into that psychotic state?
• 28:42
  SPEAKER_00: Do we use antipsychotics?
• 28:44
  SPEAKER_01: You might need to use a low dose of an antipsychotic temporarily
• 28:47
  SPEAKER_01: to manage severe agitation or hallucinations,
• 28:50
  SPEAKER_01: but you must proceed with extreme caution.
• 28:52
  SPEAKER_00: Why is that?
• 28:53
  SPEAKER_00: What's the specific risk?
• 28:54
  SPEAKER_01: You must consider the state of the patient's heart.
• 28:57
  SPEAKER_01: The hyperthyroid heart is already under immense toxic strain from the XST3.
• 29:03
  SPEAKER_01: It is racing and prone to arrhythmias.
• 29:06
  SPEAKER_01: You must absolutely avoid any antipsychotics that are known to significantly prolong
• 29:10
  SPEAKER_01: the QT interval on an electrocardiogram.
• 29:13
  SPEAKER_01: You also want to avoid low-potency antipsychotics like chlorpromazine,
• 29:18
  SPEAKER_01: which have strong anticholinergic properties and can induce further tachycardia.
• 29:23
  SPEAKER_00: Right.
• 29:23
  SPEAKER_00: You do not want to introduce medication-induced cardiac risk to an organ
• 29:28
  SPEAKER_00: that is already redlining.
• 29:29
  SPEAKER_01: Exactly.
• 29:30
  SPEAKER_01: Once you get the thyroid under control with methamazole and beta blockers,
• 29:33
  SPEAKER_01: the psychotic and anxious symptoms almost universally resolve.
• 29:36
  SPEAKER_00: It's a brilliant example of why a psychiatrist has to be
• 29:38
  SPEAKER_00: a competent internal medicine physician first.
• 29:42
  SPEAKER_00: Okay, let's leave the furnace room and follow the illuminated pathways deeper
• 29:45
  SPEAKER_00: into our smart home control system.
• 29:47
  SPEAKER_00: If the thyroid regulates the baseline speed and temperature of the machinery,
• 29:51
  SPEAKER_00: the next system manages the house's emergency response to crisis.
• 29:55
  SPEAKER_00: We are moving to the adrenal system.
• 29:57
  SPEAKER_01: Right.
• 29:57
  SPEAKER_01: The adrenal glands are small, triangular glands that sit right on top of the kidneys.
• 30:03
  SPEAKER_01: They produce a variety of steroid hormones,
• 30:05
  SPEAKER_01: but for our purposes in psychiatry,
• 30:07
  SPEAKER_01: we are overwhelmingly focused on the glucocorticoids, primarily cortisol.
• 30:11
  SPEAKER_00: The chemical pathway here starts in the hypothalamus, which releases CRH in response to stress.
• 30:17
  SPEAKER_00: That travels to the pituitary, which releases ACTH.
• 30:21
  SPEAKER_00: The ACTH travels through the blood down to the adrenal cortex,
• 30:25
  SPEAKER_00: stimulating it to pump out cortisol.
• 30:27
  SPEAKER_00: CRH to ACTH to cortisol.
• 30:29
  SPEAKER_01: Now in a healthy individual, cortisol is essential.
• 30:32
  SPEAKER_01: It is not inherently a bad stress hormone.
• 30:34
  SPEAKER_01: It follows a beautiful, highly regulated circadian rhythm.
• 30:37
  SPEAKER_01: Cortisol levels naturally peak in the early morning hours, which is what helps us wake up.
• 30:41
  SPEAKER_01: Cortisol helps us manage acute physical stress.
• 30:43
  SPEAKER_01: It breaks down proteins,
• 30:44
  SPEAKER_01: stimulates the liver to create new glucose,
• 30:46
  SPEAKER_01: and suppresses nonessential systems like the immune response
• 30:48
  SPEAKER_01: so all energy can be directed
• 30:50
  SPEAKER_00: toward immediate survival.
• 31:03
  SPEAKER_00: But what happens when the emergency alarm gets stuck in the on position,
• 31:08
  SPEAKER_00: when cortisol levels remain excessively, relentlessly high?
• 31:11
  SPEAKER_01: Then we enter the territory of hypercortisolism, clinically known as Cushing syndrome.
• 31:17
  SPEAKER_00: Let's talk about the causes.
• 31:18
  SPEAKER_00: How does someone develop Cushing's?
• 31:20
  SPEAKER_01: By far the most common cause is actually iatrogenic.
• 31:24
  SPEAKER_01: It is caused by the medical profession.
• 31:26
  SPEAKER_01: We prescribe high doses of exogenous corticosteroids,
• 31:29
  SPEAKER_01: drugs like prednisone or dexamethasone,
• 31:31
  SPEAKER_01: to suppress severe inflammation in conditions like rheumatoid arthritis,
• 31:35
  SPEAKER_01: asthma, or lupus.
• 31:36
  SPEAKER_00: Right, like a runner from the start.
• 31:38
  SPEAKER_01: Exactly.
• 31:39
  SPEAKER_01: Now, if the hypercortisolism is endogenous,
• 31:41
  SPEAKER_01: meaning it is originating from within the patient's own body,
• 31:44
  SPEAKER_01: it is most commonly caused by a benign pituitary adenoma
• 31:47
  SPEAKER_01: that is inappropriately pumping out massive amounts of ACTH.
• 31:51
  SPEAKER_01: When it is pituitary driven, it is specifically called Cushing disease.
• 31:55
  SPEAKER_01: Less commonly, it can be an autonomous tumor on the adrenal gland itself.
• 31:58
  SPEAKER_00: Because cortisol fundamentally alters how the body processes fuel,
• 32:03
  SPEAKER_00: how it stores fat and metabolizes protein.
• 32:06
  SPEAKER_00: The physical manifestations of Cushing's are quite striking once they fully develop.
• 32:10
  SPEAKER_01: Yes, patients develop truncal obesity,
• 32:12
  SPEAKER_01: where adipose tissue gathers heavily around the abdomen,
• 32:15
  SPEAKER_01: while the arms and legs remain relatively thin due to muscle wasting.
• 32:19
  SPEAKER_01: You see the classic moon faces, a distinct rounding and puffiness of the face.
• 32:24
  SPEAKER_01: Fat deposits build up on the back of the neck,
• 32:27
  SPEAKER_01: often referred to as a buffalo hump,
• 32:29
  SPEAKER_00: And their skin changes, too, right?
• 32:30
  SPEAKER_01: Yes.
• 32:31
  SPEAKER_01: The skin becomes incredibly thin and fragile,
• 32:33
  SPEAKER_01: leading to easy bruising and wide purple striae stretch marks across the abdomen.
• 32:39
  SPEAKER_00: Those are the physical signs we learned in medical school.
• 32:41
  SPEAKER_00: But the psychiatric symptoms often emerge long before the stretch marks appear,
• 32:45
  SPEAKER_00: and they can be completely devastating to the patient's quality of life.
• 32:47
  SPEAKER_01: Approximately 75 percent of patients with Cushing syndrome report
• 32:51
  SPEAKER_01: a significantly depressed mood.
• 32:53
  SPEAKER_01: And for the vast majority, this depression is moderate to severe.
• 32:57
  SPEAKER_01: They experience extreme hypersensitivity to environmental stimuli.
• 33:01
  SPEAKER_01: They are emotionally labile.
• 33:02
  SPEAKER_01: But perhaps the most prominent feature is profound irritability.
• 33:06
  SPEAKER_00: The textbook notes that irritability is increased in 86% of patients,
• 33:10
  SPEAKER_00: and it's often the very first behavioral change noticed by the family.
• 33:14
  SPEAKER_01: Yes.
• 33:15
  SPEAKER_01: They also suffer from severe insomnia.
• 33:17
  SPEAKER_01: Remember, cortisol is supposed to drop at night to let us sleep.
• 33:21
  SPEAKER_01: In Cushing's,
• 33:22
  SPEAKER_01: it remains high,
• 33:23
  SPEAKER_01: meaning the brain is constantly receiving a wake up, there's a crisis signal.
• 33:27
  SPEAKER_01: Their sleep architecture is ruined.
• 33:29
  SPEAKER_01: They have shortened time to REM sleep and suffer from early morning awakenings.
• 33:33
  SPEAKER_00: Now, earlier we talked about how hypothyroidism mimics melancholic depression.
• 33:38
  SPEAKER_00: Cushing's depression also shares many features
• 33:41
  SPEAKER_00: with classic primary melancholic depression,
• 33:43
  SPEAKER_00: particularly the severe sleep disturbances.
• 33:46
  SPEAKER_00: But there is a fascinating clinical distinction,
• 33:48
  SPEAKER_00: a specific diagnostic clue you can uncover just by asking the right question
• 33:53
  SPEAKER_00: about their daily routine.
• 33:54
  SPEAKER_01: This is a brilliant nuance of clinical reasoning.
• 33:57
  SPEAKER_01: If you have a patient with classic primary melancholic depression,
• 34:00
  SPEAKER_01: they typically experience what we call diurnal variation.
• 34:04
  SPEAKER_01: Their mood is absolutely at its worst when they wake up in the morning,
• 34:07
  SPEAKER_01: and it tends to slightly marginally lift as the evening approaches.
• 34:10
  SPEAKER_00: But patients with Cushing syndrome experience the exact opposite.
• 34:14
  SPEAKER_01: Correct.
• 34:15
  SPEAKER_01: Patients with hypercortisolism frequently report feeling their best,
• 34:19
  SPEAKER_01: or at least the most functional, in the morning.
• 34:21
  SPEAKER_01: Their mood and energy deteriorate as the day goes on.
• 34:25
  SPEAKER_00: That one specific question, when do you feel you're worse during the day?
• 34:30
  SPEAKER_00: Could completely shift your diagnostic pathway away from primary depression and
• 34:34
  SPEAKER_00: toward an endocrine workup.
• 34:36
  SPEAKER_00: Let's dive into the neuroscience here because the cognitive deficits in Cushing's are severe.
• 34:41
  SPEAKER_00: The data shows that 83% of Cushing's patients have significant trouble
• 34:45
  SPEAKER_00: with concentration and declarative memory,
• 34:47
  SPEAKER_00: the ability to consciously recall facts and events.
• 34:51
  SPEAKER_00: What is the chronic cortisol flood physically doing to the brain?
• 34:54
  SPEAKER_01: It is actively neurotoxic.
• 34:56
  SPEAKER_01: We have to look at the hippocampus,
• 34:57
  SPEAKER_01: which is the brain's primary engine for encoding new memories.
• 35:01
  SPEAKER_01: The hippocampus is incredibly dense with glucocorticoid receptors.
• 35:04
  SPEAKER_01: In a normal acute stress response, a short burst of cortisol is helpful.
• 35:08
  SPEAKER_01: It binds to the hippocampus and helps you vividly remember the stressful event
• 35:12
  SPEAKER_01: so you can avoid the predator next time.
• 35:13
  SPEAKER_00: But when the cortisol flood never recedes.
• 35:15
  SPEAKER_01: Prolonged, relentless exposure to high cortisol damages the neurons.
• 35:20
  SPEAKER_01: High cortisol levels cause actual structural hippocampal neuronal damage.
• 35:25
  SPEAKER_01: MRI studies
• 35:26
  SPEAKER_01: of chronic Cushing's patients show significant shrinkage smaller hippocampal volume
• 35:31
  SPEAKER_01: compared to healthy controls.
• 35:32
  SPEAKER_00: It's essentially corroding the memory center.
• 35:35
  SPEAKER_00: And the mechanism involves a crucial protein, doesn't it?
• 35:37
  SPEAKER_01: Yes.
• 35:38
  SPEAKER_01: The mechanism hinges on a protein called brain-derived neurotrophic factor, or BDNF.
• 35:44
  SPEAKER_01: You can think of BDNF as essentially fertilizer for the brain.
• 35:47
  SPEAKER_01: It promotes neuronal growth, synaptogenesis, neuroplasticity, and overall cell survival.
• 35:53
  SPEAKER_01: Extensive animal and human models demonstrate that chronic,
• 35:56
  SPEAKER_01: high levels of corticosteroids actively downregulate the production of BDNF in
• 36:00
  SPEAKER_01: the hippocampus.
• 36:01
  SPEAKER_00: So you are simultaneously bombarding the hippocampus with emergency stress hormones
• 36:06
  SPEAKER_00: while actively starving it of the growth factor it needs to repair itself.
• 36:09
  SPEAKER_00: No wonder it physically atrophies.
• 36:11
  SPEAKER_01: Which directly results in those devastating verbal and declarative memory deficits.
• 36:15
  SPEAKER_00: To illustrate how violently
• 36:17
  SPEAKER_00: and quickly this system can disrupt psychiatric stability,
• 36:20
  SPEAKER_00: let's go back to our hook at the beginning of the episode.
• 36:23
  SPEAKER_00: Mrs. A, the marathon runner.
• 36:25
  SPEAKER_00: She was prescribed 60 milligrams of prednisone and within a day was manic,
• 36:29
  SPEAKER_00: cleaning her house, unable to sleep, and highly irritable.
• 36:32
  SPEAKER_01: What she experienced was a steroid induced psychosis or steroid induced mania.
• 36:38
  SPEAKER_01: It is a well documented severe psychiatric adverse effect of high dose exogenous steroids.
• 36:44
  SPEAKER_01: And the statistics regarding the dose response relationship are vital
• 36:47
  SPEAKER_01: for any prescriber to know.
• 36:49
  SPEAKER_00: Break those numbers down for us.
• 36:50
  SPEAKER_01: If a physician prescribes less than 40 milligrams of prednisone per day,
• 36:54
  SPEAKER_01: the incidence of severe psychiatric symptoms is quite low, under 2%.
• 36:58
  SPEAKER_01: But as you push the dose higher, the risk climbs exponentially.
• 37:02
  SPEAKER_01: Once you push that dose over 80 milligrams a day,
• 37:04
  SPEAKER_01: nearly 20 percent of patients one in five will suffer
• 37:07
  SPEAKER_01: a severe psychiatric disturbance.
• 37:09
  SPEAKER_01: And crucially,
• 37:09
  SPEAKER_01: this usually happens very quickly,
• 37:11
  SPEAKER_01: often within the first few days of starting the medication.
• 37:14
  SPEAKER_00: So the treatment for Mrs. A, the runner, was to simply stop the prednisone.
• 37:18
  SPEAKER_00: Her tendinitis might have flared back up,
• 37:20
  SPEAKER_00: but within two weeks of discontinuing the steroid,
• 37:23
  SPEAKER_00: her mental state returned perfectly to her baseline.
• 37:26
  SPEAKER_01: A word of clinical caution here,
• 37:28
  SPEAKER_01: you generally must taper steroids slowly, not stop them abruptly.
• 37:32
  SPEAKER_00: Why is that?
• 37:34
  SPEAKER_01: Because exogenous steroids suppress the patient's own adrenal glands.
• 37:38
  SPEAKER_01: If you stop the drug instantly,
• 37:39
  SPEAKER_01: the sleeping adrenal glands cannot wake up fast enough and the patient crashes into
• 37:43
  SPEAKER_01: an adrenal crisis, which is a life-threatening medical emergency.
• 37:47
  SPEAKER_01: Now, if a patient absolutely must remain on high-dose steroids to save their life
• 37:51
  SPEAKER_01: or preserve organ function, say,
• 37:52
  SPEAKER_01: for a severe autoimmune flare,
• 37:54
  SPEAKER_01: we sometimes have to proactively use medications like lithium
• 37:57
  SPEAKER_01: or atypical antipsychotics concurrently,
• 38:00
  SPEAKER_01: specifically to prevent the manic or psychotic symptoms from emerging while
• 38:03
  SPEAKER_01: the steroid does its work.
• 38:04
  SPEAKER_00: So that is the chaos of the emergency alarm being stuck on.
• 38:08
  SPEAKER_00: What happens if the adrenal system fails completely?
• 38:10
  SPEAKER_00: The alarm system goes dead.
• 38:12
  SPEAKER_00: This brings us to adrenocortical insufficiency, most famously known as Addison disease.
• 38:16
  SPEAKER_01: Addison disease specifically refers to a primary failure of the adrenal gland itself.
• 38:21
  SPEAKER_01: The most common etiology in the developed world is autoimmune destruction of the adrenal cortex.
• 38:27
  SPEAKER_00: So in this scenario, the adrenal cortex is failing.
• 38:30
  SPEAKER_00: It can no longer produce adequate amounts of glucocorticoids like cortisol,
• 38:34
  SPEAKER_00: mineralocorticoids like albostrone,
• 38:36
  SPEAKER_00: which manages salt and blood pressure, or sex steroids.
• 38:40
  SPEAKER_01: As the cortisol levels in the blood plummet,
• 38:42
  SPEAKER_01: the hypothalamus and the pituitary glands sense the dangerous shortage.
• 38:46
  SPEAKER_01: The pituitary desperately tries to kickstart the failing adrenal glands
• 38:50
  SPEAKER_01: by pumping out massive, continuous amounts of ACTH.
• 38:54
  SPEAKER_01: But the adrenal glands are destroyed.
• 38:55
  SPEAKER_01: They cannot respond.
• 38:57
  SPEAKER_00: How does this manifest in the patient?
• 38:59
  SPEAKER_00: Because unlike the rapid onset of a steroid-induced mania,
• 39:02
  SPEAKER_00: Addison's disease is incredibly insidious.
• 39:05
  SPEAKER_01: It is entirely insidious.
• 39:06
  SPEAKER_01: The symptoms develop incredibly slowly, usually over many months or even years.
• 39:11
  SPEAKER_01: The patient complains of relentless apathy,
• 39:13
  SPEAKER_01: profound overwhelming fatigue,
• 39:15
  SPEAKER_01: general lethargy, unexplained muscle cramps, and unintentional weight loss.
• 39:19
  SPEAKER_01: Their blood pressure is often dangerously low, making them dizzy when they stand up.
• 39:23
  SPEAKER_00: And there is a very unique physical sign that develops,
• 39:26
  SPEAKER_00: which is a direct result of the pituitary trying to solve the problem.
• 39:29
  SPEAKER_01: Yes.
• 39:30
  SPEAKER_01: Hyperpigmentation of the skin and mucous membranes.
• 39:33
  SPEAKER_01: The patient's skin darkens,
• 39:35
  SPEAKER_01: particularly in the creases of their hands, on their elbows, and on their gums.
• 39:39
  SPEAKER_00: Why does that happen?
• 39:40
  SPEAKER_01: Because of the massive amounts of ACTH being produced by the pituitary.
• 39:45
  SPEAKER_01: ACTH is a peptide that is cleaved from
• 39:47
  SPEAKER_01: a larger precursor molecule called POMC pro-opio-melanocortin.
• 39:52
  SPEAKER_01: When you cleave POMC to make ACTH, a byproduct is also created, melanocyte-stimulating hormone.
• 39:58
  SPEAKER_01: So, as the pituitary floods the blood with ACTH to try and wake up the adrenals,
• 40:03
  SPEAKER_01: it simultaneously floods the blood with melanocyte-stimulating hormone,
• 40:06
  SPEAKER_01: which causes the skin to darken.
• 40:08
  SPEAKER_00: The diagnostic overlap here is an absolute minefield.
• 40:11
  SPEAKER_00: You have a patient sitting in front of you presenting with profound fatigue,
• 40:14
  SPEAKER_00: apathy, muscle aches, depressed mood, and weight loss.
• 40:17
  SPEAKER_01: If you put this presentation in the context of a busy general practitioner's clinic
• 40:21
  SPEAKER_01: or a standard psychiatric evaluation,
• 40:23
  SPEAKER_01: this patient is almost certainly going to be misdiagnosed.
• 40:27
  SPEAKER_01: They will be labeled with major depressive disorder or perhaps chronic fatigue syndrome.
• 40:32
  SPEAKER_01: Patients with Addison's can wander through the medical system for years with
• 40:35
  SPEAKER_01: the wrong diagnosis, trying various antidepressants that do absolutely nothing.
• 40:40
  SPEAKER_00: So how do we catch it?
• 40:41
  SPEAKER_00: What is the clinical mental model for finding the broken adrenal gland?
• 40:45
  SPEAKER_01: Diagnosis relies on understanding the natural rhythm of the system.
• 40:49
  SPEAKER_01: Cortisol should naturally peak in the early morning.
• 40:52
  SPEAKER_01: If you draw an early morning plasma cortisol level, say,
• 40:56
  SPEAKER_01: at 8 a.m.
• 40:56
  SPEAKER_01: and it is abnormally low,
• 40:58
  SPEAKER_01: typically less than 3 micrograms per deciliter,
• 41:00
  SPEAKER_01: your suspicion for adrenal insufficiency should be very high.
• 41:04
  SPEAKER_00: And the definitive test to confirm it.
• 41:05
  SPEAKER_01: Is the cosentropin stimulation test.
• 41:08
  SPEAKER_01: You inject the patient with a synthetic version of ACTH.
• 41:11
  SPEAKER_01: In a healthy person,
• 41:12
  SPEAKER_01: the adrenal gland receives that strong signal
• 41:15
  SPEAKER_01: and immediately spikes cortisol production.
• 41:17
  SPEAKER_01: In a patient with Addison's disease, the damaged adrenal gland does nothing.
• 41:22
  SPEAKER_01: The cortisol levels remain entirely flat.
• 41:24
  SPEAKER_00: Once you have the diagnosis,
• 41:26
  SPEAKER_00: the psychiatric symptoms,
• 41:28
  SPEAKER_00: the crushing apathy and depression,
• 41:30
  SPEAKER_00: respond remarkably quickly once you provide
• 41:32
  SPEAKER_00: the correct physiological replacement therapy.
• 41:35
  SPEAKER_01: Usually,
• 41:35
  SPEAKER_01: that involves daily oral hydrocortisone to replace the cortisol and
• 41:39
  SPEAKER_01: a mineralocorticoid like fludrocortisone to manage the sodium and blood pressure.
• 41:44
  SPEAKER_01: Once the chemical balance is restored, the treatment-resistant depression resolves.
• 41:48
  SPEAKER_00: Okay, let's step back into the hallway of our smart home.
• 41:51
  SPEAKER_00: We have seen how the thyroid controls the baseline temperature and how
• 41:54
  SPEAKER_00: the adrenals manage the emergency systems.
• 41:56
  SPEAKER_00: But earlier,
• 41:57
  SPEAKER_00: you mentioned that cortisol's job is to mobilize glucose to force the liver
• 42:01
  SPEAKER_00: to pump sugar into the blood for energy.
• 42:04
  SPEAKER_00: This logically leads us to the next vital control mechanism,
• 42:07
  SPEAKER_00: the system that manages all that energy.
• 42:09
  SPEAKER_00: We are moving into the metabolic system.
• 42:11
  SPEAKER_01: This is perhaps one of the most rapidly evolving,
• 42:13
  SPEAKER_01: crucial, and frankly alarming areas of neuropsychiatric research right now.
• 42:17
  SPEAKER_01: We are talking about diabetes mellitus and,
• 42:19
  SPEAKER_01: more specifically, the broader concept of insulin resistance.
• 42:23
  SPEAKER_00: Let's do a quick level set on the pathology.
• 42:25
  SPEAKER_00: Type I diabetes is an autoimmune condition where the beta cells in
• 42:29
  SPEAKER_00: the pancreas are systematically destroyed, meaning the body produces zero insulin.
• 42:34
  SPEAKER_00: The patient requires exogenous insulin to survive.
• 42:38
  SPEAKER_00: Type II diabetes,
• 42:39
  SPEAKER_00: however,
• 42:39
  SPEAKER_00: which accounts for over 85% of all cases, is a disease of insulin resistance.
• 42:44
  SPEAKER_01: In type II,
• 42:45
  SPEAKER_01: the pancreas is producing insulin,
• 42:47
  SPEAKER_01: often massive,
• 42:48
  SPEAKER_01: continuous amounts of it,
• 42:49
  SPEAKER_01: But the body's target tissues,
• 42:51
  SPEAKER_01: the muscle, fat, and liver cells have become deaf to the signal.
• 42:55
  SPEAKER_01: The insulin is knocking on the door trying to let glucose into the cell for energy
• 42:59
  SPEAKER_01: but the cell refuses to open the door.
• 43:01
  SPEAKER_01: This leads to high blood sugar levels and eventually pancreatic exhaustion as
• 43:06
  SPEAKER_01: the beta cells burn out from overwork.
• 43:08
  SPEAKER_00: Now the relationship between type 2 diabetes and psychiatry is not just a casual association.
• 43:12
  SPEAKER_00: It is profound and it is a two-way street.
• 43:14
  SPEAKER_01: There is a deeply established bi-directional relationship
• 43:18
  SPEAKER_01: between major depressive disorder and type 2 diabetes.
• 43:22
  SPEAKER_01: Having a diagnosis of major depression significantly increases your risk
• 43:26
  SPEAKER_01: of developing insulin resistance and subsequent type 2 diabetes.
• 43:30
  SPEAKER_01: And conversely,
• 43:31
  SPEAKER_01: having type 2 diabetes significantly increases your risk
• 43:33
  SPEAKER_01: of developing major depressive disorder.
• 43:36
  SPEAKER_00: So if I'm a patient and I'm newly diagnosed with type two diabetes, I have to prick my finger.
• 43:40
  SPEAKER_00: I have to drastically change my diet.
• 43:42
  SPEAKER_00: I have to worry about neuropathy and kidney failure.
• 43:45
  SPEAKER_00: It makes I'd be depressed about that.
• 43:46
  SPEAKER_00: Right.
• 43:47
  SPEAKER_00: It's a heavy psychological burden.
• 43:49
  SPEAKER_01: That psychological burden is undeniably real.
• 43:52
  SPEAKER_01: But if we stop our analysis there, we are missing the fundamental biology.
• 43:56
  SPEAKER_01: It is not just a psychological reaction to having a chronic illness.
• 43:59
  SPEAKER_00: Yeah.
• 44:00
  SPEAKER_01: There are shared underlying biological mechanisms driving both diseases
• 44:04
  SPEAKER_01: simultaneously at a cellular level.
• 44:06
  SPEAKER_00: This is where we break down the wall between the mind and the body.
• 44:08
  SPEAKER_00: What are these shared pathways?
• 44:10
  SPEAKER_01: First, research points to shared genetic vulnerabilities.
• 44:13
  SPEAKER_01: We see overlapping genetic risk factors involving glycogen synthase kinase 3 and
• 44:18
  SPEAKER_01: the dopamine 2 receptor pathways,
• 44:20
  SPEAKER_01: meaning some patients are genetically predisposed to failure in both systems.
• 44:25
  SPEAKER_01: But more fundamentally,
• 44:26
  SPEAKER_01: insulin resistance itself creates a systemic,
• 44:28
  SPEAKER_01: highly destructive physiological environment.
• 44:31
  SPEAKER_01: It creates a state of chronic, low-grade inflammation.
• 44:35
  SPEAKER_00: It feels like every time we look deeply into modern psychiatric pathology,
• 44:39
  SPEAKER_00: we find systemic inflammation.
• 44:41
  SPEAKER_01: Because it is central to the pathology of so many chronic diseases.
• 44:44
  SPEAKER_01: Insulin resistance,
• 44:46
  SPEAKER_01: specifically increased adipose tissue,
• 44:48
  SPEAKER_01: causes an elevation
• 44:49
  SPEAKER_01: in circulating pro-inflammatory cytokines molecules like interleukin-6
• 44:54
  SPEAKER_01: and TNF-alpha.
• 44:55
  SPEAKER_01: These inflammatory markers travel through the blood,
• 44:57
  SPEAKER_01: they cross the blood-brain barrier, and they act directly on the brain.
• 45:01
  SPEAKER_01: We know from both robust animal and human models
• 45:04
  SPEAKER_01: that systemic inflammation directly causes symptoms of sickness behavior
• 45:07
  SPEAKER_01: and depression.
• 45:08
  SPEAKER_01: It alters neurotransmitter metabolism and neuroplasticity.
• 45:11
  SPEAKER_00: And crucially for the prescribing psychiatrist,
• 45:14
  SPEAKER_00: this inflammation makes the depression harder to treat.
• 45:17
  SPEAKER_01: Exactly.
• 45:17
  SPEAKER_01: Patients with major depression who have elevated inflammatory markers,
• 45:21
  SPEAKER_01: often drawn by underlying metabolic syndrome,
• 45:24
  SPEAKER_01: are significantly less responsive to standard psychiatric treatments.
• 45:28
  SPEAKER_01: They don't respond as well to SSRIs, SNRIs, or even mood stabilizers like lithium.
• 45:33
  SPEAKER_01: The inflammatory environment prevents the brain from utilizing the medications effectively.
• 45:38
  SPEAKER_00: So insulin resistance isn't just a physical metabolic issue that happens from the neck down.
• 45:43
  SPEAKER_00: The insulin resistance is practically a mood regulator itself.
• 45:47
  SPEAKER_01: I would argue it is a primary driver of psychiatric pathology,
• 45:50
  SPEAKER_01: and the epidemiological data supports this.
• 45:53
  SPEAKER_01: Even without a formal diagnosis of type 2 diabetes,
• 45:56
  SPEAKER_01: just having the early stages of insulin resistance is a massive risk factor
• 46:00
  SPEAKER_01: for psychiatric illness.
• 46:01
  SPEAKER_00: Give us the numbers on that.
• 46:02
  SPEAKER_01: A major Dutch cohort study tracked patients over time and found that individuals
• 46:06
  SPEAKER_01: with baseline insulin resistance had a 51 percent greater odds of suffering
• 46:10
  SPEAKER_01: from non-remitted chronic major depression compared to those
• 46:14
  SPEAKER_01: with normal insulin sensitivity.
• 46:16
  SPEAKER_00: But were those people already depressed?
• 46:17
  SPEAKER_00: What if you take people with completely healthy, stable moods?
• 46:20
  SPEAKER_01: Another nine year longitudinal study did exactly that.
• 46:23
  SPEAKER_01: They looked at a large cohort of people with absolutely no history of mood disorders.
• 46:28
  SPEAKER_01: Over the next decade,
• 46:29
  SPEAKER_01: those who developed even a moderate increase in insulin resistance had
• 46:33
  SPEAKER_01: an 89 percent increased rate of developing major depressive disorder.
• 46:37
  SPEAKER_00: That is staggering.
• 46:39
  SPEAKER_00: It implies that the metabolic dysfunction often precedes and actually causes
• 46:44
  SPEAKER_00: the psychiatric dysfunction in a significant portion of the population.
• 46:47
  SPEAKER_01: And the most compelling evidence comes from intervention trials.
• 46:51
  SPEAKER_01: Meta analyses have shown that using adjuvant pioglitazone,
• 46:54
  SPEAKER_01: which is an oral diabetic medication that works by directly sensitizing
• 46:57
  SPEAKER_01: the body's tissues to insulin,
• 46:59
  SPEAKER_01: actually improves symptoms in patients with non-remitted major depression,
• 47:04
  SPEAKER_01: even in patients who do not meet the criteria for diabetes.
• 47:07
  SPEAKER_01: By fixing the metabolic resistance,
• 47:09
  SPEAKER_01: by cooling off the inflammation and allowing the cells to use energy properly,
• 47:13
  SPEAKER_01: you improve the psychiatric symptoms.
• 47:15
  SPEAKER_00: This brings us to a massive point of clinical reasoning and,
• 47:18
  SPEAKER_00: frankly, a major ethical responsibility for psychiatrists.
• 47:21
  SPEAKER_00: We are not just passive observers trying to manage our patients' metabolic syndrome.
• 47:25
  SPEAKER_00: Our treatments frequently cause it.
• 47:27
  SPEAKER_01: This raises an extremely important non-negotiable clinical warning regarding the use
• 47:32
  SPEAKER_01: of atypical antipsychotics, also known as second-generation antipsychotics, or SGAs.
• 47:38
  SPEAKER_01: We prescribe these constantly for schizophrenia,
• 47:40
  SPEAKER_01: bipolar mania, and as adjuncts in severe depression.
• 47:44
  SPEAKER_01: We know these medications profoundly increase the risk
• 47:47
  SPEAKER_01: of developing insulin resistance and type 2 diabetes.
• 47:50
  SPEAKER_01: But the risk profile is not equal across the board.
• 47:53
  SPEAKER_00: We need to know which ones are the most dangerous to the metabolic system.
• 47:56
  SPEAKER_01: Olanzapine and Clozapine carry the absolute highest risk
• 47:59
  SPEAKER_01: for inducing massive rapid weight gain,
• 48:02
  SPEAKER_01: severe insulin resistance, and incident type 2 diabetes.
• 48:06
  SPEAKER_01: These drugs can wreck a patient's metabolic profile in a matter of months.
• 48:10
  SPEAKER_01: In the mid-tier of risk, you have medications like Quachapine and Risperidone.
• 48:15
  SPEAKER_01: On the other end of the spectrum,
• 48:16
  SPEAKER_01: medications like Aripiprazole,
• 48:18
  SPEAKER_01: Ziprasidone,
• 48:19
  SPEAKER_01: and Loracidone appear to present a much lower risk to the metabolic system.
• 48:22
  SPEAKER_00: Which is why the consensus guidelines from
• 48:24
  SPEAKER_00: the American Psychiatric Association combined with
• 48:26
  SPEAKER_00: the American Diabetes Association mandate rigorous ongoing metabolic monitoring.
• 48:31
  SPEAKER_01: It is arguably clinical negligence to prescribe these high-risk medications without monitoring.
• 48:36
  SPEAKER_01: If you are starting a patient on an SGA,
• 48:39
  SPEAKER_01: you must check their baseline weight and BMI,
• 48:41
  SPEAKER_01: their blood pressure,
• 48:42
  SPEAKER_01: their fasting plasma glucose or HbA1c, and their fasting lipid profile.
• 48:47
  SPEAKER_01: And you must monitor them regularly at 12 weeks and then at least annually thereafter.
• 48:51
  SPEAKER_00: You cannot just treat the acute psychosis and ignore the fact
• 48:54
  SPEAKER_00: that you might be inducing a life-threatening chronic metabolic disease.
• 48:58
  SPEAKER_00: Absolutely.
• 48:59
  SPEAKER_00: The brain and the body are not separate entities.
• 49:01
  SPEAKER_00: If you damage the metabolic environment with your prescription pad,
• 49:04
  SPEAKER_00: the brain will suffer the consequences.
• 49:05
  SPEAKER_00: Which brings us perfectly to our final set of pathways in the control room.
• 49:19
  SPEAKER_00: We have seen how insulin resistance affects mood and inflammation,
• 49:23
  SPEAKER_00: but the pathology doesn't stop there.
• 49:25
  SPEAKER_00: The hormones overflow.
• 49:26
  SPEAKER_00: Hyperinsulinemia actually spills over and violently disrupts the reproductive system.
• 49:32
  SPEAKER_00: We are entering the gonadal and prolactin systems to discuss polycytic ovary syndrome, or PCOS.
• 49:38
  SPEAKER_01: PCOS is an incredibly important pathology for psychiatrists to understand.
• 49:42
  SPEAKER_01: It is the most widespread endocrine disorder among women of reproductive age,
• 49:46
  SPEAKER_01: affecting up to 15% of the general female population.
• 49:50
  SPEAKER_01: It is fundamentally a complex dysfunction of
• 49:52
  SPEAKER_01: the hypothalamic pituitary gonadal axis, or the HBG axis.
• 49:57
  SPEAKER_00: To make a diagnosis of PCOS,
• 49:59
  SPEAKER_00: clinicians generally use the Rotterdam criteria,
• 50:02
  SPEAKER_00: which requires a patient to exhibit two out of three specific features.
• 50:06
  SPEAKER_00: First, oligovulation or inovulation,
• 50:09
  SPEAKER_00: meaning irregular, infrequent, or entirely absent menstrual.
• 50:13
  SPEAKER_00: Second,
• 50:14
  SPEAKER_00: clinical or biochemical signs of hyperandrogenism and excess of male sex hormones,
• 50:19
  SPEAKER_00: leading to physical signs like hirsutism,
• 50:21
  SPEAKER_00: which is excess facial or body hair, severe acne or male pattern hair loss.
• 50:26
  SPEAKER_00: And third, ultrasound evidence of polycystic ovaries.
• 50:29
  SPEAKER_01: Though it is a crucial clinical nuance that
• 50:31
  SPEAKER_01: a patient can have completely normal looking ovaries on an ultrasound
• 50:34
  SPEAKER_01: and still be diagnosed with PCOS if they meet the other two criteria
• 50:37
  SPEAKER_01: of irregular cycles and high androgens.
• 50:39
  SPEAKER_00: So what is the mechanical failure here?
• 50:41
  SPEAKER_00: What is happening at the pituitary level?
• 50:42
  SPEAKER_01: The mechanism is a fascinating cascade of inappropriate signals.
• 50:46
  SPEAKER_01: The pituitary gland starts pulsing,
• 50:48
  SPEAKER_01: luteinizing hormone, or LH, at an abnormally increased amplitude and frequency.
• 50:53
  SPEAKER_01: Simultaneously, the production of follicle-simulating hormone, FSH, is relatively reduced.
• 50:58
  SPEAKER_01: This results in an elevated LH to FSH ratio in the blood.
• 51:02
  SPEAKER_00: Why does that specific ratio matter so much to the ovaries?
• 51:05
  SPEAKER_01: Normally, the system relies on balance.
• 51:07
  SPEAKER_01: The FSH tells the granulosa cells in the ovary to take androgen precursors
• 51:11
  SPEAKER_01: and convert them into estrogen.
• 51:13
  SPEAKER_01: But with impaired, low FSH, that conversion process stalls.
• 51:18
  SPEAKER_01: Instead,
• 51:18
  SPEAKER_01: the abnormally high LH aggressively stimulates the cervical cells in the ovary,
• 51:23
  SPEAKER_01: forcing them to massively overproduce androgens.
• 51:26
  SPEAKER_01: So you end up with a toxic buildup of male hormones and a relative lack of
• 51:29
  SPEAKER_01: the necessary estrogen to trigger normal ovulation.
• 51:32
  SPEAKER_00: And here is where it ties directly back to our previous discussion on the metabolic system.
• 51:36
  SPEAKER_00: Insulin resistance plays a massive driving role in this pathology.
• 51:40
  SPEAKER_01: It is the primary engine for many women with PCOS.
• 51:43
  SPEAKER_01: High levels of circulating insulin hyperinsulinemia Directly stimulate those same
• 51:49
  SPEAKER_01: the walkie soul cells in the ovary to produce even more androgens,
• 51:53
  SPEAKER_01: compounding the problem created by the hyal age.
• 51:56
  SPEAKER_01: Furthermore,
• 51:57
  SPEAKER_01: the excess insulin travels to the liver and decreases the production
• 52:00
  SPEAKER_01: of sex hormone binding globulin.
• 52:02
  SPEAKER_00: Meaning there are fewer proteins available to bind up and neutralize
• 52:05
  SPEAKER_00: the testosterone in the blood.
• 52:07
  SPEAKER_01: Exactly.
• 52:07
  SPEAKER_01: So you have more free, active,
• 52:09
  SPEAKER_01: unbound testosterone floating around, wreaking havoc on the body and the brain.
• 52:14
  SPEAKER_00: And psychiatrically, the burden of this hormonal chaos is immense.
• 52:18
  SPEAKER_00: The data is incredibly clear.
• 52:20
  SPEAKER_00: Women with PCOS suffer from a vastly deteriorated psychiatric baseline compared to
• 52:25
  SPEAKER_00: the general population.
• 52:26
  SPEAKER_01: The rates are staggering.
• 52:27
  SPEAKER_01: Women with PCOS have up to four times the rate of major depressive disorder compared
• 52:31
  SPEAKER_01: to age-matched controls.
• 52:33
  SPEAKER_01: And this remains true even when you statistically control for body mass index and obesity.
• 52:37
  SPEAKER_01: They also suffer from significantly higher rates of generalized anxiety,
• 52:41
  SPEAKER_01: social phobia, and eating disorders.
• 52:43
  SPEAKER_00: The textbook provides an excellent case study that demonstrates how to tackle this clinically.
• 52:48
  SPEAKER_00: Let's look at Ms. KB.
• 52:50
  SPEAKER_00: She is a 30-year-old woman with a known diagnosis of PCOS,
• 52:54
  SPEAKER_00: and she presents to her psychiatrist with a long history
• 52:57
  SPEAKER_00: of treatment-resistant major depression.
• 52:59
  SPEAKER_00: She is currently taking venlafaxine, an SNRI, but her mood remains chronically low.
• 53:05
  SPEAKER_01: Instead of just pushing the Venlafaxine dose higher,
• 53:07
  SPEAKER_01: her physician decides to look at the underlying metabolic engine driving her PCOS.
• 53:12
  SPEAKER_01: They run a comprehensive metabolic panel.
• 53:14
  SPEAKER_01: Her fasting blood glucose comes back at 83 milligrams per deciliter.
• 53:19
  SPEAKER_00: Which looks perfectly normal.
• 53:20
  SPEAKER_00: Most doctors would stop there and say, your blood sugar is fine.
• 53:23
  SPEAKER_00: You don't have diabetes.
• 53:24
  SPEAKER_01: But they didn't stop there.
• 53:25
  SPEAKER_01: They also checked her fasting insulin level, which came back highly elevated at 19.
• 53:30
  SPEAKER_01: Using those two numbers, they calculated her HOMA-IR.
• 53:33
  SPEAKER_00: Let's define that for the listener because it's a vital tool.
• 53:36
  SPEAKER_00: HOMA-IR stands for Homeostatic Model Assessment for Insulin Resistance.
• 53:40
  SPEAKER_00: It is a simple mathematical formula that multiplies fasting glucose
• 53:43
  SPEAKER_00: by fasting insulin to quantify exactly how resistant the patient's cells are.
• 53:48
  SPEAKER_01: Generally, a HOMA-IR score over 2.3 indicates significant insulin resistance.
• 53:54
  SPEAKER_01: Mrs. KB's score was 3.9.
• 53:56
  SPEAKER_01: She was highly,
• 53:58
  SPEAKER_01: highly insulin resistant,
• 53:59
  SPEAKER_01: even though her fasting glucose looked normal
• 54:01
  SPEAKER_01: because her pancreas was simply pumping out massive amounts of insulin to force
• 54:05
  SPEAKER_01: the sugar into the cells.
• 54:07
  SPEAKER_00: And look at the intervention here.
• 54:08
  SPEAKER_00: The psychiatrist doesn't switch her antidepressant.
• 54:11
  SPEAKER_00: They tackle the endocrine root cause.
• 54:13
  SPEAKER_00: They start her on metformin,
• 54:15
  SPEAKER_00: which is a frontline medication to improve insulin sensitivity and lower
• 54:18
  SPEAKER_00: that hyperinfluenemia, and they add spironolactone.
• 54:21
  SPEAKER_01: Spironolactone is traditionally a blood pressure medication,
• 54:24
  SPEAKER_01: a potassium-sparing diuretic, but it has a very potent secondary effect.
• 54:29
  SPEAKER_01: It acts as a direct antiandrogen.
• 54:31
  SPEAKER_01: It blocks the androgen receptors,
• 54:32
  SPEAKER_01: neutralizing the effects of the excess testosterone she was producing.
• 54:35
  SPEAKER_00: The clinical results are a testament to our core rule.
• 54:39
  SPEAKER_00: Two weeks after starting the metformin and spirodalactone,
• 54:42
  SPEAKER_00: neither of which is psychiatric medications, her mood is notably improved.
• 54:47
  SPEAKER_00: Three months later, she is completely euphemic.
• 54:49
  SPEAKER_00: Her depression has resolved.
• 54:51
  SPEAKER_00: She has effortlessly lost 10 pounds due to the correcting metabolism,
• 54:55
  SPEAKER_00: and her menstrual cycle has returned to a normal, predictable 33-day pattern.
• 55:00
  SPEAKER_00: Repeat labs show her HOMA-IR has dropped to a healthy 2.0.
• 55:04
  SPEAKER_00: By fixing the insulin resistance and the hyperandrogenism,
• 55:06
  SPEAKER_00: the treatment-resistant depression vanished.
• 55:08
  SPEAKER_01: It is a profound, real-world demonstration of the hormones-brain-behavior rule.
• 55:13
  SPEAKER_01: And there is a critical pharmacological trap that we must mention here,
• 55:17
  SPEAKER_01: specifically regarding the treatment of bipolar disorder.
• 55:20
  SPEAKER_01: We frequently use valproic acid, commonly known as Depakote, as a frontline mood stabilizer.
• 55:25
  SPEAKER_01: But valproic acid is strongly,
• 55:27
  SPEAKER_01: independently associated with causing incident PCOS in female patients.
• 55:31
  SPEAKER_00: The numbers in the text are frankly wild.
• 55:33
  SPEAKER_00: If you look at women being treated for bipolar disorder,
• 55:36
  SPEAKER_00: the rate of developing new onset PCOS was 10.5% for those taking valproic acid.
• 55:42
  SPEAKER_00: Compare that to just 1.4% for women taking other mood stabilizers like lithium or lamotrigine.
• 55:48
  SPEAKER_01: That is almost a tenfold increase in risk.
• 55:50
  SPEAKER_01: Valproic acid appears to directly alter androgen biosynthesis and exacerbate insulin resistance.
• 55:56
  SPEAKER_01: The clinical mandate here is clear.
• 55:58
  SPEAKER_01: You must proactively screen your female reproductive age patients
• 56:01
  SPEAKER_01: for menstrual irregularities and clinical signs of hyperandrogenism before you start
• 56:06
  SPEAKER_01: the mandalprote, and you must monitor them continuously during treatment.
• 56:09
  SPEAKER_00: Finally,
• 56:10
  SPEAKER_00: we must briefly touch upon the last pathway on the master control board,
• 56:13
  SPEAKER_00: the prolactin system.
• 56:15
  SPEAKER_00: Prolactin is a peptide hormone produced by the anterior pituitary,
• 56:19
  SPEAKER_00: and its primary physiological role is to stimulate milk production in
• 56:22
  SPEAKER_00: the mammary glands postpartum.
• 56:24
  SPEAKER_01: But the regulation of prolactin is unique compared to the other pituitary hormones.
• 56:29
  SPEAKER_01: It is not driven by a releasing hormone.
• 56:32
  SPEAKER_01: Instead, it is under constant active tonic inhibition by dopamine.
• 56:37
  SPEAKER_01: Dopamine originates in the hypothalamus and travels down
• 56:39
  SPEAKER_01: the tubero-infundibular pathway to the pituitary,
• 56:42
  SPEAKER_01: constantly telling it, do not release prolactin.
• 56:45
  SPEAKER_01: Dopamine is a heavy foot resting on the brake pedal.
• 56:48
  SPEAKER_00: Which brings us back to our prescription pads.
• 56:51
  SPEAKER_00: What is the primary mechanism of action for all of our typical antipsychotics
• 56:54
  SPEAKER_00: and many of our atypical antipsychotics when we are trying to treat
• 56:58
  SPEAKER_00: the hallucinations and delusions of schizophrenia?
• 57:00
  SPEAKER_01: They block dopamine D2 receptors.
• 57:03
  SPEAKER_01: They are dopamine antagonists.
• 57:04
  SPEAKER_00: Exactly.
• 57:05
  SPEAKER_00: We are trying to block dopamine in the mesolembic pathway to stop the psychosis.
• 57:10
  SPEAKER_00: But the drug goes everywhere in the brain.
• 57:12
  SPEAKER_00: When you prescribe a strong D2 antagonist like haloperidol,
• 57:15
  SPEAKER_00: you are also blocking dopamine in the tuberoinfundibular pathway.
• 57:20
  SPEAKER_00: You are removing the heavy foot from the brake pedal.
• 57:22
  SPEAKER_01: And the result is immediate.
• 57:24
  SPEAKER_01: The anterior pituitary,
• 57:25
  SPEAKER_01: freed from inhibition,
• 57:27
  SPEAKER_01: floods the systemic circulation with massive amounts of prolactin.
• 57:31
  SPEAKER_01: Among the second generation atypicals,
• 57:33
  SPEAKER_01: risperidone and its active metabolite paliperidone are notorious for this,
• 57:37
  SPEAKER_01: with studies showing a 70% to 100% rate of inducing hyperprolactinemia in patients.
• 57:43
  SPEAKER_00: The clinical manifestations of hyperprolactinemia are highly distressing.
• 57:47
  SPEAKER_00: In women,
• 57:48
  SPEAKER_00: it frequently causes amenorrhea,
• 57:50
  SPEAKER_00: which is the cessation of menstrual periods,
• 57:52
  SPEAKER_00: and glycaria, which is inappropriate, spontaneous lactation.
• 57:56
  SPEAKER_00: In men, it can cause gynecomastia, breast tissue enlargement, and severe sexual dysfunction.
• 58:02
  SPEAKER_00: In both sexes, it absolutely plummets libido and decreases fertility.
• 58:05
  SPEAKER_01: And from a psychiatric perspective,
• 58:07
  SPEAKER_01: chronically high prolactin levels are heavily associated with elevated levels
• 58:11
  SPEAKER_01: of depression, anxiety, and increased hostility.
• 58:14
  SPEAKER_00: So if a patient's schizophrenia is beautifully controlled on risperidone,
• 58:17
  SPEAKER_00: but they develop severe hyperprolactinemia, what is the clinical solution?
• 58:21
  SPEAKER_01: You have a few options.
• 58:22
  SPEAKER_01: A highly effective and common strategy is to cross titrate and switch the patient
• 58:27
  SPEAKER_01: to aripiprazole.
• 58:29
  SPEAKER_01: Aripiprazole is unique.
• 58:30
  SPEAKER_01: It is a partial D2 agonist.
• 58:33
  SPEAKER_01: It provides just enough intrinsic dopamine-like stimulation at the receptor
• 58:37
  SPEAKER_01: to re-engage that brake pedal and bring the prolactin levels back down
• 58:41
  SPEAKER_01: while still controlling the psychosis.
• 58:43
  SPEAKER_00: Alternatively, the text notes you can use a direct dopamine agonist, right?
• 58:47
  SPEAKER_01: You can use medications like romocryptine or cabrigaline,
• 58:50
  SPEAKER_01: which directly stimulate the dopamine receptors to lower prolactin.
• 58:54
  SPEAKER_01: However, adding a dopamine agonist to a patient with a history of psychosis Okay.
• 59:05
  SPEAKER_01: We
• 59:08
  SPEAKER_00: have thoroughly explored the smart home architecture.
• 59:11
  SPEAKER_00: We have inspected the thyroid furnace,
• 59:13
  SPEAKER_00: the adrenal emergency system,
• 59:14
  SPEAKER_00: the metabolic energy grid, and the gonadal prolactin reproductive systems.
• 59:19
  SPEAKER_00: We've seen how often our own treatments damage these systems.
• 59:22
  SPEAKER_00: So what does this all mean for the clinicians sitting in their office tomorrow morning?
• 59:26
  SPEAKER_01: If we synthesize the core philosophy of this entire chapter, it is a call for integration.
• 59:31
  SPEAKER_01: Psychiatrists must learn to think with the structural, systemic mindset of endocrinologists.
• 59:37
  SPEAKER_01: And frankly,
• 59:37
  SPEAKER_01: endocrinologists and general practitioners must learn to recognize
• 59:40
  SPEAKER_01: that psychiatric presentations are often the first sign of endocrine failure.
• 59:45
  SPEAKER_01: The brain is not an isolated organ floating in a jar.
• 59:48
  SPEAKER_01: It is the most sensitive receiver of chemical signals in the human body.
• 59:52
  SPEAKER_00: We need to build some rapid fire mental models for our daily practice to catch these failures.
• 59:57
  SPEAKER_00: Model one, the baseline workup.
• 59:59
  SPEAKER_00: You simply do not diagnose a primary treatment resistant psychiatric illness in
• 1:00:04
  SPEAKER_00: a new patient without first checking their TSH,
• 1:00:06
  SPEAKER_00: their electrolytes, their fasting glucose, and their calcium.
• 1:00:09
  SPEAKER_01: Spot on.
• 1:00:10
  SPEAKER_01: Model two, the lithium rule.
• 1:00:12
  SPEAKER_01: If a patient is relying on lithium for mood stability,
• 1:00:14
  SPEAKER_01: you must obsessively continuously watch the thyroid system for overt
• 1:00:18
  SPEAKER_01: or subclinical hypothyroidism.
• 1:00:20
  SPEAKER_00: Model 3, the SGA rule.
• 1:00:22
  SPEAKER_00: If a patient is taking olanzapine or clozapine,
• 1:00:24
  SPEAKER_00: you are actively monitoring the metabolic system for massive weight gain,
• 1:00:27
  SPEAKER_00: insulin resistance, and the onset of type 2 diabetes.
• 1:00:30
  SPEAKER_00: Model 4, the risperidone rule.
• 1:00:33
  SPEAKER_00: You are actively questioning your patients about sexual dysfunction and monitoring
• 1:00:37
  SPEAKER_00: the prolactin system for hyperprolactinemia.
• 1:00:40
  SPEAKER_01: And Model 5, the Valprote rule.
• 1:00:42
  SPEAKER_01: You are carefully watching the gonadal system for menstrual irregularities and signs
• 1:00:47
  SPEAKER_01: of PCOS in your female patients.
• 1:00:49
  SPEAKER_00: The overarching clinical framing is this.
• 1:00:52
  SPEAKER_00: Do not just treat a downstream psychiatric symptom with
• 1:00:55
  SPEAKER_00: yet another psychotropic medication if
• 1:00:57
  SPEAKER_00: the upstream hormonal valve is visibly broken.
• 1:01:01
  SPEAKER_00: If a pipe is leaking in the ceiling,
• 1:01:03
  SPEAKER_00: putting a bucket on the floor is a temporary, ultimately failing measure.
• 1:01:07
  SPEAKER_00: You have to go upstairs and fix the pipe.
• 1:01:09
  SPEAKER_00: Treat the endocrine root cause,
• 1:01:11
  SPEAKER_00: whether that means prescribing levothyroxine,
• 1:01:13
  SPEAKER_00: starting metformin,
• 1:01:14
  SPEAKER_00: or safely tapering exogenous steroids alongside providing
• 1:01:17
  SPEAKER_00: the necessary psychological and psychiatric support.
• 1:01:20
  SPEAKER_01: Let's put these mental models to the test.
• 1:01:22
  SPEAKER_01: Before we wrap up,
• 1:01:23
  SPEAKER_01: I want to run a few clinical vignettes by you,
• 1:01:25
  SPEAKER_01: a differential diagnosis rapid fire based on the textbook's core concepts.
• 1:01:29
  SPEAKER_01: Listeners, see if you can be our expert to the punch.
• 1:01:32
  SPEAKER_00: All right, let's do it.
• 1:01:33
  SPEAKER_00: Vignette one.
• 1:01:34
  SPEAKER_00: A 35-year-old female patient presents with rapid cycling bipolar disorder.
• 1:01:39
  SPEAKER_00: We need to initiate a mood stabilizer.
• 1:01:41
  SPEAKER_00: However,
• 1:01:42
  SPEAKER_00: her history reviews she has been struggling with extreme,
• 1:01:45
  SPEAKER_00: unexplainable fatigue,
• 1:01:47
  SPEAKER_00: recent weight gain,
• 1:01:48
  SPEAKER_00: and she mentions in passing that her mother has Hashimoto's thyroiditis.
• 1:01:52
  SPEAKER_00: I have Valprote, Lithium, Llamatrigine, and Carbamazepine on the table.
• 1:01:57
  SPEAKER_00: Which one of those medications should make me incredibly nervous
• 1:02:00
  SPEAKER_00: to prescribe given her specific history?
• 1:02:02
  SPEAKER_01: You would want to be extremely hesitant to use lithium.
• 1:02:05
  SPEAKER_01: Given her symptoms of fatigue and weight gain,
• 1:02:07
  SPEAKER_01: plus a family history of autoimmune thyroid disease,
• 1:02:10
  SPEAKER_01: she is at incredibly high risk for developing overt hypothyroidism.
• 1:02:14
  SPEAKER_01: As we discussed,
• 1:02:15
  SPEAKER_01: lithium carries a massive 20% risk of pushing her into thyroid failure,
• 1:02:18
  SPEAKER_01: which would paradoxically worsen her bipolar depression.
• 1:02:21
  SPEAKER_00: Spot on.
• 1:02:22
  SPEAKER_00: Vignette 2.
• 1:02:23
  SPEAKER_00: I'm evaluating a 48-year-old man in the emergency department.
• 1:02:27
  SPEAKER_00: He presents with severe, heavy depression and marked cognitive impairment.
• 1:02:32
  SPEAKER_00: He can barely remember his address.
• 1:02:34
  SPEAKER_00: On physical exam,
• 1:02:35
  SPEAKER_00: I notice he has significant truncal obesity and very thin skin on his arms
• 1:02:39
  SPEAKER_00: with several bruises.
• 1:02:40
  SPEAKER_00: I'm trying to differentiate if this is a primary melancholic depression or
• 1:02:44
  SPEAKER_00: if it could be Cushing syndrome.
• 1:02:46
  SPEAKER_00: What specific question about his daily routine will give me the strongest diagnostic clue?
• 1:02:50
  SPEAKER_01: You need to ask him about diurnal mood variation.
• 1:02:53
  SPEAKER_01: Specifically, what time of day do you feel your best and what time do you feel your worst?
• 1:02:57
  SPEAKER_01: If he says he feels his absolute worst in the morning and slightly better at night,
• 1:03:01
  SPEAKER_01: that leans toward melancholic depression.
• 1:03:04
  SPEAKER_01: But if he tells you he feels his best or most functional in the morning,
• 1:03:07
  SPEAKER_01: despite his severe depression,
• 1:03:09
  SPEAKER_01: that strongly points toward hypercortislemia and Cushing syndrome.
• 1:03:12
  SPEAKER_00: Excellent.
• 1:03:13
  SPEAKER_00: Vignette 3.
• 1:03:14
  SPEAKER_00: I have a 22-year-old male patient with a first-episode psychosis.
• 1:03:18
  SPEAKER_00: We are discussing initiating an atypical antipsychotic.
• 1:03:22
  SPEAKER_00: He's highly concerned about sexual side effects.
• 1:03:25
  SPEAKER_00: Which of the atypical antipsychotics carries the highest estimated risk between 70%
• 1:03:29
  SPEAKER_00: and 100% of inducing massive spikes in prolactin,
• 1:03:32
  SPEAKER_00: which would directly cause the sexual dysfunction he is afraid of?
• 1:03:36
  SPEAKER_01: That would be risperidone.
• 1:03:38
  SPEAKER_01: Due to his highly potent blockade of the D2 receptors in the tubero
• 1:03:41
  SPEAKER_01: and sundibular pathway,
• 1:03:42
  SPEAKER_01: it completely removes the dopamine inhibition on the pituitary,
• 1:03:46
  SPEAKER_01: leading to severe hyperprolactinemia.
• 1:03:48
  SPEAKER_01: You might want to consider an agent with a lower risk profile
• 1:03:51
  SPEAKER_01: for prolactin elevation, like a piprazole, for this specific patient.
• 1:03:55
  SPEAKER_00: Vignette 4.
• 1:03:56
  SPEAKER_00: I am treating a 28-year-old female patient with bipolar disorder.
• 1:04:00
  SPEAKER_00: She currently has a history of irregular,
• 1:04:01
  SPEAKER_00: infrequent periods and struggles with severe acne and facial hair growth.
• 1:04:05
  SPEAKER_00: We're considering her medication management.
• 1:04:07
  SPEAKER_00: Which mood stabilizer carries nearly a tenfold increased risk around 10.5%
• 1:04:11
  SPEAKER_00: of inducing incident polycystic ovary syndrome and therefore should be avoided
• 1:04:15
  SPEAKER_00: or used with extreme caution in her case?
• 1:04:18
  SPEAKER_01: You must avoid valproic acid.
• 1:04:20
  SPEAKER_01: It is strongly associated with exacerbating hyperandrogenism and insulin resistance,
• 1:04:25
  SPEAKER_01: which would pour gasoline on the fire for underlying likely undiagnosed PCOS.
• 1:04:31
  SPEAKER_00: And finally, vignette five.
• 1:04:33
  SPEAKER_00: Let's go back to our marathon runner who was given high dose prednisone
• 1:04:36
  SPEAKER_00: for tendonitis and became acutely manic.
• 1:04:39
  SPEAKER_00: We know that exogenous corticosteroids can cause severe psychiatric symptoms,
• 1:04:43
  SPEAKER_00: but when we look at the cognitive impairments,
• 1:04:45
  SPEAKER_00: specifically the severe deficits in declarative memory seen
• 1:04:48
  SPEAKER_00: in chronic hypercortisolemia,
• 1:04:50
  SPEAKER_00: what is the underlying neurobiological mechanism causing that specific brain damage?
• 1:04:55
  SPEAKER_01: The mechanism is structural hippocampal neuronal damage driven by a severe decrease
• 1:04:59
  SPEAKER_01: in brain-derived neurotrophic factor, or BDNF.
• 1:05:03
  SPEAKER_01: The relentless high cortisol is literally toxic to the hippocampus,
• 1:05:06
  SPEAKER_01: downregulating the essential growth factor and causing physical volume loss
• 1:05:10
  SPEAKER_01: that destroys the patient's ability to encode and retrieve memories.
• 1:05:14
  SPEAKER_00: Beautifully reasoned.
• 1:05:15
  SPEAKER_00: If you want to master this control room,
• 1:05:17
  SPEAKER_00: if you want to be the clinician who catches the diagnosis that everyone else missed,
• 1:05:20
  SPEAKER_00: we highly direct you back to Chapter 27.7 of Kaplan
• 1:05:24
  SPEAKER_00: and Sadoc's Comprehensive Textbook of Psychiatry.
• 1:05:27
  SPEAKER_00: Read it carefully alongside your daily clinical practice.
• 1:05:30
  SPEAKER_00: Start looking at your patients through this integrated systemic lens.
• 1:05:35
  SPEAKER_01: I will leave you with a final thought to mull over as you head into the clinic this week.
• 1:05:39
  SPEAKER_01: If insulin resistance alone just the subtle microscopic metabolic inefficiency of
• 1:05:43
  SPEAKER_01: a muscle cell refusing to process sugar Can accurately predict the onset of
• 1:05:47
  SPEAKER_01: a major debilitating depressive episode years before a formal diagnosis
• 1:05:51
  SPEAKER_01: of diabetes is ever made on a chart,
• 1:05:53
  SPEAKER_01: we have to ask ourselves a difficult, humbling question.
• 1:05:57
  SPEAKER_01: Are we currently treating the brain as an isolated,
• 1:05:59
  SPEAKER_01: untouchable organ safely locked away in the skull
• 1:06:02
  SPEAKER_01: when it is actually just one highly sensitive node in
• 1:06:04
  SPEAKER_01: a vast body-wide chemical network?
• 1:06:07
  SPEAKER_01: The line between medical illness and psychiatric illness is a human invention drawn
• 1:06:11
  SPEAKER_01: on paper for our own administrative convenience.
• 1:06:14
  SPEAKER_01: I assure you, your patient's body certainly doesn't know the difference.