psychopharmacology

Psychiatric Approach to Delirium

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This week on the podcast, I am joined by Dr. Timothy Lee, the Loma Linda residency program director and the head of medical consult and liaison services. One of his specialities is delirium, so this week we will be discussing both hypoactive and hyperactive delirium.  

What is delirium?

Delirium is an acute change in a person’s sensorium (the perception of one’s environment or understanding of one’s situation). It can include confusion about their orientation, cognition or mental thinking.

With hyperactive delirium, a patient can become aggressive, violent and agitated with those around them. A patient experiencing delirium can have hallucinations and hear things, they can become paranoid, and they are overall confused. A family, or non-psychiatric medical staff, might be concerned that the patient is experiencing something like schizophrenia.

Hyperactive delirium symptoms in patients:

  • Waxing and waning—it comes and goes

  • Issues with concentration

  • Pulling out medical lines

  • Yelling profanities

  • Throwing things

  • Agitated

  • Responding to things in the room that aren’t there

  • Not acting like themselves

Hypoactive delirium is often missed because the presentation is much less dramatic compared to hyperactive delirium. People with hypoactive delirium are confused and disoriented, but they are not pulling out their lines, yelling, or physically restless.

Hypoactive delirium symptoms:

  • Slower movement

  • Softer speech

  • Slower responses

  • Withdrawn

  • Not eating as much

Often, nurses and physicians can miss the fact that the patient has the typical confusion that denotes delirium because the patient is quieter, so it doesn’t come to the attention of the medical team or psychiatrist consult service.

Delirium can even be confused for depression. One study showed that when consulting a doctor about their depression, 41.8% of the time, the patient ended up having delirium. These delirious patients reported thoughts of death, low mood and worthlessness (Farrell, 1995).

Why does delirium happen?

Often we see it happen, even to relatively healthy people, in physically stressful situations—post surgery, during an acute illness, or even just being stuck in the hospital for a few days. This does not mean it is indicative of a sudden onset of a long term mental illness, such as schizophrenia.

To consider what can cause delirium, I like to think systematically from the top of the body and work my way down. This is by no means exhaustive, but it can be helpful.

Many things can cause delirium. I like to think about starting at the top of the body and going down, as a way to not miss the cause. Here are a few we would consider as we go down the body:

  • Stroke—check strength in both arms and legs, have the patient smile

  • Hypertensive emergency

  • Infection or meningitis

  • Physical trauma—concussion, head injury with initial loss of consciousness, then after regaining consciousness they can have delirium

  • Brain bleeding

  • Medications that affect the brain, such as ones that produce anticholinergic side effects. (They suppress acetylcholine, causing brain imbalances and confusion. Anti-allergy medicines, pain medications, and some psychiatric medications are anticholinergic.)

  • Circulatory issues

  • Thyroid imbalances or parathyroid hormones

  • Cancer

  • Heart attack

  • Traumatic injury to the heart

  • Aspiration pneumonia

  • Lung infection

  • Lung cancer

  • Viral pneumonia

  • Pancreatic inflammation

  • Urinary tract infections in women

  • Liver cirrhosis

  • Hepatitis

  • Gallbladder inflammation

  • Low bilirubin

  • Hepatic encephalopathy

How do we identify delirium in a patient?

Asking certain questions to the patient and/or medical team and family can help us understand if the patient is experiencing delirium. Often, a patient experiencing delirium will still know where they are, what they are doing, and who they are. The main test to really determine if it’s delirium is the “clock drawing” where we ask the patient to draw a clock with the hands showing 11:10.

Here are some questions and tasks we ask the patient to answer and perform to test for delirium:

  • Does the person know who they are?

  • Does the person know where they are?

  • In what detail does the person understand where they are?

  • Does the person know the date?

  • Can they orient to the situation? Do they know why they are there and the circumstances that led to them being in the hospital?

  • We might ask the patient to repeat back a few words for us.

  • We will ask them later if they remember the three words we asked previously.

  • We test for concentration, like asking the days of the week in reverse order.

  • We try to assess their visual and spatial ability.

  • We might ask them to draw a clock to look for spacing, impairments, or difficulties.  

Some tests that are common to determine delirium are:

  • The Mini Mental Status Exam (MMSE)

  • The Montreal Cognitive Assessment

How to help

It is important, if the patient has loved ones with them, to educate the family about delirium, because both hypoactive and hyperactive delirium can be terrifying to watch.

When it comes to giving medications, it’s important to follow a few rules. Giving medications with anticholinergic side effects can make the patient more agitated. When prescribing meds, be careful not to switch from a hyperactive delirium presentation to a hypoactive delirium presentation by just sedating the patient but maintaining confusion. Medications like benzodiazepine, barbiturates, sedatives and pain medications (beyond what is needed for pain) can all cause worsening of delirium.

If the confusion is from an infection, an antibiotic should eventually help the cause of the delirium, however it may take a few days for the confusion to improve after the cause is eliminated.  At times antipsychotic medications are used to help the delirium and reduce the time needed to stay in the hospital.

Even after the cause of the delirium is gone, and the delirium seems to have improved very quickly, a person may still have lingering cognitive issues. It’s important to be conservative in terms of how quickly you taper them off of the antipsychotic medication used to treat the delirium.

Next Steps:

Good article on hypoactive delirium:

Hosker, C., & Ward, D. (2017). Hypoactive delirium. Bmj, 357, j2047.

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The History and Use of Antipsychotics

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In my last post, Dr. Cummings and I talked about what psychopharmacology is, how medicine works in our body, and what factors affect medicine absorption rates.

In the latest podcast, Dr. Cummings and I talked about antipsychotics, the particular branch of psychopharmacology that deals with medicines that treat psychotic experiences and other mental disorders, such as:

  • Schizophrenia

  • Severe depression

  • Severe anxiety

  • Bipolar disorder

  • Psychosis exhibiting hallucinations and delusions

The history of first generation antipsychotics

The use of antipsychotics as medication began in 1933 in France. The research around developing antihistamines evolved into the introduction of promethazine. This drug produced sedative side effects, so doctors started prescribing it before surgeries as a calming agent.

Eventually, a doctor studied the derivatives of promethazine, altered it, and developed chlorpromazine. It was mostly used as a pre-surgery anti-anxiety pill, until psychiatrists took note of the calming effect of the drug and began prescribing it to their patients.

Prior to chlorpromazine, the options for treating psychotic patients were electroconvulsive therapy, hydrotherapy, and putting patients in an insulin coma. None of those are antipsychotic in nature.

When two psychiatrists, Dr. Delay and Dr. Deniker, gave 38 psychotic patients a test round of chlorpromazine, they noticed the patients were calmer, and also less psychotic—they had less delusional thinking, fewer hallucinations, and fewer psychomotor-agitation symptoms. Deniker and Delay began giving talks on the benefits of the drug, and in 1955, chlorpromazine became available in the United States. Chlorpromazine is still used today as a treatment for different mental illnesses and mood disorders.

Once the government saw the positive effects of chlorpromazine, it began to shut down mental health facilities. There was no longer as large of a need to house psychotic patients, and they saw an opportunity to cut costs. However, they did not create adequate sources in the community for ongoing care. California alone is estimated to have 40-60% of homeless people that have a mental disorder.

Once chlorpromazine became a success, pharmaceutical companies rushed to create their own version of an antipsychotic drug. Because chlorpromazine was the grandfather of the first generation of antipsychotic drugs, the rest of that generation can be categorized by their ability to merely block dopamine D2 receptors in the brain.

In repeated studies, dopamine antagonism is responsible for 92% of their effectiveness. It also led to the thought that people were psychotic because they had too much dopamine. Since then we have found that their are much more complex psychopharmacological dynamics going on in psychosis.   

Second generation antipsychotics

The next set of antipsychotics that came on the market were clozapineolanzapine, risperidone, and other related drugs. Those medications had less effects on motor movement than the first generation drugs.

Clozapine is a poor antagonist of dopamine- blocking 30-40% of dopamine receptors but also promotes the activation of glutamate through activation of NMDA receptor, which increases activity in the frontal lobe (which helps with schizophrenia’s negative symptoms).  

Clozapine had more system-wide changes than just dopamine suppression, and it had more positive response from patients. It was more effective—40-60% of people who won’t respond to a first generation antipsychotic, do respond to clozapine.

However, in Finland in 1975, 6 people taking clozapine died due to agranulocytosis (lowered white blood cell count, leading to a severe lack of immunity). A lowered neutrophil count (called agranulocytosis) can show potential problems with fighting off normal bacteria we live with all the time.  When patients are on clozapine, initially they need weekly blood checks for this reason.

Despite the risks, clozapine can be an incredible drug—I have one patient who was schizophrenic and homeless, and she is now back in school and recently graduated with a perfect GPA! People who had been dysfunctional for decades, who are given clozapine, can become extremely high functioning.  Key to success here was her willingness to work with me, despite having to try different things before something worked. 

A trial run on a antipsychotic should be done at a minimum of 6 weeks, and blood tests must be conducted to make sure that the concentration of the medicine is at good therapeutic-dose levels. Dosage alone is sometimes not enough because we all metabolise drugs so differently.  I have uploaded recommended levels in my resource page.

Third generation antipsychotics

What is deemed the third generation of antipsychotics, aripiprazole and brexpiprazole are partial dopamine receptor agonists.  They keep dopamine at a max of 25% in the brain which due to the high affinity to the receptor it does not vary much based on dose.  

The good thing about this generation of drugs is that they don’t lower blood pressure, cause insulin resistance, and are not sedating in nature.

It works for some people, it doesn’t for others. But when it does work, it works really well.

Side effects of psychiatric medicines

Akathisia is the inability to stay still, characterized by a feeling of inner busyness. It is a miserable side effect, exhausting to the patient.

If someone is experiencing this, they should immediately call their psychiatrist or go to an emergency room.

One of Dr. Cumming’s patients described it as “ants running up and down the bones of his legs.” It usually involves an anxious feeling, and a desire to move the lower extremities of the legs. Akathisia can be caused by any drug that lowers dopamine (including SSRIs).

This syndrome is so complex because it involves several compounds, including dopamine, norepinephrine, acetylcholine, and serotonin inputs. Options for treatment include: choosing a lower dosage, picking another dopamine antagonist that is less strong (quetiapine or clozaril), or prescribing a drug like amantadine, propranolol, mirtazapine or clonazepam (more nuance in the podcast on this).

It is a harmful disorder, and one to watch out for in patients. If a patient is sent home from the hospital experiencing these symptoms, but is not properly vetted for akathisia, a doctor could be subject to serious legal repercussions.

The questions to test a patient for akathisia are:

  • Is the person moving? Can they not sit still?

  • What is their internal sense of restlessness and anxiety?

  • How much are they distressed by these feelings?

Acute dystonia involves muscle spasms and it affects movement, causing the posture to twist abnormally. It can be painful for patients to experience. This occurs because of too little dopamine in the basal ganglia part of the brain.

Parkinsonism involves muscle stiffness and slower movements. It’s usually uncomfortable, but not a miserable side effect. This also occurs because of too little dopamine in the basal ganglia part of the brain.

The future of antipsychotics

With each generation of new medicines, we’ve gotten closer to being able to help people stabilize their psychosis. We haven’t been able to achieve complete wellness.

Dr. Cummings says he has hope that with further advances in the medical field, we will be able to identify who is at risk. There is hopeful data that we may be able to one day prevent the development of schizophrenia.


History of Antipsychotics (notes by Arvy Tj Wuysang).

  • 1933, France

    • Initiative to develop antihistamine as treatment began

    1. 1947

      • Promethazine

        • Produced sedation and calmness in animal models

        • Not highly effective in humans, but found to provide calmness in preoperative settings

    2. 1950

      • Discovery of Promethazine Derivatives, especially Chlorpromazine

        • Initially tried in a surgical military hospital in France by Dr. Henri Laborit (1914-1995)

        • Successful in making people calm and indifferent to impending surgery

        • The medication was tried it in a volunteer

          • The individual reported favorable effects, until he stood up and promptly fainted

          • Determined as not safe in pre-operative setting because it was too effective as alpha-adrenergic antagonist in lowering blood pressure

    3. 1952

      • Dr. Pierre Deniker (1917-1998), psychiatrist, with Dr. Jean Delay (1907-1987), his superintendent in Sainte-Anne’s Hospital in Paris, led the Chlorpromazine introduction as a psychopharmacologic agent

        • They were interested in the calming effect of the drug

        • Tried the drug in psychotic agitated patients

          • Treatment options in those days were limited to:

            • Electroconvulsive Therapy

            • Hydrotherapy

            • Insulin coma

          • None of which were antipsychotic in nature

        • Tried it in 38 patients, made patients calmer, and less psychotic!

          • Especially effective for positive psychotic symptoms like hallucinations, delusional thinking, psychomotor agitation

        • Findings were impressive enough that Deniker began giving talks about the drug, including a conference in Montreal, that led to its introduction in North America

    4. 1955

      • Chlorpromazine was approved for usage as antipsychotic in the US

      • Subsequently used worldwide

      • Led to the deinstitutionalization of a lot of psychotic patients

        • Created a problem of lack of follow up of psychotic patients

          • I.e. California has around 357,000 homeless individuals, estimated 40-60% suffer from mental disorder with schizophrenia spectrum highly represented in that percentage

          • State spends about $200,000 per year per person to care for people committed to state hospitals. Funds committed to patients that are discharged from state hospitals are very minimal.

      • Led to development of a whole host of antipsychotic agents

    5. 1960s

      • There was an explosion in the invention of antipsychotic drugs

      • US FDA took a stance, did not allow approval of antipsychotic drugs that are not clearly better than chlorpromazine or haloperidol

      • 1st generation antipsychotics all work by blocking Dopamine D2 receptors in the brain, counts for 92-23% of variance in mechanism

      • Led to the simplistic dopamine hypothesis of psychosis

    6. 1958

      • 2nd generation antipsychotic discovered by Eichenberger and Schmutz from the Swiss pharmaceutical company Wander AG, Clozapine

      • Created because 2 other -antadine antipsychotics have been successful, Loxitane (Loxapine) and Perlapine

      • Clozapine was initially thought of as a failure because it did not produce dystonia in white lab mice, as expected in 1st generation antipsychotics where it blocks dopamine effects in the brain

      • Clozapine found to be a poor antagonist to dopamine, only blocks 30-40% of dopamine receptors. Although, it promotes release of glutamate, by binding to an allosteric site for glycine in the NMDA receptor, which in turn increases activity in the frontal lobe and suppresses dopamine release in the mesolimbic system.

      • A number of small studies in the 1960s found that patients that don’t respond to 1st generation antipsychotics responded well to Clozapine treatment by showing better response of both positive and negative symptoms of schizophrenia.

    7. 1970s

      • 1972, Clozapine usage was introduced in Austria

      • 1974, Clozapine usage was introduced in Germany

      • 40-60% of people that did not respond well to 1st generation antipsychotics, responded well to Clozapine

      • 1975, 5 people in Finland died after Clozapine treatment due to agranulocytosis

        • Clozapine found to trigger formation of antibodies targeting bone marrow cells that make neutrophils and essentially shut down a person’s immune system

        • Must monitor Absolute Neutrophil Count closely when prescribing Clozapine

          • Monitor weekly for 6 months, then every 2 weeks for another 6 months, and monthly for another year (in the USA)

          • Risk for agranulocytosis decreases with time: peaks at 4 months of exposure at about 1.3%, .38% after 1 year of exposure, .06% after 2 years of exposure

    8. Clozapine usage in the US today

      • Siskind, D., McCartney, L., Goldschlager, R., & Kisely, S. (2016). Clozapine v. first-and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. The British Journal of Psychiatry, 209(5), 385-392.

      • 15-20% of patients in California State Hospitals are on Clozapine, 53% in New York State

      • Response rates to drugs other than Clozapine is pretty miserable in State Hospitals

      • Olanzapine response rate even at high plasma concentrations is only 9%, compared to 40-60% for Clozapine. Every other antipsychotics’ response rate is between 0-5% for the severely psychotic, mentally ill patients.

      • If patients meet Kane criteria (after John M. Kane)---treatment failure after two clearly adequate trials of antipsychotic treatment with minimum of 6 weeks duration with therapeutic plasma concentration---odds that they will respond to anything other than Clozapine is fairly low.

      • Common mistake that clinicians make is to go by dosage as a measure of whether a person is receiving adequate medication

        • Dosages only weakly correlates with plasma concentration since the metabolism of antipsychotic drugs is so variable

        • Measuring plasma concentration to reach therapeutic levels is crucial in antipsychotic drugs administration, especially in patients who are seemingly refractory to treatment, to ensure adequate treatment

      • Akathisia as side effect of antipsychotics

        • Very rarely happens with Clozapine use

        • Akathisia is a very miserable side effect of antipsychotics, described as “ants crawling up and down the bone of your legs” by a particular patient

        • Characterized both by internal sense of anxiety and a near irresistible urge to move

        • Barnes Akathisia Rating Scale, most commonly used to measure akathisia symptoms. Based on three main factors:

          • Objective movement

          • Internal sense of restlessness and anxiety

          • How much are they distressed by these feelings

        • Akathisia is a concerning and common reason for malpractice

        • Underlying pathophysiology of akathisia is distinct compared to other extrapyramidal symptoms, involves not only dopamine and acetylcholine. It also involves norepinephrine and serotonin inputs to basal ganglia, makes it a difficult syndrome to treat successfully.

        • Treatment options for akathisia:

        • Akathisia may present as side effect in SSRIs and antiemetics (compazine)

  • Expected or Therapeutic plasma concentration ranges for antipsychotics and mood stabilizers

  • Aripiprazole (Abilify)

    • 3rd generation antipsychotics, partial dopamine agonist

    • Has high affinity for dopamine receptors, higher than 1st and 2nd generation antipsychotics. If Aripiprazole is present at therapeutic concentrations, 1st and 2nd generation will have very little interaction with dopamine receptors.

    • Keeps dopamine signaling at about 25% of dopamine’s maximum signal transduction, tends to produce all or nothing response in terms of treating psychotics. Not much ability to vary where dopamine is blocked because of it’s high affinity.

    • Side effect profile is very favorable. Largely metabolically neutral, tend not to cause weight gain, glucose intolerance, and lipid abnormalities. Low affinity for alpha receptors or histamine receptors, is not very sedating and does not lower blood pressure.

    • Use outside of schizophrenia

      • I.e. risperidone and olanzapine also exhibit utility as mood stabilizer and antidepressant.

      • 3rd generation antipsychotics also tend to improve mood, driven by quality of the molecules and in part by the desire of pharmaceutical companies to broaden their market

      • Use in dissociative state, such as Borderline Personality Disorder

        • Antipsychotics can help bring patients out of dissociative state in short period of time

        • Borderline patients was found to have a significant limbic dysfunction, hence antipsychotics may be helpful

  • Future of Schizophrenia Spectrum Treatment

    • There is great need to identify individuals at risk for the disease and treat them with lower dose of antipsychotics. Hopeful data is currently present in support of this approach to lower the incidence and prevalence of schizophrenia.

 

 

 

 

 

 

 

How Psychiatric Medications Work with Dr. Cummings

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This week I interviewed Dr. Cummings, a psychopharmacologist, on the Psychiatry and Psychotherapy Podcast. Below is a brief introduction to the episode. For more detailed notes by Dr. Cummings, go to my resource page.  

What is psychopharmacology?

Psychopharmacology is a branch of psychiatry that deals with medications that affect the way the brain works. The medicines used in psychopharmacology treat illnesses whose primary concerns and issues are mood, cognitive processes, behavioral control, and major mental disorders.

It is a unique branch of pharmacology because the illnesses are usually addressed by both medication and psychotherapy.

What makes a drug psychiatric in nature?

What makes a drug labeled as psychotherapeutic, is the intent behind the prescription. Some drugs will serve more than one purpose, so understanding why it was prescribed is important. For example, valproic acid is helpful in treating seizure disorders, and also bipolar disorder. For the seizure disorder, it would not be considered a psychotherapeutic drug. For the bipolar disorder, it would be considered a psychotherapeutic drug.

How do medications work?

All medicines go through the same steps of digestion in our bodies. They are liquified in the stomach, and then absorbed. The drug travels through the liver, and then into the blood supply, which brings it to the organ it was designed to target.

Our bodies have receptor sites, made of protein, that sit on the surface of a neuron, or a nerve cell in the brain. The drug, when it reaches that receptor, either binds to it and blocks it, or it can help the neurotransmitter work to further what it does naturally.

For example, caffeine is an adenosine blocker. Adenosine is a naturally occurring molecule in our bodies that calms us down as the day wears on, preparing us for sleep. Caffeine, as a drug, blocks our natural adenosine from reaching its receptor; it keeps us awake.

Medicines work in the same way—inhibiting or helping certain molecules reach their targeted organs.

How absorption and dosage rates affect medicine

Many things can affect absorption rate, and medications absorb at different rates, and at different potencies.

Things like gastric bypass, (when they take out a part of the stomach and intestines) can affect absorption rate of drugs. One of my patients had a stomach surgery, and afterwards, their depression came back. I told them to start grinding their pills to help with absorption rate of their antidepressant, and their medication started working again.

Our livers play the main part in absorption. Sometimes they are gatekeepers, and they can hinder absorption rates dramatically. Animals and plants have been at war for thousands of years. Plants create toxins to try to discourage animals from eating them. Our livers develop different enzymes to break down those toxins in order to make the plants safe for our bodies. Those same enzymes break down medications. Our bodies are constantly adapting and changing, adjusting to what we consume.

As a psychiatrist, it’s important to pay attention to absorption rates to make sure our patients are getting maximum benefit. Maybe a patient has defected genes that limit absorption rate, or deficient enzymes to break down the medication. Or maybe other medications are interacting and changing absorption rates.

A few times in my practice I have seen patients come in on multiple medications which are interacting poorly. For example, they are on a medication called amitriptyline and also on something that blocks its breakdown like fluoxetine. In our session they complain that they are confused and disoriented. I figure out that the drugs they’ve been prescribed is either inhibiting, interacting with, or increasing the effect of another medication. Once we learn that, we can make changes to their prescriptions, and they return to feeling normal.

When you change the concentration of a medication, you can destroy the entire point of the prescription in the first place. There are numerous computer programs that can help us determine problems with drug interactions. Those programs can sometimes point out what could become a clinical problem, but often point out minor, irrelevant interactions.

Just prescribing medicines, without taking into account the individual ecosystems we each have, is often a practice of trial and error. With properly administered tests and observation, we can move towards an effective dose and effective treatment plan.

Because there are so many things that can change a drug level in the body, taking a plasma concentration may be the best way to assess if the dose is appropriate (check out my resource page for a list of appropriate levels). A high or low blood level might hint that the person is a rapid metabolizer, poor metabolizer, has GI issues with absorption, or has other medications or supplements that are increasing or decreasing the dose.  

How to reduce negative side effects

One of the reasons that people develop problems with psychiatric side effects to medications is because they are increased too fast. There is a balance between wanting to get someone to an appropriate dose, and minimizing side effects.  

Too often, patients are prescribed a medication at full force and, due to sudden side effects patients will quit taking the medication.

If the medicines were administered in a slower onramp, giving time and attention to their perceived absorption rates and side effects, many problems with those medications would stop.

Is therapy or medication more helpful?

There are many trains of thought on psychotherapy and medication. Some people want a pill to fix everything. However, not everything is a chemical imbalance in the body and can be fixed with a pill.

If someone comes to me with a psychiatric problem, I almost always recommend psychotherapy, and often prescribe medication. Medications help, especially if someone has severe mental illness. If levels are mild to moderate, I find psychotherapy and lifestyle changes (like strength training and diet) are more effective for long term success.

Rates of prescribing medication has increased and use of psychotherapy has decreased. Too many patients are taking medication without psychotherapy or lifestyle changes. One study shows that 73% of antidepressants are prescribed by primary care physicians (Mojtabai, 2008).  Antidepressant use has increased from 1996 to 2005 from 6% to 10% while rates of therapy have gone down from 31% to 20% for those on antidepressants (Olfson, 2009).

Because of that, people are not being treated in the most effective way possible. This is especially the case when considering the treatment of psychological trauma, for which talk therapy can cure in ways medications can not.

Through both medications and psychotherapy, we can rewire the brain. In one study on obsessive compulsive disorder (OCD), two groups of people were studied—those who underwent cognitive behavioral therapy, and those that took medication. The therapy was found to be as helpful in eliminating OCD symptoms. However, the OCD symptoms returned when the medication was stopped. The symptoms did not return when the person had received cognitive behavioral therapy.

Dr. Cummings uses a simple guideline to see if someone would benefit from medicine or talk therapy. If what the person is depressed about is something in their lifestyle—their weight, their job, their relationship, lifestyle changes and talk therapy will probably be most effective.

If someone is experiencing neurovegetative symptoms of depression, such as: loss of appetite or increased appetite, severe energy loss, severe sleep disturbance with early morning awakening, physically slowed down, they are suffering from brain disturbances that are helped by medication.

For more notes by Dr. Cummings, go to my resource page.  

Mojtabai, R., & Olfson, M. (2008). National patterns in antidepressant treatment by psychiatrists and general medical providers: results from the national comorbidity survey replication. The Journal of clinical psychiatry.


Olfson, M., & Marcus, S. C. (2009). National patterns in antidepressant medication treatment. Archives of general psychiatry, 66(8), 848-856.


See below for notes on the episode writen by Arvy Tj Wuysang.  

  • Defining Psychopharmacology and Psychopharmacologic Agents

    • Psychopharmacology: Study of medications and substances that affect how the brain works, both positively and negatively

    • “Intent” in using versatile drug classes as psychotherapeutic agents

      • Valproic Acid usage as an anti-epileptic drug vs mood disorder drug

      • Caffeine usage as stimulant

  • Metabolism and Physiologic Distribution of Psychopharmacologic Agents

    • Gastrointestinal surgeries and their effect on psychiatric drugs’ absorption

      • Olanzapine will not be absorbed as effectively in individuals who had Gastric Bypass Surgery because of its slow absorption. Lorazepam, on the other hand, has a characteristically rapid absorption and will not have much disturbance in its absorption even in the context of post Gastric Bypass Surgery.

    • Properties of drug absorption within the liver

      • Cytochrome P450 enzymes

        • Evolutionary developed to metabolize plant toxins

        • Common classes that plays significant role in psychiatric drug metabolism

          • 2D6, 2A4, 1A2

      • Interaction with other drugs

        • 2D6 blockers (Fluoxetine, Paroxetine, Bupropion) will elevate plasma Amitriptyline levels.

        • Inducers will decrease plasma levels

      • Benefits of using drug-drug interaction applications/softwares

      • Importance of monitoring plasma levels versus genetic testing in determining effective/safe dosage

      • UCLA Imipramine Titration Study

        • If receptors are given time to adapt to the medications, oftentimes side effects may be minimal

        • Imipramine titration goal of 150 mg

          • 1st group: increase of 25 mg increments per week

            • experienced significant side effects (sleepy, dry mouth, low BP)

          • 2nd group: increase of 10 mg increments per week

            • achieved the same blood levels as the first group but experienced minimal side effects

  • How do psychiatric drugs work?

  • How long should one stay on antidepressants?

    • Dependent on frequency and severity of depressive episodes

      • Single depressive episode

        • Treat to remission, keep in remission for 1 year, gradually taper the antidepressant

      • 2-3 episodes of depression

        • Essentially, needs to stay on antidepressants permanently

        • Remains vulnerable to depression

        • Antidepressants ameliorates symptoms, but does not cure underlying pathophysiology

        • Each episode makes the next episode more likely!

      • Analogous to Diabetes Mellitus treatment

        • I.e., Blood sugar needs to be controlled for the rest of the patient’s life

  • How do we determine between using medications versus lifestyle therapy in treating psychiatric conditions?

    • Depends on presentation

      • If merely dysphoric, can start by introducing lifestyle changes

      • If greater severity, showing neurovegetative signs, may start with medications right away

        • Neurovegetative signs: Loss/increase of appetite, significant weight changes, severe loss of energy, severe sleep disturbance, psychomotor agitation/reduction

  • Pathophysiology of Depression


Dr. Cummings has recommended these articles to read along with this session (thank you Mona Mojtahedzadeh M.D. for organizing them and adding some notes):

 

1. Duman, R. S., & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: potential therapeutic targets. science, 338(6103), 68-72.

  • Depression is associated with reduced brain size and decreased neuronal synapses in regions that regulate mood and cognition (the prefrontal cortex and the hippocampus).

  • Antidepressants can block or reverse these deficits.

  • Typical antidepressants have limited efficacy and delayed response times (weeks to months).

  • Ketamine is a N-methyl-D-aspartate receptor antagonist that has been proven to produces antidepressant responses in patients who are resistant to typical antidepressants within hours.

  • Ketamine has been shown to rapidly induce synaptogenesis.

  • Ketamine can also reverse the synaptic deficits caused by chronic stress.

  • Findings highlight the importance of a synaptogenic hypothesis of depression and treatment response.

2. Thompson, J., Thomas, N., Singleton, A., Piggott, M., Lloyd, S., Perry, E. K., ... & Ferrier, I. N. (1997). D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics, 7(6), 479-484.

3. Hyman, S. E., & Nestler, E. J. (1996). Initiation and adaptation: a paradigm for understanding psychotropic drug action. The American journal of psychiatry, 153(2), 151.

4. Tracy, T. S., Chaudhry, A. S., Prasad, B., Thummel, K. E., Schuetz, E. G., Zhong, X. B., ... & Tay-Sontheimer, J. (2016). Interindividual Variability in Cytochrome P450–Mediated Drug Metabolism. Drug Metabolism and Disposition, 44(3), 343-351.

5. Hunsberger, J., Austin, D. R., Henter, I. D., & Chen, G. (2009). The neurotrophic and neuroprotective effects of psychotropic agents. Dialogues in clinical neuroscience, 11(3), 333.

6. psychotropic medications: overview seminar core handout

7. McCutcheon, R., Beck, K., Bloomfield, M. A., Marques, T. R., Rogdaki, M., & Howes, O. D. (2015). Treatment resistant or resistant to treatment? Antipsychotic plasma levels in patients with poorly controlled psychotic symptoms. Journal of Psychopharmacology, 29(8), 892-897.

  • Big number of patients with schizophrenia have poor response to antipsychotics medications.

  • Possible causes are subtherapeutic plasma levels of the medication or medication ineffectiveness.

  • This study examines 36 patients with treatment resistant schizophrenia and assesses the extent of subtherapeutic antipsychotic plasma levels and the frequency of antipsychotic plasma level monitoring in standard clinical practice.

  • Antipsychotic plasma levels were found to have been measured in only one patient in the year prior to our study.

  • Over one-third of patients had subtherapeutic antipsychotic levels.

  • In detail: sixteen (44%) patients showed either undetectable (19%) or subtherapeutic levels (25%), and 20 (56%) patients had levels in the therapeutic range.

  • Black ethnicity, shorter duration of current treatment, and antipsychotics other than olanzapine and amisulpride were factors significantly associated with subtherapeutic plasma levels.

  • This study indicates higher chances for under-treatment rather than treatment-resistance for those patients with poor response to antipsychotic medications.

  • On another note, the measurement of antipsychotic levels may be under-utilised.

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