- Depression is an imbalance of norepinephrine and serotonin in CNS.
- Major disease process with a lot of cultural bias associated with it
- Black men—sign of weakness and no religious belief
- Women have a higher degree of depression than men; men suffer in silence
- Depression is closely associated with chronic disease states: diabetes, Parkinson’s, etc.
- If commit suicide from depression men—gun and women—pills; highest rates in 18-24yo
- Clinical Depression: intense feelings of sadness, hopelessness, and despair, as well as the inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts. This depression is constant and persistent; changes your lifestyle
- Reactionary Depression: loss of a loved one or job. Patient’s will eventually come around after moving through the period of mourning.
- Antidepressants are the most prescribed drug by PCP’s
- 25% of Americans are on an antidepressant drug
- VERY IMPORTANT THAT BEFORE THE PT IS PLACED ON MEDICATION THEY SEEK OTHER TREATMENT; COGNITIVE THERAPY (THERAPIST, SUPPORT SYSTEM—SOCIAL WORKER)
- Must do a good workup on patient before placing on anti-depressant drug and do follow up
MAOI –Monoamine Oxidase Inhibitors
- Some of the first antidepressant drugs used
- “cheese effect” if the patient eats aged cheese, chicken liver, beer, red wine (foods that contain tyramine) and taking MAOIs it can result in
- HA, Tachycardia, Nausea, Hypertension Episode, Stroke, DEATH
- Very effective in treating depression but could be life threatening
- If you are on Zoloft or any drug that has anything to do with SNS you must not be on MAOI for 14-20 days out because these drugs prevent breakdown of dopamine, norepinephrine, & epinephrine
- Patient on cocaine or Sudafed and takes an MAOI—will cause HTN emergency because levels of dopamine, norepinephrine, and epinephrine will increase
- DDI: SSRI’s and MAOI’s
- Sudafed, cocaine
- Serotonin is also broken down by MAOIs (Prozac, Paxil, Effexor, etc.)
- These drugs use to be used for anticholinergic effect with bedwetting
- A lot of life threatening side effects; a very narrow lethal dose (SUICIDE)
|O||Orthostatic hypotension ; carefully titrate dose when start|
|T||Thrombocytopenia (agranulocytosis, fever, sore throat, bruising/bleeding, CBC)|
|C||Cardiac Abnormalities—Get a baseline EKG—will precipitate arrhythmias|
|A||Anticholinergic (Anti-sludge) Be careful in glaucoma pt (mental changes, blurry vision) and pt with respiratory issues (causes drying and with decreased hydration the mucous plug will get thicker) pt with BPH (unable to pee)|
|S||Sedation and Seizures|
Selective Serotonin Reuptake Inhibitors—SSRIs
Paroxetine hydrochloride (Paxil)
Paroxetine mesylate (Pexeva)
- Pt that are depressed have a deficiency of Serotonin in the CNS and these agents will increase amount of serotonin in the CNS
- Serotonin plays a role in migraines, antiemetic
|S||Stimulatory; sedation; stomach ache|
|I||Insomnia, increased appetite|
S Serotonergic syndrome
- Most commonly a result of an interaction with MAOIs
- Life-threatening condition characterized by:
- Altered mental changes
- Fever, tachycardia, hypertension
- Agitation, tremor, myoclonus, hyperreflexia, ataxia, incoordination, Seizure
- Diaphoresis, shivering, GI symptoms
- Drugs that can cause serotonergic syndrome: MAOIs, antimicrobial agents (zyvox), other serotonergic drugs (dextromethorphan (Demerol), sumatriptan (Imitrax), tramadol, Zofran, St johns wart
- Longest half-life of all the other drugs and very stimulatory (take early in am)
- Highest degree of DDI; can elevate the other drug levels bc it inhibits the metabolism of other drugs
- Not often used, cheap
- Decreased appetite is a side effect and promotes weight loss
- Causes the most GI upset
- Titrate dose carefully because a lot of DDI
- When you think about Zoloft think about S for stomach
Paroxetine hydrochloride (Paxil)
- A lot of weight gain, nervousness, sweating, irritation, and jitteriness
- When you think about Paxil think of PACKING ON THE POUNDS
- It has a high degree of QTc interval prolongation
- A lot of DDI
- 1st cousin to Celexa but less side effects
- Celexa is 20-40mg and Lexapro is 5-10mg; mg to mg Lexapro is more potent
- Rarely used
- A lot of DDI
- A lot of weight gain
Serotonin Norepinephrine Reuptake Inhibitors—SNRI
Venlafaxine (Effexor, XR)
- Block serotonin and norepinephrine
- These drugs are good at treating Atypical pain or neuropathic pain (diabetic neuropathy and fibromyalgia)
- Associated with an increase elevation of Blood pressure (esp. Effexor)
- Lower the seizure threshold
- Effexor—increase BP and cause a lot of sweating, nervous, agitated
- Used as an anti-depressant or nicotine sensation (Zyban)
- Atypical: less sexual side effects, Less GI side effects
- Side effects: can elevate Blood pressure and lower seizure threshold
- Do not use if pt is bulimic or anorexic (lower seizure threshold)
- Used with elderly; very sedating and less stimulatory (give at night)
- Less sexual side effects
- Causes increased weight and can affect the lipids
- Good drug for elderly with decreased appetite and jittery
- Very sedating (put pt in trance)
Bipolar Illness (Manic-Depressive Illness)
- Mood swings… schizophrenic episodes cycling with episodes of depression
- Swings generally not related to identifiable triggering events in the patient’s life
- TX. Often involves antipsychotics, antidepressants, and lithium(or another mood-stabilizing drug)
Bipolar Illness: Lithium (Li⁺)
- Main use as mood stabilizing drug in bipolar illness, to prevent manic phase
- antipsychotic drugs, not lithium or other mood-stabilizing drugs, are indicated for treating acute manic(psychotic) phase of bipolar illness
- Effective 60-70% of time
- Use of Li as mood-stabilizing drug declining as use of other agents (e.g., certain drugs mainly used as anticonvulsants)with fewer common side-effects is increasing
Common Side Effects that can Occur When Serum Lithium Levels are “Therapeutic”
- GI: vomiting, diarrhea, appetite loss are common but usually disappear
- Progression to increase appetite↑ weight gain
- Neurologic: fatigue, muscle weakness, headaches
- Polyuria sufficient to cause dehydration unless other measures are taken to prevent it(hydration, certain diuretics);potential nephrotoxicity
- Hypothyroidism(possibly with benign goiter, occurs because lithium can↓ iodine uptake by the thyroid gland)
- Teratogenicity: NOT IN Pregnancy
|L||LEVELS very important, narrow therapeutic index (.6-1.2) 2 Toxic, RENAL FXN, lethargic, leukocytosis; impairs movement of WBCs|
|I||Increase appetite—initial will decrease appetite (N/V, wt loss) but then increase and cause weight gain, Diabetes Insipidus (body cannot conserve water) Suppress SIADH, Increase urination, Will have a toxic effect on kidneys =Nephrogenic diabetes Insipidus (polydipsia, polyuria, loss of electrolytes= heart problems=arrhythmias|
|T||Teratogenicity (Ebstein Anomaly=congenital heart defect), thinning hair (alopecia), tremors, muscle weakness, fatigue from dehydration|
|H||Hypothyroidism- lithium can block iodine from getting into thyroid (↑TSH, ↓T4↓T3)|
|U||Ugly skin, psoriasis, Acne|
Lithium Toxicity (excessive blood levels)
- Fairly common, as are side effects:
- Very low margin of safety
- Typical progression of toxicity….
- initially nausea, vomiting, diarrhea, weakness,
- fine tremors
- then confusion, coarse muscle tremors,
- then profound↓↓BP, seizures, coma, death
Lithium and Sodium
- Play close attention to SODIUM
- Renal sodium depletion →lithium retention, ↑risk of lithium SE or toxicity
- Renal sodium retention(or excess Na intake)→↑lithium excretion, ↓lithium levels and ↓ effects
- Consistency of daily Na intake(and loss) important for consistent effects)
- Educate pt to avoid exercise, sunbathing, sweating to lose sodium..also educate pt to not decrease their NA intake
- Watch medications that block NA—Diuretics, ACE/ARB, Most HTN
- Watch Bipolar pt with HTN
Mood-Stabilizing Anticonvulsants as Lithium Alternatives for Bipolar Illness
- Depakene (valproic acid),Tegretol (carbamazepine) and some of the newer anticonvulsants are being used increasingly as lithium alternatives
- Generally are effective, associated with fewer milder/common side-effects than lithium, but some toxicities can be serious
Major Classes of Antidepressants and General Treatment Guidelines
Major classes of antidepressants include:
- Selective serotonin-reuptake inhibitors (SSRIs). These have become the standard antidepressants. They target the brain chemical (neurotransmitter) serotonin. They can be effective and usually have moderate side effects.
- Other neurotransmitter inhibitors. These drugs target neurotransmitters other than or in addition to serotonin, such as norepinephrine. Many are proving to be effective in patients who do not respond to standard antidepressants or in specific patients, such as smokers who want to quit or patients with chronic pain.
- Tricyclic antidepressants (TCAs). These drugs are effective but can have severe adverse effects, particularly in older people.
- Monoamine oxidase inhibitors (MAOIs). These drugs include newer selective MAOIs. MAOIs are the most effective antidepressants for atypical depression, but have some severe side effects and require restrictive dietary rules.
- St. John’s wort and other herbal remedies are included in the Lifestyle section of this report.
Reviews of studies indicate that there are no substantial differences among SSRIs and other newer types of antidepressants. All of these drugs appear to work equally well, although they may vary in terms of side effects. Your doctor will select an antidepressant based on side effects, cost, and your personal preference.
Approach and Duration of Initial Treatment. The guidelines for the duration of an initial antidepressant regimen are as follows:
- Patients should start at a low dose, which is increased over a period of 5 – 10 days.
- Patients should see their doctor every 1- 2 weeks until substantial improvement occurs. It may take 4 – 8 weeks before a patient experiences the effects of any antidepressant.
- Side effects usually diminish within 1 – 4 weeks. (Exceptions may be weight gain and sexual dysfunction.)
- If no improvement occurs within 6- 8 weeks of starting drug treatment, the doctor may either increase the dosage or switch to an alternative drug. More than 80% of patients respond to some antidepressant, although specific drugs are helpful for only about half of patients. This suggests that if one medication fails, another has a good chance of being helpful. In general, the fewer drug treatment strategies required, the better a patient’s chances of recovering completely from depression. Patients who become symptom-free have the best chance for complete recovery compared to patients whose symptoms merely improve.
- In general, patients should continue taking antidepressants for at least 4 – 9 months after symptom relief to help prevent relapse. Patients who have had at least 2 episodes of depression may need to continue drug treatment for longer than 9 months. (Patients who improve within 2 weeks of taking medications may not require lengthy treatment.)
Treating Recurrence. Recurrence of depression is very common. About a third of patients will relapse after a first episode within a year of ending treatment, and more than half will experience a recurring bout of depression at some point during their lives. Among those at highest risk for early relapse and who may require ongoing antidepressants are:
- Patients with at least two episodes of major depression or major depression that lasts for 2 years or longer before initial treatment.
- Patients who continue to have low-level depression for 7 months after starting antidepressant treatments.
Patients may need maintenance therapy. Doctors disagree, however, on the optimal length or the appropriate dosage of maintenance therapy. Some patients may need to stay on antidepressants for 1 – 2 years — or even indefinitely. Some doctors recommend withdrawing from medication after a year. (This should be done gradually, over 2 – 3 months.) If depression recurs, the patient should go back on the antidepressants.
There is no risk for addiction with current antidepressants, and many of the common antidepressants, including most standard SSRIs, have been proven safe when taken for a number of years.
Common Side Effects of Most Antidepressants. No matter how well a drug treats depression, the ability of patients to tolerate its side effects strongly influences their compliance with therapy. Lack of compliance is probably the major barrier to success. Side effects can be avoided or moderated if any regimen is started at low doses and built up over time. Although specific side effects are discussed under individual drugs, there are a few that are common to many of them:
- Sexual dysfunction is a common side effect of many of the standard antidepressants and some of the newer drugs. Some of the newer antidepressants, such as bupropion, may be effective alternatives without as high a risk for this problem. Sildenafil (Viagra), used for erectile dysfunction in men, may help reverse sexual dysfunction from antidepressants. It does not heighten sexual interest, however.
- An increased risk of oral health problems caused by dry mouth is associated with long-term use of most antidepressants. Patients can increase salivation by chewing gum, taking vitamin C tablets, using saliva substitutes, and rinsing the mouth frequently.
- Virtually all antidepressants have complicated interactions with other drugs; some are very important. Patients should inform the doctor of any drugs they are taking, including over-the-counter medications and herbal remedies.
- Nearly all antidepressants are metabolized in the liver, so anyone with liver abnormalities should use them with caution.
- Abrupt withdrawal from many antidepressants can produce severe side effects; no antidepressant should be stopped abruptly without consultation with a doctor.
Suicide Risk and Antidepressant Medications
In recent years, there has been concern that SSRI antidepressants can increase the risk for suicidal behavior. Of particular concern is a greater risk for suicide in young people taking these medications. While depression is itself the major risk factor for suicide, and antidepressant medication may revitalize suicidal attempts in patients who were too despondent before treatment to make the effort, evidence suggests that in some cases the medication itself can cause suicidal thoughts and behavior (suicidality). One specific SSRI, paroxetine (Paxil), has been definitely linked with suicidal behavioral risk in adults ages 18 – 30.
In the U.S., all antidepressant medications now carry “black box” warnings on their prescribing label explaining the association between antidepressant use and increased risk for suicidality in children and adolescents, especially during the first few months of treatment. (In general, the average risk is minimal. Data from clinical trials have indicated that children and adolescents treated with these drugs had a 4% risk for suicidality compared with 2% for patients who received placebo.)
There may also be increased risk of suicidal thoughts and behavior in young adults (ages 18 – 24) during the first 1 – 2 months of antidepressant drug treatment. However, there is a decreased risk of suicidality for adults age 65 years and older taking antidepressants.
The U.S. Food and Drug Administration (FDA) recommends that caregivers monitor children being treated with antidepressants for sudden behavioral changes, and immediately notify their doctor if such changes occur. These behavioral signs include:
- Panic attacks
- Hyperactivity in actions and speech
- Worsening of depression
- Increased thoughts of suicide
The FDA ‘ s guidelines for medication usage also recommend that all patients see their doctors regularly after initiating drug treatment. The recommended schedule is:
- Once per week for 4 weeks (1st month)
- Every 2 weeks for the next month (2nd month)
- At the end of week 12 following the start of drug treatment (3rd month)
- More frequently if changes in mood or behavior occur
- Patients should also be closely monitored if their drug dosage is changed.
Patients should immediately contact their doctor if depression symptoms worsen or if suicidal thoughts or behavior increase.
- SSRI + MAOI (greatest risk)
- MAOIs, TCAs, SSRIs, SNRIs, (ie, venlafaxine, duloxetine), (triptans : zomig (Zolmitriptan) Amerge (Naratriptan) Imitrex (Sumatriptan), trazodone, nefazodone, L-tryptophan, (Demerol) meperidine, Zofran, buspirone (Buspar), carbamazepine (Tegretol), mirtazapine (remeron), (Ultram) tramadol, (Zyvox)linezolid, and (MDMA or Ecstasy), lithium
- clonus (inducible, spontaneous, ocular),
- hyperreflexia (muscle rigidity),
- use of serotonergic agent <5wk,
- s/s start when new agent is started, dose, or after adding 2nd serotonergic agent
S/S: AMS, fever, Hr & resp, tremors
- Reduce fever with cooling blankets, intubate AMS or seizures,
- Benzo’s preferred to restraints ( Lorazepam or Diazepam)
- BP mgt: short acting esmolol or nitroprusside
- Serotonergic antagonists (cyproheptadine, olanzapine, chlorpromazine)
Differential Diagnosis SS vs NMS
SS: develops over 24 hrs, involves neuromuscular hyperactivity & begins to resolve within 24 hrs of appropriate treatment
NMS: develops over days-weeks, involves sluggish response, resolves over an average period of 1wk-10days
Neuroleptic Malignant Syndrome
NMS inducing agents:
- All-DA blocking drugs Haldol, clozaril, compazine, phenergan, reglan, Zyprexa TCA’s, Risperdal, lithiumDrugs for Parkinson’s: levodopa and amantadine
Sign & Symptoms:
- F- Fever, HR, Resp Autonomic instability (diaphoresis, sialorrhea, skin pallor, urinary incontinence)
- L- Leukocytosis
- T- Tremor
- E- enzymes (CPK)
- R- Rigidity (hypertonia, cogwheeling, or lead pipe rigidity) catatonic
Labs: CPK, urinary myoglobin, leukocytosis 10-40,000/mm3 ,
- Fever with cooling blankets
- Benzodiazepines (relax muscles, control agitation)
- Bromocriptine (Cycloset) a dopamine receptor agonist
- Amatadine (Symmetrel)& Dantrolene
Edmunds, M. W., & Mayhew, M. S. (2014). Pharmacology for the primary care provider (4th ed.). St. Louis, MO: Elsevier Mosby.
Harvey, R. A., Clark, M. A., Finkel, R., Rey, J. A., & Whalen, K. (2012). Pharmacology (5th ed.). Baltimore, MD: Lippincott.