Psychopharmacology

(2)

• A branch of pharmacology that deals with drugs that influence mental or emotional processes
• Drugs co ntrol symptoms rather than curing or reversing the primary pathologocal state

Psychopharmacology

Schizophrenia

Positive (active) symptoms

(5)

• Thought disturbances
• Dellusions, hallucinations
• Motor hyperactivity
• Paranoia
• Sometimes aggressive behavior

Psychopharmacology

Schizophrenia

"Negative" (passive) Symptoms

(4)

• Social withdrawal
• Loss of drive
• Diminished affect
• Paucity of speech

Psychopharmacology

Schizophrenia

Cognitive Sypmtoms

(3)

• Poor executive functioning
• Inability to sustain attention
• Problems with working memory

Psychopharmacology

Schizophrenia

Dopamine Hypothesis

The "dopamine hypothesis" - The dopamine hypothesis suggests that schizophrenia is promoted by a relative excess of dopaminergic tone to brain limbic (emotional) centers.  This excess tone then gradually distorts higher (cognitive) brain centers to disrupt the capacity for assessing objective reality

Psychopharmacology

Schizophrenia

Circumstantial Evidence for the Dopamine Hypothesis

(3)

• Drugs that facilitate or mimic dopamine transmission(i.e. amphetamine, L-DOPA) exacerbate symptoms in schizophrenic patients or precipitate or precipitate symptoms during remission
• High chronic doses of some indirect dopamine agonists(i.e. amphetamines) can induce symptoms identical to those of an acute paranoid schizophrenic reaction
• Many anti-psychotic drugs block post-synaptic D2 receptors in the CNS 

Psychopharmacology

Schizophrenia

Problems with the Dopamine Hypothesis

• Although disruption of dopaminergic transmission by neuroleptics can occur w/in hours, 2-3 weeks of treatment are required before schizophrenic symptoms are relieved
• Other symptoms (GABA, glutamate, norepinephrine, histamine, neuropeptides) have been implicated in schizophrenia

Psychopharmacology

Anti-psychotics (neuroleptics)

Resrpine

Psychopharmacology

Anti-psychotics (neuroleptics)

First Generation Agents

• "Typical" antipsychotics
• Chlorpromazine (Thorazine) *
• Haloperidol (Haldol) *

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

General Properties

(4)

• All lack liability for depression of respiration and chemical dependence
• These agents are more effective against "positive" vs. "negative" symptoms
• Latency to benefits may be weeks to months
• Noncompliance is common

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

MOA

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

Overview of side effects (4)

Extrapyramidal symptoms

• Slow movement 
• rigidity and tremor
• akathisia (uncontrollable motor restlessness)
• dystonisa

a set of subcortical circuits and pathways that includes the corpus striatum (caudate nucleus, putamen, and globus pallidus) together with the subthalamic nucleus, substantia nigra, red nucleus, and brain stem reticular formation.  The system is called “extrapyramidal” to distinguish it from the tracts of the motor cortex that reach their targets by traveling through the “pyramids” of the medulla.

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

Overview of side effects

Tardive Dyskinesia (3)

• The most limiting side effect can be tardive dyskinesia.
• This condition is characterized by; involuntary movements of the face, mouth, and toungue, and sometimes the upper limbs, trunk, and neck.
• It can be irreversible

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

Overview of side effects

Neuroleptic Malignant Syndrome

• The incidence is ≈1% of all patients receiving neuroleptics, and the mortality rate among them is   ≈15%

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

Antilcholinergice effects

(5)

• Dry mouth
• Blurred vision
• Confusion
• Conctipation
• Urinary retention

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

Cardiovascular Effects

• Hypotension
• Reflex tachycardia

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

Table

Psychopharmacology

Anti-psychotics (neuroleptics)

Chlorpromazine (Thorazine) *

Haloperidol (Haldol) *

Side Effects (Big Card)

(7)

• Extrapyramidal Symptoms – slow movement, rigidity and tremor, akathisia (uncontrollable motor restlessness), dystonias.
• The most limiting side effect can be tardive dyskinesia.  This condition is characterized by involuntary movements of the face, mouth, and tongue, and sometimes the upper limbs, trunk and neck.  It can be irreversible.
• Neuroleptic malignant syndrome  - The incidence is ≈1% of all patients receiving neuroleptics, and the mortality rate among them is ≈15%.
• Hyperprolactinemia
• Weight gain
• Anticholinergic effects: dry mouth, blurred vision, confusion, constipation, urinary retention
• Sedation
• Cardiovascular effects: hypotension, reflex tachycardia 

Psychopharmacology

Anti-psychotics (neuroleptics)

Other Uses Typical Antipsychotics

(6) 

• Anti-manic treatment
• Tourette's syndrome (haloperidol)
• Treat emesis
• Autsim
• Intractable hiccups
• Drug-induced psychoses (e.g. alcoholic hallucinations)

Psychopharmacology

Anti-psychotics (neuroleptics)

Boxed warning (Chlorpromazine, Haloperidol) 

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. 

Psychopharmacology

Anti-psychotics (neuroleptics)

Selected Drug Interactions

Pharmacodynamic interactions can be significant (i.e., additive with other sedating drugs, a antagonists, anticholinergics, etc.)

Psychopharmacology

Anti-psychotics (neuroleptics) 

Therapeutic Note

Therapeutic note: Drug holidays are important over prolonged use to test for continued need and reduce tendency for tardive dyskinesia.

Psychopharmacology

"Atypical" Antipsychotics

General Properties

(15)

Psychopharmacology

"Atypical" Antipsychotics

Clozapine (Clozaril)

• Mechanism of action: D₄ antagonist, also 5HT₂, H₁, muscarinic, a₁ and a₂ antagonists; some D_1-3 and D₅ affinity
• b. Side Effects: 
• hypersalivation, tachycardia, constipation 
• agranulocytosis requiring WBC monitoring (1%); mechanism unknown (boxed warning)
• myocarditis       

Psychopharmacology

"Atypical" Antipsychotics 

Olanzapine (Zyprexa)

• Mechanism of action: 5HT₂, D_1-4, H₁, M₁-M₅ and a₁ antagonist
• Side effects: constipation, dry mouth

Psychopharmacology

"Atypical" Antipsychotics 

Quetiapine (Seroquel)

Mechanism of action: 5HT₂, 5HT_1A, D_1-2, H₁, a₁ and a₂ antagonist 

Psychopharmacology

"Atypical" Antipsychotics

Risperidone (Risperdal)

• Mechanism of action: 5HT₂, D₂, H₁ and a₁ antagonist
• Side effects: nausea, extrapyramidal events
• Other FDA-Labeled Indication: irritability associated with autistic disorder 

Psychopharmacology

"Atypical" Antipsychotics

Ziprasidone (Geodon)

• Mechanism of action: D₂, 5HT_2A antagonist
• Side effects: nausea

Psychopharmacology

"Atypical" Antipsychotics

Lurasidone (Latuda)

• – (FDA-approved for schizophrenia on 10/29/10, and awaiting approval for bipolar disorder…..);  
• Mechanism of action: an antagonist both D₂ and 5HT₂ receptors, also high affinity for a₁, “other DA and 5HT receptors” and H₁ receptor.

Psychopharmacology

"Atypical" Antipsychotics

Aripipraxole (Abilify)

• Mechanism of action: "Aripiprazole functions as a partial agonist at the dopamine D₂and the serotonin 5-HT_1Areceptors, and as an antagonist at serotonin 5-HT_2Areceptor"  (a "dopamine transmission stabilizer")
• Side effects: constipation, akathisia, headache, nausea, insomnia, extrapyramidal disorder, anxiety
• Additional boxed warning - Children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders are at increased risk of suicidal thinking and behavior
• Other FDA-Labeled Indications: major depressive disorder (adjunctive treatment in patients already receiving antidepressants)

Psychopharmacology

Depression

Symptoms

(11)

* Persistent sad, anxious or "empty" feelings

* Feelings of hopelessness and/or pessimism

* Feelings of guilt, worthlessness and/or helplessness

* Irritability, restlessness

* Loss of interest in activities or hobbies once pleasurable

* Fatigue and decreased energy

* Difficulty concentrating, remembering details and making decisions

* Insomnia, early–morning wakefulness, or excessive sleeping

* Overeating, or appetite loss

* Thoughts of suicide, suicide attempts

* Persistent aches or pains, headaches, cramps or digestive problems that do not ease even with treatment

Psychopharmacology

Depression

Table

(4)

Psychopharmacology

Depression

The "Monoamine Hypothesis" (Dysregulation????)

The monoamine hypothesis suggests that depression is promoted by a neurochemical imbalance in the brain; especially involving the 5HT and norepinephrine systems.

Psychopharmacology

Depression

General Comments

(5)

•  Antidepressants are effective in 60 - 70% of patients.
• Often latency of 2 - 4 weeks before onset of antidepressant action.
• Numerous uses including: 
• generalized anxiety disorder, 
• panic disorder, 
• social phobia, 
• post-traumatic stress disorder, 
• obsessive-compulsive disorder, 
• premenstrual dysphoric disorder, 
• enuresis,
• attention deficit disorder, 
• bulimia, 
• neurogenic pain, 
• narcolepsy, 
• smoking cessation........
• Boxed warning: Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24, and there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. This risk must be balanced with the clinical need.
• Serotonin Syndrome -

Psychopharmacology

Depressionn

Serotonin Syndrome Table

Atypical Antipsychotics

Drugs

(7)

• Clozapine (Clozaril)
• Olanzapine (Zyprexa)
• Quetiapine (seroquel)
• Risperidone (Risperdal)
• Ziprasidone (Geodon)
• Lurasidone (Latuda)
• Arpipraxole (Ablilify)

Antidepressant Agents

Categories

• Tricyclic Antidepressants (TCAs)
• Selective-serotonin Reuptake Inhibitors (SSRIs)
• Monoamine Oxidase Inhibitors (MAOIs)
• Other Agents

Antidepressant Agents

TCAs

Drugs

(4)

• Imipramine (Tofranil)
• Desipramine (Pertofrane Norpramine)
• Amitriptyiline (Elavil)
• Nortriptyline (Aventyl

Antidepressant Agents

TCAs

MOA

• All TCAs affect amine (particularly norepinephrine and serotonin) reuptake. 
• TCA's can block muscarinic receptors, a₁ receptors, a₂ receptors, H₁ receptors, and cardiac sodium channels

Antidepressant Agents

TCAs

Side Effects

(7)

1. weakness and fatigue

2. orthostatic hypotension

3. tachycardia (especially with overdoses)

4. tremor (especially among geriatric patients)

  5. anticholinergic effects

  6. weight gain

  7. confusion

Antidepressant Agents

TCAs

Therapeutic Uses Other Than Depression

(3)

• Panic disorder
• Enuresis
• Chronic Pain

Antidepressant Agents

TCAs

Drug interactions

(2)

• Antimuscarinic agents
• Sympathomimetics

Antidepressant Agents

TCAs

Therapeutic Notes

(2)

• Overdoses - Can be extremely dangerous including arrhythmias and death
• Withdrawal
• Agitation
• Malaise
• Chills
• Muscle aches
• Sleep disturbances

Antidepressant Agents

SSRIs

Drugs

(6)

Antidepressant Agents

SSRIs

MOA

Antidepressant Agents

SSRIs

Side Effects

(5)

• nausea, 
• vomiting,
• restlessness, 
• agitation, 
• sexual dysfunction

Antidepressant Agents

SSRIs

Therapeutic Uses Other than Depression

(4)

• panic disorder, 
• posttraumatic stress disorder, 
• obsessive-compulsive disorder, 
• eating disorders

Antidepressant Agents

SSRIs

Withdrawal Symptoms

(7)

• malaise, 
• chills, 
• muscle aches, 
• sleep disturbances, 
• gastrointestinal distress, 
• sensory symptoms (paresthesias)
•  and irritability can occur with abrupt discontinuation of SSRIs

Antidepressant Agents

Comparison between SSRIs and TCAs:*

(6)

Antidepressant Agents

MAOIs

Drugs

(4)

• phenelzine (Nardil),
• tranylcypromine (Parnate), 
• Isocarboxazid (Marplan), 
• selegeline (Carbex))

Antidepressant Agents

MAOIs

MOA

Antidepressant Agents

MAOIs

Dide Effects

(6)

• orthostatic hypotension, 
• sleep disturbances, 
• weight gain, 
• sexual dysfunction,
•  sedation, 
• behavioral excitation

Antidepressant Agents

MAOIs

FDA Approved Uses

• Depression
• Atypical
• Non-endogenous
• Neurotic

Antidepressant Agents

MAOIs

Therapeutic Notes

Antidepressant Agents

MAOIs

Drug Interactions

(3)

1. Sympathomimetics: hypertension (can be severe)

2. Dextromethorphan: hyperpyrexia, coma and death have been reported.

3. Narcotic analgesics: hypertension, rigidity, excitation; meperidine may be more likely to interact than morphine.

Antidepressant Agents

Atomoxetine (Strattera)*

(4)

• Mechanism of action: a norepinephrine-selective reuptake inhibitor; a "non-stimulant"
• Side effects:
• In children, 
• abdominal pain, 
• decreased appetite, 
• weight loss, 
• nausea/vomiting, 
• somnolence 
• and headaches. 
•  In adults, 
• constipation, 
• dry mouth, 
• nausea, 
• decreased appetite 
• FDA-approved use:  attention deficit hyperactivity disorder 
• Therapeutic notes: rarely, liver damage

Antidepressant Agent

Venlafaxine (Effexor)*

(4) 

• also the succinate salt of the isolated major metabolite of venlafaxine - Desvenlafaxine; Pristiq. 
• Mechanism of action: inhibits 5HT and norepinephrine uptake; weakly inhibits and dopamine reuptake
• Side effects:
•  nausea,
•  nervousness, 
• constipation, 
• sweating, 
• weight loss, 
• somnolence, 
• dizziness, 
• hypertension
• Other FDA-approved uses besides depression: 
• generalized anxiety disorder, 
• panic disorder, 
• social phobia

Antidepressant Agents

Duloxetine (Cymbalta)*

(3)

• Mechanism of action: inhibits norepinephrine and 5HT reuptake
• Side effects: 
• nausea, 
• dry mouth, 
• constipation, 
• diarrhea, 
• insomnia, 
• somnolence, 
• hepatotoxicity (especially in heavy alcohol users)
• Other FDA-approved uses besides depression:
•  diabetic peripheral neuropathy, 
• fibromyalgia, 
• generalized anxiety disorder

Antidepressant Agents

Bupropion (Wellbutrin) *

(4)

• Mechanism of action: inhibits dopamine reuptake; some norepinephrine reuptake inhibition
• Side effects: 
• dry mouth, 
• nausea, 
• headache, 
• dizziness, 
• insomnia, 
• weight change
• Other FDA-approved uses besides depression: 
• seasonal affective disorder, 
• smoking cessation
• Therapeutic Note: Contraindicated in patients with increased risk of seizures.

Antidepressant Agents

Mirtazapine (Remeron) *

• Mechanism of action: 
• an antagonist at central presynaptic α₂ adrenergic inhibitory autoreceptors and heteroreceptors
• Also antagonist of 5HT₂, 5HT₃, H₁, a₁ adrenergic and muscarinic antagonist
• Side effects: 
• sedation/somnolence (major reason for discontinuing therapy), 
• increased appetite

Antidepressant Agents

Trazodone (Desyrel) *

(2)

• Mechanism of action unclear, although some serotonin reuptake blockade.

• Strongly sedating!!!!!

Antidepressant Agents

St. John's Wort

Mechanism of action unclear -  Hyperfolin interferes with the neuronal uptake of 5HT, dopamine and norepinephrine – but not as a competitive inhibitor.  Instead, it activates transient receptor protein TRPC6 channels (e.g., non-specific cation channels), thus altering intracellular sodium and calcium and disrupting transporter function 

Bipolar Disorder 

Symptoms Table

Bipolar Disorder

Treatments 

(5)

• Lithium Carbonate (Eskalith)
• Valproate (valproate, Depakene, Depakote; note: non-FDA-labeled indication)
• Lamotrigine (Lamictal) 
• Carbamazepine (Equetro)
• Other Agents

Bipolar Disorder

Lithium Carbonate (Eskalith)*

(5)

• Mechanism of action: not established; alters cation transport across cell membranes, influences serotonin and/or norepinephrine reuptake; second messenger systems involving the phosphatidylinositol cycle inhibited
• Side effects include;
•  fatigue, 
• diarrhea, 
• nausea, 
• fine tremor, 
• polyuria
• Therapeutic notes:
• Lithium has a relatively low therapeutic index, so plasma levels must be monitored.  (Boxed Warning: Lithium toxicity is related to serum levels, and can occur at concentrations close to therapeutic levels.)
• Lithium may take days to weeks to have a full therapeutic effect.

Bipolar Disorder

Valproate

(valproate, Depakene, Depakote; note: non-FDA-labeled indication)
(3) 

• The mechanism of action of valproate in treating bipolar is not established, although valproate affects central GABAergic systems
•  Side effects: 
• nausea, 
• vomiting, 
• weight gain/loss, 
• and tremor
•  Boxed warnings: Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. Children under two years of age are at increased risk of developing fatal hepatotoxicity. Life-threatening pancreatitis has been reported in both children and adults receiving valproate. Valproate can produce teratogenic effects such as neural tube defects  (eg, spina bifida).

Bipolar Disorder

Carbamazepine (Equetro)

(3)

• Mechanism of action: not established
•  Side effects: 
• dizziness, 
• headache, 
• somnolence, 
• nausea, 
• vomiting
•  Boxed warnings: Potentially fatal blood cell abnormalities (eg, aplastic anemia, neutropenia, agranulocytosis leukopenia, pancytopenia, thrombocytopenia and anemias) have been reported in association with carbamazepine use.   In addition, patients of Asian descent should be screened for the variant HLA-B*1502 allele prior to initiating therapy as this genetic variant has been associated with increased risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis (carbamezapine has been associated with Stevens-Johnson syndrome).

Bipolar Disorder

Lamotrigine (Lamictal)*

(3)

• Mechanism of action: not established
• Side effects: 
• nausea, 
• Insomnia, 
• somnolence, 
• fatigue (8%), 
• Boxed warnings:  Severe and potentially life-threatening skin rashes requiring hospitalization have been reported; risk may be increased by co-administration with valproic acid, higher than recommended starting doses, and rapid dose titration.

Bipolar Disorder

Other Agents 

quetiapine (Seroquel),

olanzapine (Zyprexa),

risperidone (Risperdal),

aripiprazole (Abilify),

and ziprasidone (Geodon)

Alzheimer’s Disease

Symptoms

• Memory loss (short term), 
• social withdrawal, 
• problems with word selection.   
• Later, 
• increased dependence, 
• long-term memory loss, 
• confusion over identities of friends/relatives,
• disruptive behaviors, psychiatric symptoms.  
• Still later, 
• complete dependence, 
• decreased verbal output, 
• disappearance of personality, i
• ncontinence, 
• weight loss

Alzheimer's Disease

Histological/neurochemical effects

(4)

• Amyloid plaques, which are made up of fragments of a protein called beta-amyloid peptide mixed with a collection of additional proteins, remnants of neurons, and bits and pieces of other nerve cells.
• Neurofibrillary tangles found inside neurons are abnormal collections of a protein called tau. (Normal tau is required for healthy neurons. However, in AD, tau clumps together. As a result, neurons fail to function normally and eventually die.)
•  Decreased number of cholinergic receptors
•  Persistent activation of NMDA receptors by glutamate is postulated to contribute to the progression of Alzheimer's disease. 

Alzheimer's Disease

Treatment

Currently, there are no medicines that can slow the progression of Alzheimer’s Disease.  

Cholinesterase inhibitors are common treatments, noting that failure of one particular agent doesn’t predict failure of others.

Alzheimer's Disease

Treatment

Mild to Moderate Symptoms

(4)

• Tacrine (Cognex)
• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Razadine; formerly Reminyl

Alzheimer's Disease

Treatment

Mild to Moderate Symptoms

Tacrine (Cognex)*

(2)

• Mechansims of Action: “First generation” cholinesterase inhibitor
• Note: Rarely used owing to risk of liver toxicity

Alzheimer's Disease

Treatment

Mild to Moderate Symptoms

Donepezil (Aricept)*

(2)

• Mechanism of Action:  “Second generation” cholinesterase inhibitor
•  Side effects: 
• nausea, 
• diarrhea, 
• insomnia, 
• vomiting, 
• muscle cramp, 
• fatigue, 
• anorexia

Alzheimer's Disease

Treatment

Mild to Moderate Symptoms

Galantamine (Razadine; formerly Reminyl)*

(3)

• Mechanism of Action:  “Second generation” cholinesterase inhibitor
•  Side Effects:  
• diarrhea, 
• nausea, 
• vomiting, 
• fatigue, 
• headache, 
• anorexia
•  Other FDA-approved use:  Mild to moderate dementia in Parkinson’s Disease

Alzheimer's Disease

Treatment

Moderate to Severe Symptoms

Treatments

(3)

• Donepezil*
• Memantine (Namenda)*
• Other Treatment

Alzheimer's Disease

Treatment

Moderate to Severe Symptoms

Memantine (Namenda)*

(2)

• Mechanism of Action: low to moderate affinity, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist
•  Adverse effects: 
• dizziness, 
• confusion,
• headache, 
• constipation (marketed as “low rate of side effects”)

Alzheimer's Disease

Treatment

Moderate to Severe Symptoms

Other Treatments

• antidepressants, 
• antipsychotics, etc. to treat behavioral symptoms although must consider potential side effects

Alzheimer's Disease

Treatment

Moderate to Severe Symptoms

Future Treatments???

(3)

• Inhaled insulin
• Tarenflurbil (Flurizan)
• Bapinuzumab:

Psychostimulants

(10)

• Cocaine*

• Amphetamines (Amphetamines (d-amphetamine (Dexedrine,) Methamphetamine (Desoxyn), amphetamine + d-amphetamine (Adderall)

   
• Lisdexamfetamine dimesylate(Vyvanse)
• Methylphenidate(Ritalin) 
• Guanfacine(Tenex) 
• Phentermine (Phentride, Fastin)  
• Modafanil(Provigil)  
• Xanthines and related compounds (caffeine, theophylline, theobromine)
• Nicotine 
• Other - Lorcaserin (Belviq) -  5HT2C agonist

Amphetamines (Amphetamines (d-amphetamine (Dexedrine,) Methamphetamine (Desoxyn), amphetamine + d-amphetamine (Adderall)

MOA

(2)

• releases dopamine, norepinephrine and 5HT; some blockade of reuptake
•  weak inhibitor of monoamine oxidase

Amphetamines (Amphetamines (d-amphetamine (Dexedrine,) Methamphetamine (Desoxyn), amphetamine + d-amphetamine (Adderall)

Pharmacological Effects

(5)

• elevation of mood, euphoria, increased alertness
• reduced feeling of fatigue
• reduced food intake
• peripheral sympathomimetic effects irritability and manic behavior (after high dose administration)
• abuse; toxic psychosis (difficult to distinguish from paranoid schizophrenia)

Amphetamines (Amphetamines (d-amphetamine (Dexedrine,) Methamphetamine (Desoxyn), amphetamine + d-amphetamine (Adderall)

Therapeutic Effects

(3)

• Narcolepsy
• ADD
• Weight loss

Lisdexamfetamine dimesylate(Vyvanse)

• Prodrug of d-amphetamine.  Lysine conjugated to amino group of amphetamine. 
• The amino bond is hydrolyzed to form lysine and d-amphetamine.

Methylphenidate(Ritalin)

(3)

• Mechanism of action: similar to amphetamine, but more of an uptake blocker than a releaser.
•  Side effects: 
• nervousness, 
• insomnia, 
• appetite changes, 
• other typical stimulant effects….
•  Therapeutic use: attention deficit disorder

Guanfacine(Tenex)

(3)

• a_2A adrenergic receptor agonist - used to treat hypertension
•  non-FDA-approved use to treat attention deficit disorder
•  Side effects:  
• somnolence, 
• dizziness, 
• headache, 
• dry mouth, 
• constipation

Phentermine(Phentride, Fastin)

• Mechanism of action:  may involve increased extracellular norepinephrine and dopamine concentrations
•  Effects: 
• weight loss, 
• dizziness, 
• dysphoria, 
• euphoria, 
• headache, 
• insomnia, 
• restlessness, 
• tremor, 
• hypertension, 
• palpitations, 
• constipation, 
• diarrhea, 
• dry mouth.
•  3. Phentermine/Topiramate (Qsymia) - The drug is approved only for the obese (people with a body-mass index, or BMI, of 30 or above) or overweight people (body mass 27 or higher) who also suffer from conditions such as hypertension, type II diabetes or high cholesterol.
•  Contraindicated in pregnancy (increased risk of oral clefts owing to topiramate)
• Weight loss and type II diabetes

Modafanil(Provigil)

(3)

• Mechanism of action: unknown
•  Therapeutic use: promotes wakefulness (non-FDA-approved for ADHD)
•  Typical stimulant effects, but generally minor relative to other CNS stimulants

Xanthines and related compounds (caffeine, theophylline, theobromine)

• Mechanism of action: block adenosine receptors
•  Pharmacological effects
• less drowsiness; less fatigue; faster and clearer flow of thought
• improved motor performance; decreased reaction time
• restlessness, insomnia, tremors, seizures
• cardiac stimulation
• bronchodilation
• mild diuretic
• stimulates gastric acid secretion
•  Therapeutic applications
• Bronchial asthma and other pulmonary diseases (theophylline)
• Apnea of preterm infants
• Migraine headaches
• CNS stimulant (NoDoz)

• Side effects: 
• headache, 
• throat irritation (inhaler), 
• dyspepsia, 
• cough (inhaler), 
• rhinitis (inhaler)
• Mechanism of Action: Stimulation of nicotinic receptors in the brain, particularly α4β2 receptors,   and is reinforcing
• Treatment of Addiction:
• Exogenous agonists (nicotine gum, patch, spray, lozenge)
• Bupropion (Zyban)
•  
• -DA and NE reuptake inhibitor
• -Metabolite is α₄β₂ nAChR antagonist
• Varenicline tartrate (Chantix)
•  - α₄β₂ nAChR partial agonist
• Black box warning: association between varenicline or bupropion use and neuropsychiatric adverse effects such as changes in behavior, agitation, hostility, depressed mood, suicidal thoughts and behavior, and attempted suicide

Psychostimulant

Lorcaserin (Belviq)*

5HT2C agonist