Psychopharmacology (Pharmacotherapies)

Biological Therapies

1. Classification of Psychopharmacons

§  Antipsychotics: Block postsynaptic

1.      Dopamine-2 (D2) &

2.      Serotonin 2A (5-HT2A) receptors

§  Antidepressants:

1.      Inhibits reuptake of SE & NE from synaptic cleft

2.      Blocks MAO

3.      Downregulate postsynaptic receptors

§  Lithium:

1.      Modifies second messenger signaling

2.      Membrane stabilizing

3.      Corrects circadian rhythm

§  Benzodiazepines:

1.      Activates binding sites on GABA-A receptor, which leads to:

2.      Cl inflow-------hyperpolarization-----inhibition

Antipsychotic drugs (formerly are also called Neuroleptics; Major tranquillizers)

Used in treatment of

§Psychosis

§Agitation

§Anxiety

§They are excellent in introducing analgesia during anesthesia

Classes of antipsychotic drugs:

1. “Traditional” antipsychotics

1.      High potency agents:

a.       Main indications

a.       Extremely agitated ptx

b.      Mania

c.       Schizophrenia

d.      Withdrawal syndrome

e.       Tourette disease

f.       Huntington disease

g.       Organic psychosises

h.      Body dismorphic disorder

i.        OCD  (combined with with SSRI drugs)

Frequently used high potency agents:

a.       Haloperidol (Haldol)  (2-30 mg/d)

b.      Fluphenazine (Prolixin) (2-15 mg/d) (Fluphenazine decaonat)

c.       Trifluoperazine (Stelazine) (4-20 mg/d)

                                                                                                                    i.      OI: anxiety

d.      Perphenazine (Trilafon) (8-64 mg/d)

                                                                                                                    i.      OI: Nausea, vomiting

e.       Pimozide (Orap) (1-10 mg/d)

2. Low potency agents

a.       Chlorpromazine (Thorazine, Hibernal, Largactil) (100-800mg/d)

a.       OI: nausea, vomiting, hiccups

b.      Thioridazine (Melleril) (200-600 mg/d)

a.       OI: anxiety & agitation in depression

Adverse effects: they are many, severe, and sometimes dangerous. Immediate and chronic, reversible and irreversible

 Low potency agents have primarily non-neurological adverse effects, which are classified as anticholinergic and antihistaminergic type of adverse effects:

a.       Anticholinergic adverse effects

pOn Peripheral receptors

pDry mouth

pConstipation

pUrinary retention

pBlurred vision

pOn Central (CNS) receptors

pAgitation

pDisorientation

c.       Antihystaminic adverse effects

pWeight gain

pSedation

Neurological adverse effects of traditional antipsychotic drugs might be inconvenient for the patient, severe and serious, exceptionally life threatening:

Adverse effects of high potency agents

a.       Primarily neurological adverse effects are torturing experience for the patient

                                                                          i.      Acute dystonia

nTorticollis

nBlepharospasm

nOculogyric crisis

nGlossophrayngeal dystonia

nOpisthotonus

pTherapy of the above adverse effects

nBenzodiazepine

nAnticholinergic drugs

nAntihystaminergic

nCa

                                                                        ii.      Akathisia

nTorturing subjective feeling of motoric restlessness

nInability to remain still

nPacing

nRocking

pTh:

nAntihistaminergic agents (diphenylhydramine)

nPropranolol

nBenzodiazepine

nAnticholinergic agents

nDose reduction

                                                                      iii.      Parkinsonism

p“Pseudo”-Parkinsonism

pMuscle rigidity

pBradykinesia

pShuffling gait

pMask-like facial expression

pCogwheel rigidity

pDrooling

                                                                      iv.      Neuroleptic malignant syndrome (Life threatening condition)

nHyperpyrexia

nDiaphoresis

nP & RR increase

nDystonia

nApathy

nAkinesia

nAgitation

pTherapy of neuropleptic malignant syndrome:

nStop the agent

nSymptomatic medical support

nDantrolene

nBromocriptine (Parlodel)

                                                                        v.      Tardive dyskinesia  (Facio-bucco-lingual dyskinesia = Breughel syndrome)

pInvoluntary writhing movements of the tongue, face

pTherapy of TD:

pUse atypical antipsychotic drugs

pDose reduction

                                                                      vi.      Epileptic Seizures

Other non neurological adverse effects of traditional antipsychotic drugs:

Circulation

 Orthostatic hypotonia

 ECG: QT & PR prolongation

 Cardiotoxicity (Thioridazine overdose)

Endocrine

 Increased prolactine level

 Gynecomastia, galactorrhea, erectile dysfunction, amenorrhea, decreased libido

Hematologic

Leukopenia, agranulocytosis

Hepatic

Jaundice

Elevated liver enzymes level (chlorpromazine)

Dermatologic

Photosensitivity, skin eruptions, blue-gray skin decoloration (chlorpromazine)

Ophtalmologic

Irreversible retinal pigmentation (thioridazine)

Deposits in the lens & cornea (chlorpromazine)

p Generally used therapeutics to prevent (wrong?) or alleviate adverse effects:

pAnticholinergic agents (benztropine) Propranolol

pAmantadine

pBenzodiazepine

pDose reduction

2. Atypical Antipsychotic Drugs: As a rule they act on 5-HT2 + series of DA sub-receptors. They pharmacology is new. Some of them act on as many as 8 receptors

Clozapine (Clozaril)

Risperidone (Risperdal)

Olanzapine (Zyprexa)

Quietapine (Seroquel)

Ziprasidone (Geodon)

Aripiprazole (Abilify)

pAdverse effects of atypical antipsychotic drugs

nAgranulocytosis (clozapine)

pWbc count below 2000

pGranulocytes below 1000

pClinically: pharyngitis + high fever

nSeizures

nAnticholinergic

pDry mouth

pConstipation

pUrinary retention

pBlured vision

pAgitation

pDisorientation

nPancreatitis

nWight gain

nExacerbate type 2 diabetes

Antidepressants

pSecond best selling prescription drug group worldwide are the antidepressants  (The first best-sold drugs are the benzodiazepines).

pTypes:

nHCA (TCA) (heterocyclic antidepressants or tricyclic antidepressants)

nMAOI (mono amino oxidase inhibitors)

nSSRI (selective serotonin reuptake inhibitors)

pMechanism of action:

nIncrease availability of neurotransmitters through

nReuptake inhibition

nMAO inhibiton

nDown regulation of post synaptic receptors

Pharmacologic properties:

pIt takes 3 -6 weeks for an antidepressant to work

pDon’t work in non depressed person

pHave no abuse potential

pOverdose is dangerous: HCA & MAOI

pCan precipitate manic episode in bipolar cases

pFirst line drugs are: SSRI

1. HCAs (TCAs)

nBlock reuptake of both norepinephrin & serotonin

nSecondary tricyclics (desipramine) more potent blocker of NE reuptake

nTertiary tricyclics more potent in serotonin reuptake (amitriptyline)

Block also other receptors which is why they cause adverse effects

§  (Muscarinic) acetylcholine = anticholinergic

§  Histamine = antihistaminic

Side effects

§  Anticholinergic

• Antihistaminergic
• Blockade of alpha adrenergic receptors:
• Cardiovascular side effects: orthostatic hypotension
• Neurologic side effects:
• Tremor
• Sexual dysfunction

pCommonly used HCAs

pDesipramine

pNortriptyline

pAmitryptiline

pClomipramine

pDoxepin

pImipramine

pmaprotiline

2. MAOI

E.g. Phenelzine, Tranylcypromine

nMAO-A involved in transmitter breakdown in depression

nMOI inhibit NE & 5-HIA (serotonine) breakdown

nThe reaction is irreversible

nThey have dangerous adverse reactions:

1.      “Cheese reaction”

pMAO metabolize Tyramine (PHE-TYR-NE-E)

pTyramine reach food = potentially fatal reaction

§Cheese

§Broad beans

§Beef

§Chicken liver

§Smoked or pickled fish & meet

§Wine, Beer

p Interaction with other drugs: Chese reaction with Sympathomimetic drugs:

§Ephedrine

§Methylphenidate

§Phenylephrine

§pseudoephedrinene

Clinical symptoms of cheese reaction:

pElevated blood pressure

pHypertensive crisis

pSweating

pHeadache

pVomiting

pStroke

pDeath

2.      Serotonine syndrome:

pMAOI + SSRI if they are used together: life threatening:

pAutonomic instability

pHyperthermia

pConvulsions

pComa

pDeath

3.      MAOI overdose is dangerous (e.g. suicide)

4.      Indication of classic MAOI is therefore limited:

pTherapy resistant cases

pAtypical depression

3. RIMA  (Reversible Mono Amino Oxidase Inhibitors)

pmaclobemide – inhibit MAO-A: used in derpession

pselegiline Inhibit MAO-B: Used in Parkinson’s disease

4. SSRI are first line drugs in any antidepressant treatment

pLess cardiotoxic

pSafer in overdose

pFever side effect

Commonly used SSRI drugs:

pCitalopram

pEscitalopram

pFluoxetine

pParoxetine

pSertaline

pFluvoxamine

pSSNRIs (Selective Serotonin and Noradrenalin Reuptake Inhibitors):

pDuloxetine

pVenlafaxine

Mood stabilizers

A. Lithium:

Main indications:

nMDP

nAggression

nCluster headache

nEnhance TCA effect

nPMS

nBorderline PD

nBulimia Nervosa

nCaveats:

pRenal dysfunction

pCardiac conduction problems

pMild cognitive impairment

pTremor

pHyperthyroidism

pGastric distress

pContraindicated in early pregnancy

nLithium Intoxication and therapeutic sera levels: lithium’s therapeutic range is 0,05-15 maeq/L. Below this level has no therapeutic effect at al, above is toxic

B: Anticonvulsants as Mood stabilizers

pCarbamazepine

pAdverse effects

pAnaplastic anaemia

pAgranulocytosis

pLeukopenia

pPeripheral anticholinerg effects:

Dizzines

Sedation

Ataxia

pOxycarbamazepine

pValproic acid

pBipolar disorders with psychotic features

pSubstance abuse and PD

pMigraine prophylaxis

pRefractory schizophrenia

§ Can be combined with atypical antipsychotics

pAdverse effects:

§GIT

§Liver

§Congenital neural tube defects

§alopecia

pLamotrigine

pGabapentine

pTopiramate

pTiagabine

nMood stabilizers are more effective in mania than depression (except lamotrigine)

nSuggested mechanism through GABA = Reduced neuronal excitability

nRecommended in

p“rapid cycling” (more than 4/y episodes) cases

pMixed episode

pNon Li respondents

pLi adverse effect in ptx history

nCan combined with LI in therapy resistant cases

Other drugs frequently used in mood disorders:

Benzodiazepines (Anxiolytics)

pThey act on GABA-A

pThey have short, intermediate, long onset & duration of action

p Used because of fast Sedation

p Long term use is limited because of danger of dependence

They wanted therapeutic benefit is based on that they are

pAnxiolytics

pAntipeileptics

pMuscle relaxants

pHypnotics

In case of overdosage diagnostic and gives short term improvement: Flumazenil: which is an bzd receptor ANTAGONIST

Most frequently used drugs:

diazepam

clonazepam

nitrazepam

lorazepam

Phenobarbital (drug for generalized tonic clonic seizures)

Buspiron:

pNo sedation

pNo dependence & abuse or withdrawal

pRecommended in chronic treatment (GAD)

pAntidepressant effects in high doses

pCan be combined with antidepressants

pTakes 2 weeks to work

pPharmacology

pHT-1A receptor agonist

pActivate 5-HT2 & DA receptors

Beta blockers

Propranolol (Inderal) anti anxiety agent, especially in social situations like public speaking

Alfa adrenergic receptor agonists

Clonidine

Indication:

pAnti anxiety agent

pAlso used in opiate & sedatives withdrawal

ECT (electroconvulsive) treatment

Most efficient and rapid treatment in severe cases of depression. Also indicated in schizophrenia and sever mania.

Treatment of Alzheimer disease and dementias

Investigations suggest that acetylcholine deficit is present in dementias, therefore increasing brain acetylcholine level temporarily may alleviate the symptoms.

ACE inhibitors

Tacrine

Donepezil (Aricept)

Rivastigmine

Galantamine

Indication: Alzheimer type dementia

Explanatory Pictures:

Three systems are crucial in psychopharmacology. 1./ The limbic system (above), which is where we want our pharmacons act and target structures related with mental disturbances like schizophrenia, depression, aggressive behavior, certain types of epilepsy etc. 2./ The nigro – striatal system, which is a system responsible for smoothness of movements. Our drugs unfortunately act also in nigrostriatal system , causing series of movement disorders and adverse effect. 3./ The tubero – infundibular system which is the axis of CNS endocrine regulations also works with DA.

One of the most important adverse effects of neuroleptic drugs is the (pseudo) parkinsonistic symptoms. Note the lack of mimic of the patient on the left, and the typical bend posture caused by the drug on the right. It is important to note, that Parkinson disease is a serious condition, which presented with similar symptoms, but not related with drug adverse effects.

Dystonic movements. The torticollis spastica (first two pictures on the top) is a possible acute adverse effect of antipsychotic drug treatment. Any of the above can also presented (e.g. acute dystonia, writers cramp, muscular spasm) as adverse effect of neuroleptics. Please also note, that there are diseases causing the same symptoms, which are not related with adverse effects of drug treatment.

Oculogyric crisis. The eyes are rotated outward and upward in a very disturbing, sometimes painful spasm. The head is also rotated to the right side and upward. (Compare with the photo on previous picture: this patient also shows an acute spastic torticollis or cervical dystonia) This is an acute adverse effect of neuroleptics. Please note, that more often you may observe this adverse effect on young pregnant women who are taking antiemetic drugs at the first trimester of pregnancy. This condition is presented because some of antiemetic drugs are acting also on DA receptors, though they targeting cells of vomiting centers in the medulla. Unfortunately drugs don’t know which DA cells they shall reach), and affect all DA receptors throughout the CNS.

Serial photography of involuntary movements of the face, buccal regions, lips and tongue. This is the facio– bucco–lingual or FBL diskynesia, caused by long lasting antipsychotic drug treatment, usually for years.

Gingiva hyperplasia caused by diphenylhydantoin treatment.

Case Studies

v  A 28-year-old woman whom you have treated for bipolar disorder informs you that she is 3 weeks pregnant and is anxious about the baby’s health. You are treating her with lithium and she has not had a manic episode in 3 years.

Which of the following statements is correct regarding bipolar disorder and pregnancy?

(A) Lithium is safe after the first trimester and can be safely continued through birth.

(B) Divalproex sodium (Depakote) is a safe alternative to lithium.

(C) Carbamazepine is a safe alternative to lithium.

(D) Lithium substantially increases the risk of Ebstein anomaly of the tricuspid valves by 75%.

(E) Clonazepam does not carry an increased risk of major fetal malformations.

(E) All of the commonly used mood-stabilizing medications, except clonazepam (a benzodiazepine), appear to carry an increased risk of fetal malformations or a potential deleterious effect on later cognitive development. Use of lithium during the first trimester increases the risk of cardiac malformations. A fetal echocardiogram should be done between weeks 16 and 18 of pregnancy. Lithium may be used in the second and third trimesters but it should be stopped peripartum because of the rapid fluid shifts and changes in glomerular filtration. Carbamazepine increases the risk of neural tube defects and divalproex sodium increases the risk of intrauterine growth retardation and neural tube defects.

v  You are called to consult on an 85-year-old patient who has become combative, yelling, punching staff, and pulling out her IVs. She demands to leave but is too weak to get out of her hospital bed. Which of the following would be the most appropriate intervention at this time?

(A) diphenhydramine

(B) donepezil

(C) lorazepam

(D) orientation to her surroundings

(E) risperidone

(E) It is not unusual for delirious patients to become hostile or combative posing a risk to themselves or other hospital staff. Low-dose atypical antipsychotics, such as risperidone, are very effective in reducing agitation in delirious patients. Diphenhydramine should be avoided as the anticholinergic effects may actually worsen the delirium and confusion. Donepezil is an anticholinesterase inhibitor used for dementias. Although benzodiazepines can be used for agitation in delirium, they may overly sedate or conversely disinhibit the patient further. Orientation to surroundings is often additionally helpful in delirium but it will not immediately calm the patient.

v  A 72-year-old man is admitted to a general hospital’s because of altered mental status. His medical workup has revealed pneumonia and congestive heart failure (CHF). On the second hospital day, he is agitated and pulls out his IV access. He also has been noted to speak out loud with no one in the room. His level of consciousness seems to wax and wane. He does not have a psychiatric history and is not allergic to any medications. Besides his CHF and pneumonia, he does not have other comorbid conditions.

1. Which of the following agents would be the most appropriate to administer for his agitation?

(A) thioridazine

(B) chlorpromazine

(C) lorazepam

(D) olanzapine

(E) haloperidol

2. Which of the following agents would be least likely to cause orthostatic hypotension?

(A) haloperidol

(B) perphenazine

(C) thioridazine

(D) risperidone

(E) quetiapine

1. (E) This patient is likely delirious and prompt identification and treatment of the underlying cause is indicated. To help control the agitation that may accompany delirium, low-dose haloperidol is frequently used. Haloperidol does not treat the delirium, however. It is used most frequently because it is the most potent of the typical antipsychotics, therefore, requiring lower doses with fewer anticholinergic or orthostatic side effects. Additionally, low-potency agents such as chlorpromazine or thioridazine are not only associated with orthostatic hypotension and anticholinergic side effects but also with prolongation of the QT interval. Olanzapine is not used in the intensive care setting partly because it is not available in a parenteral form.

Lorazepam may help sedate the patient but it will not help his psychosis.

2. (A) Of the typical neuroleptics listed (haloperidol, perphenazine, and thioridazine), haloperidol is the most potent and has the least activity at alpha1-receptors. Therefore, it is the least likely to cause orthostatic hypotension. The atypical agents listed (risperidone and quetiapine) have activity at alpha1-receptors and are both associated with orthostatic hypotension.

v  A 36-year-old woman is referred to you for management of anxiety and fear that has persisted for several months. She reports that she was raped and held hostage on a boat for several days by two armed men. During this, she experienced intense fear for her life. Since then, she has had intense stress whenever she is near the water and has frequent nightmares. She cannot recall details of the ordeal but tries to avoid walking within sight of the ocean, which has been difficult because of the location of her home. She feels detached from her husband and family and has abandoned plans to pursue her career as a painter. She has difficulty falling asleep and is easily startled by phone calls. She no longer goes to public places alone.

1. Which of the following agents is believed to help relieve the numbing symptoms she is experiencing?

(A) alprazolam

(B) fluoxetine

(C) carbamazepine

(D) thioridazine

(E) naltrexone

2. Whenever she walks near the water, which is unavoidable, she experiences intense anxiety, fear, and palpitations, and feels that she is reexperiencing her abduction. Which of the following agents may help reduce these symptoms?

(A) olanzapine

(B) naltrexone

 (C) perphenazine

(D) divalproex sodium

(E) clonidine

1. (B) This patient is likely suffering from PTSD. Several studies have found that SSRIs were useful in reducing the numbing symptoms of PTSD. In one trial with rape victims, fluoxetine reduced symptoms of reexperiencing, avoidance or numbing, and hyperarousal. Further double-blind controlled trials are needed to confirm these findings. Benzodiazepines have not been useful for these symptoms. Antipsychotics such as thioridazine have generally not been useful, although some clinicians are beginning to try the atypical neuroleptics. Anticonvulsants are not routinely used but some studies found that carbamazepine reduced the reexperiencing and arousal symptoms. Naltrexone, an opioid antagonist, has not been extensively studied in PTSD.

2. (E) Open-label trials of the antiadrenergic agent clonidine (an alpha2-adrenergic agonist) have demonstrated decreases in symptoms of reexperiencing and hyperarousal. Double-blind controlled trials are needed to confirm these findings.

v  A 25-year-old man is brought into the emergency department lethargic and stuporous. He responds only to painful stimuli, wakes up briefly and yells, then goes back to sleep. Ambulance personnel report that they found him near a house known for drug trafficking. There is no evidence of physical injury.Which of the following medications should he receive first?

(A) dextrose and flumazenil

(B) dextrose, flumazenil, and naloxone

(C) dextrose, flumazenil, naloxone, and

thiamine

(D) dextrose and naloxone

(E) dextrose, naloxone, and thiamine

52. (E) Patients who present with altered levels of consciousness need to be medically managed, evaluated, and treated for several reversible causes. These include hypoglycemia, opioid overdose, and alcohol intoxication. Airway protection and monitoring of air exchange and cardiovascular status are required. Several treatments that should be immediately considered include IV dextrose, usually D50, to treat hypoglycemia; thiamine to guard against the development of Wernicke-Korsakoff syndrome when giving the dextrose to an alcoholic patient and thiamine deficiency; and naloxone, an opioid antagonist, to reverse the effects of opioid intoxication. Flumazenil is a benzodiazepine antagonist that should not be used before obtaining further history because it may theoretically lower the seizure threshold.

v 
 A 40-year-old woman with a history of psychotic depression resistant to many trials of antidepressant medication is being considered for ECT. Which of the following conditions is an relative contraindication to ECT?

(A) pregnancy

(B) degenerative joint disease

(C) hypertension

(D) recent MI

(E) psychotic depression

(D) ECT has relatively few contraindications and in some cases is preferred for its rapid onset of action. However, because of the cardiovascular effects of ECT, a history of a recent MI (within the past 6 months) is a relative contraindication. Another relative contraindication is the presence of a clinically significant intracranial space-occupying lesion because of the risk of brain stem herniation. ECT may be performed during pregnancy. The most common complaints patients have following ECT are impairments in both anterograde and retrograde memory. Although most memory problems resolve, some may persist indefinitely.

Chapter 13

Psychotherapies

Analytic therapies

lKey concepts:

lThere is an Unconscious part of mind

lTransference reactions

lDefense mechanisms

lSolve internal (unconscious) conflicts by exploration and re-experiencing

lRole of interpretation, insight, catharsis

lMethods of therapy:

Free association

Dream interpretation

Analysis of transference reactions

Abalysis of resitance

Behavioral & cognitive behavioral therapies

Based on ‘learning theory’

lConditioned are wrong or maladaptive behaviors

‘unlearning’ maladaptive behavior

‘unlearning’ negative thinking patterns

Hypothesis = cognitive model of depression: result from errors in cognition = learned helplessness

Cognitive triad: Negative interpretation of the

World

Self

Future

Goal: correct ‘automatic thoughts’ – replace negative with positive, self assuring thoughts, e.g.:

Catastrophic thinking: I know that  I fail the exam

Overgeneralization: ‘I cant do anything right’

Types of behavior therapies

Systematic desensitization

Aversive conditioning

Flooding

Implosion

Token economy

biofeedback

Other psychotherapies

Group therapy

Family therapy

One dysfunctional member reflects dysfunction onto the entire family

Normal and abnormal ‘dyads’

Executive dyad

Normal and abnormal ‘Boundaries’

E.g.. Generational boundaries

Triangles: pathological games and roles, persons involved are not aware and can not fully perceive problems without interpretation

Address dysfunctional alliances between two family members

Normalize boundaries between subsystems and reducing triangles

Redefining blame

Mutual accommodation

Marital/couples therapy

Conjoint therapy (1 therapist + couple)

Supportive psychotherapy

Stress management