disorders

DRUGS TO TREAT DISORDERS

Chapter Overview

• Topics covered include the use of drugs in treating various mental disorders including anxiety disorders, affective disorders, and schizophrenia.

Introductory Remarks

• Reminder to turn off cell phones and sign the attendance sheet.

THINGS YOU WILL LEARN TODAY

• How the urine of a Munich waitress named Barbara likely made the first anesthetic drug.

• Why SSRIs (Selective Serotonin Reuptake Inhibitors) take many weeks to be effective.

• The reason we cannot cure schizophrenia with antipsychotics.

ANXIETY DISORDERS

DSM-5 Classification of Anxiety Disorders

• Generalized Anxiety Disorder (GAD)

• Panic Disorder

• Phobias

• Social Anxiety Disorder (SAD)

• Post-Traumatic Stress Disorder (PTSD)

• Obsessive-Compulsive Disorder (OCD)

• Comorbid conditions commonly associated with depression.

WHAT IS ANXIETY?

Definition of Anxiety

• Emotional state characterized by strong feelings of concern or worry that range from vague discomfort to intense sensations of terror.

Adverse Effects of Anxiety

• Increased muscle tension

• Restlessness

• Impaired concentration

• Sleep disturbances

• Irritability

Physiological Effects

• Activation of the sympathetic autonomic nervous system (ANS), resulting in:

  • Increased heart rate

  • Sweating

  • Initiation of “fight or flight” responses.

DRUGS FOR TREATING ANXIETY

Anxiolytics

• Classification of drugs specifically designed to relieve anxiety; most are sedative-hypnotics.

• Classified as central nervous system (CNS) depressants.

Mechanism of Action

• Primary mechanism involves enhancing GABA (gamma-aminobutyric acid) transmission:

  • Includes barbiturates and benzodiazepines (BDZ), both of which have binding sites on the GABAA receptor, enhancing hyperpolarization from GABA.

Barbiturates

• Thiopental (Pentothal): Used for IV anesthesia.

• Amobarbital (Amytal): Used for surgical anesthesia and sleep induction.

• Phenobarbital (Luminal): Used for prolonged sedation and seizure control.

• Characteristics:

  • Oldest sedative-hypnotics, now mostly replaced by BDZs

  • Still used for anesthesia and seizure control

  • High potential for abuse and severe side effects, including:

  • Reduced REM sleep

  • Mental clouding

  • Loss of judgment and slowed reflexes

  • High doses may lead to intoxication, coma, and death, particularly with alcohol.

Benzodiazepines (BDZ)

• Effective for reducing anxiety with fewer side effects compared to barbiturates.

• Generally exhibit little to no tolerance; however, chronic use can lead to dependence.

• Commonly treated conditions include GAD, panic disorder, OCD, and SAD.

• Mechanism of action includes:

  • Hypnotic (sleep aids)

  • Muscle relaxant properties

  • Anticonvulsant effects

  • Management of alcohol or barbiturate withdrawal symptoms.

• Flumazenil: An antidote for benzodiazepine overdose, acting as a competitive antagonist for BDZ receptor sites.

Buspirone (BuSpar)

• A second-generation anxiolytic that functions as a partial agonist at 5-HT1A serotonin receptors.

• Mechanism:

  • Inhibits cAMP (cyclic adenosine monophosphate) production.

  • Does not enhance GABA action.

• Advantages:

  • Reduces anxiety and depression without sedation or mental cloudiness.

  • Lacks withdrawal symptoms and potential for abuse.

• Disadvantages:

  • Slow onset and ineffective for alcohol withdrawal, insomnia, seizures, and lacks muscle relaxant effects.

Other Anxiolytics

• Alternative treatments for anxiety include:

  • Antidepressants (e.g., SSRIs)

  • Ketamine

  • Non-traditional treatments for OCD and PTSD such as LSD, psilocybin, and MDMA.

AFFECTIVE DISORDERS

Definition

• Characterized by extreme changes in mood:

  • Major Depression: Involves recurring episodes of dysphoria and negative thinking, which reflects in behavior.

  • Reactive Depression: Triggered by external events.

  • Clinical Depression: More chronic and severe.

  • Bipolar Disorder: Features cyclic mood swings, alternating between states of depression and mania.

NEUROCHEMICAL BASIS OF AFFECTIVE DISORDERS

Monoamine Hypothesis

• Postulates that a reduced level of monoamines (Dopamine [DA], Norepinephrine [NE], Serotonin [5HT]) is responsible for depressed mood.

• Observations from reserpine, which reduces levels of monoamines, show that mania coincides with excess monoamine activity; however, this theory is too simplistic with some discrepancies.

Serotonin Dysfunction

• Most antidepressants increase 5HT levels by blocking reuptake through the serotonin transporter (SERT).

• Selective Serotonin Reuptake Inhibitors (SSRIs):

  • Show a slow onset for reducing depressive symptoms; often require weeks of chronic treatment to be effective.

  • Approximately 60-70% of patients fail to achieve complete remission, and 30-40% exhibit no significant response.

Acute vs. Chronic SSRI Administration

• Acute SSRI Administration: Autoreceptors may reduce 5HT synthesis, with presynaptic 5HT1A autoreceptors being strongly implicated in depression models.

• Chronic SSRI Administration: Autoreceptor downregulation could potentially explain the delayed therapeutic onset and the limited efficacy observed.

DRUGS FOR TREATING AFFECTIVE DISORDERS

• Antidepressant drugs can reduce, but not eliminate symptoms in about 2/3 of cases. Challenges include:

  • Unpredictable responses to specific drugs.

  • Variability in effectiveness among different drugs; no one drug is proven to be more effective across the board.

  • Maximal effectiveness may not be realized until 4 to 6 weeks of administration, with continued use helping to prevent relapse.

Types of Antidepressants

1st Generation Antidepressants

• Monoamine Oxidase Inhibitors (MAO-I): Reduce metabolism of monoamine neurotransmitters.

• Tricyclic Antidepressants: Inhibit reuptake of NE and 5HT, serving to prolong their duration of action; however, they often have strong adverse side effects.

2nd Generation Antidepressants (SSRIs)

• Examples include:

  • Fluoxetine (Prozac)

  • Sertraline (Zoloft)

  • Paroxetine (Paxil)

• Mechanism: Block reuptake of 5HT more than NE transporters and also used for treating anxiety disorders, OCD, obesity, and alcohol use disorder (AUD).

• Common side effects:

  • Anxiety

  • Movement disorders

  • Muscle rigidity

  • Nausea

  • Headaches

  • Insomnia

  • Sexual dysfunction.

Bipolar Disorder Treatment

• Lithium (as a salt): Used to eliminate manic episodes without causing depression or sedation.

• Found to be effective in reducing suicidality.

• Mechanism: Enhances 5HT actions and reduces catecholamine activity, also affecting circadian rhythms, with mild side effects.

SCHIZOPHRENIA

Overview

• Classified as a chronic psychosis where patients exhibit a broad spectrum of symptoms.

• Not subject to cure or prevention, and symptoms typically emerge in late teenage years or early 20s.

Symptoms of Schizophrenia

Positive Symptoms

• These include delusions and auditory hallucinations, with patients often displaying grossly disorganized or abnormal motor behavior and incoherent language.

• Patients who are older at the onset tend to respond better to antipsychotic treatments.

Negative Symptoms

• Include reduced emotional expression, lack of volition, social withdrawal, apathy, and cognitive defects.

• These are generally resistant to current medications.

NEUROCHEMICAL BASIS OF SCHIZOPHRENIA

Dopamine Hypothesis

• Asserts that positive symptoms are due to excessive mesolimbic DA activity.

• Notable evidence includes:

  • Amphetamine-induced symptoms in healthy individuals.

  • Symptoms can be reversed by dopaminergic antagonists.

  • Correlations between D2 receptor blockage and reduced schizophrenia symptoms.

  • Schizophrenic patients exhibit increased DA release following amphetamine challenge and an increase in D2 receptors.

Glutamate Role

• Impaired glutamate function may contribute to increased mesolimbic dopamine and decreased function in the prefrontal cortex (PFC).

• NMDA receptor hypofunction likely plays a critical role in the pathology of schizophrenia.

ANTIPSYCHOTIC DRUGS

General Overview

• "Neuroleptics" is an older term for antipsychotic drugs; no specific drug is consistently more effective than others, and individual responses may vary.

• Antipsychotic action necessitates D2 receptor antagonism.

Types of Antipsychotics

• Classic Antipsychotics: Examples include chlorpromazine and butyrophenones.

• 2nd Generation Antipsychotics: Generally have fewer side effects, examples include:

  • Clozapine

  • Risperidone

  • Aripiprazole.

Side Effects and Risks

• Strong side effects can cause patients to discontinue medication, notable side effects include:

  • Tardive Dyskinesia (TD): Characterized by stereotyped involuntary movements, often affecting the face and jaw, occurring in 10-20% of individuals treated with antipsychotics.

Comparison of Receptor Interactions

Atypical Antipsychotics

• Part of the second generation, these drugs reduce positive symptoms without major motor side effects.

• Examples include:

  • Sulpiride

  • Aripiprazole (Abilify): A broad-spectrum partial agonist with weak affinities for D1 and D2 but strong interactions with other non-dopaminergic receptors.