Attention Deficit Hyperactivity Disorder (ADHD)

Diagnosis

-ADHD is the most common physiocratic disorder in children. 

-Its prevalence is 5-11% in school-aged children 

-It often presents with a classic triad of inattention, hyperactivity, and impulsivity 

– However, it can present as mixed, or primarily inattentive or hyperactive 

-Symptoms must include at least 6 signs of inattention and/or six signs of hyperactivity/impulsivity for 6 months. 

-For patients 17 years and older on 5 symptoms are required 

Symptoms of inattention include

-failure to pay close attention 

-difficulty sustaining attention on tasks or activities 

-failure to listen when spoken to 

-difficulty organizing tasks 

-avoidance of activities that require mental effort 

-losing things necessary for tasks or activities 

-distractibility and forgetfulness in daily activities 

Symptoms of hyperactivity

-fidgeting with hands or feet 

-inability to sit still 

-running around when not appropriate 

-difficulty engaging quietly in activities 

-feeling on the go or driven by a motor 

-talking excessively 

Symptoms of Impulsivity

-answering questions before they are completely asked 

-having trouble waiting ones turn 

-interrupting others 

The pattern of behavior must be more severe and occur more often than in other children of the same age. The symptoms of the disorder must be present before the age of 12 years. The diagnosis can be made after 12 years of age but there must be evidence of symptoms before the age of 12. The last important point is the symptoms must occur in two different settings (e.g., home and school). 

Many patients may be familiar with screening scales like the Vanderbilt or Conners which can be used to help confirm the diagnosis usually one is completed by the parent the other by a teacher. 

Most Commonly Prescribed Psychiatric Medications: Desvenlafaxine/Pristiq

Desvenlafaxine is the active metabolite O-desmethylvenlafaxine (ODV) of venlafaxine and is formed as a result of CYP450 2D6. It shares many of the same properties as venlafaxine. 

  • It’s FDA approved for Major depressive disorder 
  • Mechanism of action: This medication will boost the neurotransmitters serotonin, norepinephrine, and dopamine. It does so by blocking the serotonin reuptake pump, the norepinephrine reuptake pump, and increases dopamine in the frontal cortex because dopamine is largely inactivated by the norepinephrine reuptake pump in the frontal cortex. 
  • The dosing is a little easier than venlafaxine. You can start with 50 mg/day with a maximum dose of 100 mg/day. In some cases, doses of 400 mg/day have been shown to be effective but there is increased risk for side effects at higher doses. 
  • Desvenlafaxine is more potent at the serotonin transporter but has greater norepinephrine transporter inhibition relative to venlafaxine. This is one advantage along with lower does required to achieve that inhibition. 
  • These tablets should not be broken, crushed, or chewed, it will alter the controlled release.
  • It has some of the same issues as venlafaxine when it comes to withdrawal or discontinuation. It can be difficult to taper off and may require starting fluoxetine prior to tapering. 
  • Blood pressure must be monitored regularly during treatment.
  • Most common side effects include: nausea (most common 12%), dizziness (8%), increased sweating (6%), constipation (5%).
  • Other side effects: decreased appetite, decreased libido, erectile dysfunction, abnormal dreams, tinnitus, vertigo 
  • I’ve had many questions about combining this with mirtazapine. It can be combined with mirtazapine. Trazodone and bupropion are other popular medications to combine with desvenlafaxine if monotherapy does not result in remission. 
  • Desvenlafaxine offers some benefits over venlafaxine including more consistent plasma levels due to lack of metabolism by CYP 2D6, it has more potent action at the norepinephrine transporter than venlafaxine. It may be a better option if you are targeting the norepinephrine system. 

Most Commonly Prescribed Psychiatric Medications: Trazodone

  • The only FDA approved use of trazodone is for depression. However, this medication is rarely prescribed for this purpose. The higher dose requirements and lower affinity for the serotonin transporter allows the side effect profile to make the medication intolerable for most patients. 
  • The most common way it’s used is as an adjunctive therapy for sleep disturbances secondary to depression. 
  • The mechanism of action is blockade of serotonin 2A receptors and blockade of the serotonin reuptake pump. 
  • Dosing: To take advantage of the sedating properties you want to use a lower dose. A dose of 25-150 mg/night is appropriate. For depression the dose must be much higher anywhere from 150-600 mg/day 
  • For depression start with 150 mg/day in divided doses (short half-life) and increase every 3-4 days by 50 mg/day as needed to a target dose of 400 mg/day. For insomnia start with 25-50 mg/night and increase as tolerated to a target dose of 50-150 mg/night. That same target range of 50-150 mg/day can be used if trazodone is being added as an adjunct therapy for depression. 
  • It’s very important to start low and go slow when increasing the dose. Patients can have carryover sedation, ataxia, and intoxicated like feeling if titrated too rapidly. 
  • Do not stop the medication prematurely. In difficult to treat patients’ higher doses may be required 150-300 mg or up to 600 mg in some cases. 
  • It’s ideal to try and limit dosing to once nightly at bedtime to avoid daytime sedation 
  • Notable Side effects: Nausea, vomiting, constipation, dry mouth, dizziness, sedation, fatigue, headaches, life threatening side effects include priapism (1 in 8,000 men), seizures, activation of suicidal ideation in patients under 24 years of age.
  • The onset of therapeutic actions for insomnia should be immediate once an adequate dose is reached. There is no evidence of tolerance, abuse potential, or withdrawal
  • Therapeutic action for depression is delayed by 2-4 weeks if it’s not working by 6-8 weeks consider a dosage increase or switch depending on dosage reached 
  • Trazodone offers a nonaddictive option for insomnia treatment and can be used as an adjunct for depression treatment. It’s less likely than other antidepressants to cause sexual dysfunction. It may be less likely to precipitate hypomania or mania and may have some benefit for treating agitation and aggression associated with dementia. 

Most Commonly Prescribed Psychiatric medications: Seroquel or Quetiapine

  • Quetiapine offers some benefits over other dopamine blocking medications. It has a much lower risk for EPS and a broad spectrum of effects. The main limitations are weight gain, sedation, and orthostasis. The extended-release formulation offers a once nightly dosing that can reduce daytime sedation. 
  • It has a number of FDA approved indications including use in schizophrenia, bipolar disorder, bipolar depression, and major depression as an adjunct 
  • It’s mechanism of action is blocking dopamine D2 receptors which targets positive symptoms of psychosis and serotonin 2A receptors which enhance dopamine release in certain regions of the brain reducing motor side effects and possibly improving cognitive side effects. It’s effects on depression and bipolar depression may be related to 5HT1A partial agonist activity, norepinephrine reuptake blockade, and 5HT2C and 5HT7 antagonist properties.
  • Clinically quetiapine is often underdosed and stopped or switched before an adequate trial is completed. Higher doses generally achieve greater response for manic or psychotic symptoms. 
  • For schizophrenia start with 25 mg BID or 300 mg XR QHS. Target doses 400-800 mg/day 
  • For bipolar start with 50 mg BID or 300 XR QHS. With a target dose of 400-800 mg daily for mania and 300 mg/day for depression (studies indicate that 600 mg was not better for depression than 300 mg)
  • For depression start at 50-100 mg/day in divided doses with a target of 150-300 mg/day (data indicates that 150 mg and 300 mg do equally well so either dose is appropriate depending on patient response) 
  • You can increase the dose 50-100 mg/day every 1-4 days to a target dose 
  • The max daily dose in adults is 800 mg/day, occasionally patients may require 800-1,200 mg/day for psychosis or mania 
  • Monitoring is similar to other dopamine blocking medications, specifically fasting blood glucose and lipid profile, BMI, blood pressure 
  • Side effects include sedation, hypotension, dry mouth, dizziness, constipation, weight gain and fatigue. Watch for orthostatic hypotension at high doses or with rapid titration. There is essentially no motor side effects or prolactin elevation. 
  • For XR formulations do not crush or chew them, if a patient has been off the medication for more than 1 week you want to restart as if initial therapy. Quetiapine has some abuse potential reported in the literature particularly in incarcerated populations 
  • In the initial studies with beagle dogs cataracts developed but human studies have not shown this association 

The Only Medication Proven to Reduce Suicide

As a psychiatry trainee you will never forget that the two medications that reduce suicide are lithium and clozapine. In the case of clozapine, it has been shown in RCTs to reduce suicidal thoughts but not necessarily completed suicides. Lithium on the other hand has RCT data that indicates it reduces suicidal thoughts as well as completed suicide.

Lithium has anti-suicidal effects even at low doses. Lithium’s anti-suicidal effects are beneficial for both unipolar and bipolar depression. Unlike standard antidepressants that can increase the risk of suicide specifically in younger patients under the age 24, lithium has a prophylactic effect to prevent suicide. 

While lithium overdoses can be fatal, this outcome is less likely given the anti-suicidal properties of this medication. We should not avoid prescribing it for this reason. 

New medication Monday: Combination Dextromethorphan and Bupropion AXS-05

The result of research to develop a nonaddictive cough suppressant produced dextromethorphan. It was FDA approved in 1954 but the pharmacology of this cough suppressant is complex. It functions as an uncompetitive NMDA-glutamate blocker (thin ketamine), sigma-1 stimulator, and serotonin reuptake inhibitor. It should start to become clear why there is renewed interest in this medication. 

Bupropion functions as a selective norepinephrine/dopmaine reuptake inhibitor. It’s currently used to treat depression, seasonal affective disorder, and nicotine dependence. Recent research suggests it acts as a potent inhibitor of cytochrome P450 2D6 (CYP2D6). Understanding the cytochrome P450 system is not a primary concern here but this enzyme metabolizes dextromethorphan. 

The combination of these two drugs dextromethorphan 45 mg and bupropion 105 mg two times per day is AXS-05. The proposed mechanism is prolongation of dextromethorphan activity by CYP2D6 inhibition with the added benefit of norepinephrine/dopamine reuptake inhibition. 

A phase-3 RCT of AXS-05 in patients with MDD outperformed placebo and improved depression scores over 6 weeks. 

Intramuscular Medication (IM) in Psychiatry: Is it Better?

Intramuscular medication as the name implies is a long-acting injectable form of medication that is usually administered into the gluteal muscle or deltoid muscle and it’s designed to take the place of PO or oral formulations.

The medications available in IM formulations

  • Aripiprazole (Abilify Maintena) 
  • Aripiprazole lauroxil (Aristada) 
  • Fluphenazine (prolixin)
  • Haloperidol (Haldol)
  • Olanzapine pamoate (Zyprexa Relprevv) 
  • Paliperidone (Invega Sustenna, Invega Trinza) 
  • Risperidone (Risperdal Consta) 

Most last between 2-4 weeks but medications like Invega trinza lasts up to 3 months 

This solves one of the major issues when prescribing medication, which is adherence with treatment. 

Notice that all these medications are first- or second-generation dopamine blockers. These medications are commonly used to treat disorder like Bipolar and Schizophrenia (serious mental illness). These populations often have difficulty with medication adherence. 

Clinically most psychiatrists will tell you IM medication improves patient outcomes. However, they may not outperform PO medication taken daily and consistently. Where these medication formulations have the biggest impact is for people who had improvement on oral medication but often forget to take medication or do not want to take medication daily. Many patients with serious mental illness stop taking medication when symptoms resolve making relapse likely. 

Side effects will be similar to the oral medication with the added logistical issue of coming to the office for the injection, and pain at the injection site. Normally we assess tolerability and risk of side effects with oral medication before giving IM medication. This avoids the potential for long lasting side effects. 

Immediate Release Vs Extended-Release Formulations in Psychiatry

Highlights From the Video

Immediate release the medication is released immediately and results is quick onset and a peak blood level. This type of formulation is generally less expensive and may be advantageous in some cases. For example, if you are using quetiapine at night in part for its sedating effects, I will use immediate release because I want a rapid effect. The same with methylphenidate or bupropion. 

The problem is this formulation requires twice a day or even three times per day dosing and results in more peaks and troughs. In general, for medications that are being used for maintenance you want consistent blood levels and not peaks and troughs.

With IR formulations, there can be more side effects and addictive potential. We believe it’s the rapid rise in blood levels of the medication that cause side effects and with medications like amphetamines for ADHD it’s the rapid rise in medication levels that can result in euphoria and thus addictive potential.

Extended release does not change the active ingredient in the medication, rather it provides a different delivery mechanism that slows the release of medication over an extended period of time. This has the opposite effect on blood levels when compared to IR. There will be less peaks and troughs and more sustained blood levels of medication. The advantage is once daily dosing and potentially fewer side effects for the pervious mentioned reasons. 

The downside is these medications tend to cost more money and some have argued when initiating these medications, a patient who has an adverse reaction will have symptoms longer with XR. Although clinically I’m not sure this is true and will generally use extended release if possible for maintenance medications.

Medication Side Effects: “I feel nauseous”

Introduction:

Did you know that the researchers that conduct drug trials do not ask patients about specific side effects? Rather, they ask a generic question such as “are you having adverse reactions to the medication” the patient then has to self-report any specific side effects they are having. Sometimes physicians during medication management sessions will use a similar question when asking about side effects. Some physicians also make statements when prescribing the medication such as “don’t worry most people do not have side effects with this medication.” This is egregious, considering we know these medications have side effects as all medications do. What I want to do over the next several posts, is discuss the common side effects of SSRIs and what you can do about them. The biggest issue we face with psychiatric medications is adherence, and many times side effects play a role. 

I want to start with the most common side effects and work our way down. Nausea is one of the early side effects that is disturbing to patients and may result in discontinuation of the medication. Several things can be done to reduce the risk of nausea. 

Medication Starting Dose and Titration

One simple step could be to start the medication at the lowest possible dose and titrate slowly. Titrating the dose over one week has been shown to cut the risk of nausea in half. Another potential intervention is to split the dose and give the split dose with separate meals. If possible, use sustained/extended release preparations of the medication. For example, starting a patient on escitalopram 5 mg instead of 10 mg might help reduce the risk of nausea. Another simple change could be the timing of medication administration. Taking the medication after a meal may be helpful. Many patients find that food helps reduce the nausea and most of these medications can be taken with or without food. 

Ginger Is Good

If the above interventions fail to help you can consider ginger root. This dietary supplement can be purchased over the counter from your local health food store. Ginger root 550 mg one to two capsules up to three times per day if the slow titration and other intervention are ineffective. 

If All Else Fails

Finally, if the nausea does not respond to the above interventions then anti-nausea medications are appropriate. The two most commonly used at ondansetron and Mirtazapine which also blocks 5HT-3 receptors leading to reduced nausea. 

Medication Side Effects: Doctor my mouth is a little dry

Regular Dental Care and Oral Hygiene

Dry mouth is another common side effect from psychiatric medication. Patients on psychiatric medication often have poor dental care and poor dental outcomes. There is increased incidence of dental caries and oral ulcers in this population. This patient population is also three times more likely to lose all their teeth. Let that sink in for a moment. Now some of this is related to not following the recommended dental hygiene guidelines such as regular cleanings at least every 6-months. Thus, this is the first step in the process. Ensure the patient first has a dentist, and second be sure they are making regular 6-month appointments, and if they have issues with dental health, they should be going for cleanings as often as every 3 months. Oral hygiene is the foundation for the remainder of the interventions.

Gum, Candy, and Pilocarpine

Most patients are told to carry a bottle of water around and take frequent sips throughout the day. This does not work. It provides temporary relief, and does not address the underlying issue. You can educate the patient about drinking more water while eating which can help facilitate the swallowing process especially when dry mouth is an issue. Carrying a cup of ice can be helpful but is not convenient. What I prefer is the use of sugarless gum or candy which can be easily carried and chewed as needed. Studies have demonstrated that xylitol containing gum can reduce the levels of Mutans streptococci and lactobacilli in saliva and plaque. This has the potential to reduce the incidence of dental caries, and is an inexpensive option for most patients. I will also recommend as a second line using a mouth wash for dry mouth such as Biotene. If these interventions are not effective a medication to stimulate saliva production such as pilocarpine. In many cases pilocarpine eye drops which act locally is a better option than a medication that acts systemically. 

Final Words

Dry mouth is a common side effect patent’s experience but may not always bring to the clinician’s attention. There are interventions to treat this side effect that range from simple interventions like xylitol containing gum to pharmacological interventions such as pilocarpine eye drops. Most patients will experience relief with the above treatments. This highlights the importance of asking about specific side effects so they can be treated early and prevent long term Complications such as tooth loss. 

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