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Psychopharmachology

Lecture 8 – Bipolar Disorder

Dopamine Hypothesis

Dopamine is related to pleasure and thus rewards drug use. Slot machine argument: We pull the lever on the slot machine

because it fills us with dopamine and dopamine feels good.

Beyond Dopamine: Individuals with addiction have lower dopamine response to drug

but higher response to drug cues. Some studies indicate that those with addiction problems fail to

“habituate” to the reward signals of drug behavior. Some studies indicate that the under activation in OFC (front brain

related to regulation of impulsivity) and ACC (Anterior cyngulate cortex related to compulsivity) mean that poor executive control, emotion regulation and decision making may be central to addiction processes.

Alcohol Intoxication and Withdrawal

Hallucinations (auditory, visual, or tactile)

Delusions, usually of paranoid or persecutory varieties

Grand mal seizures

Hyperthermia

Delirium/disorientation with regard to time, place, person, and situation; fluctuation in level of consciousness

Restlessness, irritability, anxiety, agitation

Anorexia, nausea, vomiting

Tremor, elevated heart rate, increased blood pressure

Insomnia, intense dreaming, nightmares

Poor concentration, impaired memory and judgment

Increased sensitivity to sound, light, and tactile sensations

Alcohol Withdraw Management

Not all individuals with alcohol addiction will need medical attention.

Discomfort and stress often predict a relapse.

Things that might indicate the need for attention are: 1. Clients who have a history of the most extreme forms of withdrawal,

that of seizures and/or delirium. (Immediate attention needed).

2. Patients who are already in withdrawal and demonstrating moderate symptoms of withdrawal also require immediate medication.

3. For those still intoxicated reevaluate need for treatment over the course of a day. Higher risk group: long-term use, older age, number of withdrawals.

Medications Used in Alcohol Withdrawal

Barbiturates

Anticonvulsants

Beta blockers/alpha adrenergic agonists

Antipsychotics

Benzodiazepine and/or barbiturate intoxication need a differential assessment

Managing Addiction: Alcohol

Disulfiram (Antabuse): Inhibits bodies ability to brake down alch. causing increased symptoms and discomfort intended as a punishment paridigm can result in death. No data indicates that it is clearly effective or increases abstinence rates.

Naltrexone (ReVia): Effects the opiod system (antagonist) effects drinking sequence e.g. reduced craving, and reinforcement and increased nausea and headaches.

Acamprosate (Campral): Agonist GABA, Inhibits NMDA (glutamate). Equal in head to head trials to Naltroxone.

Treatment of Opiod Withdrawal

Non-medically supported withdrawl is contraindicated for opiods.

Methadone is the most common drug: Blocks μ-opioid receptor displacing heroin. Intial dose based on use amount. Tapered to 5 – 10 mgs of 3-5 days.

Colidine (Catapres) – Lower abuse potential Clonidine alleviates some symptoms of opioid withdrawal, it usually is relatively ineffective for insomnia, muscle aches, and drug craving. Initial dose based on use amount.

Buprenorphine (Suboxone, Subutex)

Managing Addiction: Opioids

Methadone: Requires going to methadone clinic daily. More then 150,000 people are in clinics in US. Best practices require sig. psychosocial support along with tx many places do not offer these services.

Buprenorphine (Suboxone and Subutex): Similar to methadone for outcomes. No need to visit registered clinic.

Levoalpha Acetyl Methadol (LAAM): Less frequent dosing then methadone, comparable abstinence rates the methadone (higher drop out then methadone).

Stimulant Withdrawal

Most common stimulants: Cocaine and amphetamine.

Stimulant withdrawal symptoms: Depression, Hypersomnia or insomnia, Fatigue, Anxiety, Irritability, Poor concentration, Psychomotor retardation, Paranoia, Drug craving.

No medication exist for stimulant withdrawl.

Seizures can occur during stimulant use/abuse and withdrawl, alch. and stimulants combined can cause heart conditions.

Medications under review: Disulfiram and Amantadine may help reduce cocaine use in patients; Modafinil, an anti-narcolepsy agent with stimulant-like action; Antidepressants can be prescribed for the depression that often accompanies methamphetamine or other amphetamine withdrawal.

Biopsychosocial Treatment

Medication Adherence: Stages of change for medication adherence, understanding health beliefs and psychoeducation. (Medication, Education, Motivation)

Developing Social Support: Enhancing current social support, developing new constructive relationships, developing good relationship habits and self-respect.

Cognitive and Affective Support: Developing emotional regulation skills, cognitive skills, healthy self-talk, changing core beliefs and good coping habits for triggers.

Developing healthy habits: Eating, sleeping, exercise, healthy fun (hungry angry, lonely, tiered, no exercise).

Treatment Team: Develop and support treatment team and treat comorbid MH concerns (ACE’s).

Co-morbidity: Addiction and Mental Health

High comorbidity of MH and and addiction.

Many people have Health, MH and Addiction problems. Each of these can be a trigger for relapse. Treatment team approach is vital.

Often MH and Substance Abuse were siloed and there was no connection with PCP. This lead to a ping-ponging between services and clinicians playing a game of wac-a-mole.

If you are going to remove a coping mechanism a person needs some coping to put in its place.

Medication of the Week Presentation

Describe a medication briefly,

Describe what it is used to treat

Describe its side effects

Describe other relevant information.

Crooked Beauty is a poetic documentary that chronicles artist-activist Jacks McNamara's transformative journey from childhood abuse to psych ward patient to pioneering mental health advocacy.

It is an intimate portrait of her intense personal quest to live with courage and dignity, and a powerful critique of standard psychiatric treatments.

Poignant testimonials connect the fissures and fault lines of human nature to the unstable topography and mercurial weather patterns of the San Francisco Bay Area.

Crooked Beauty reshapes mental health stigmas through a new healing culture and political model for living with madness as a tool of creativity, inspiration and hope. www.crookedbeauty.com

https://www.youtube.com/watch?v=qgAaIBlq-cs

Mood Disorders Unipolar Depression: Disrupts life through

increased irritability, isolation and robs people of joy.

Bipolar Disorder a Disorderly Disorder. It leads to extremes in behaviors and moods.

An Unique Mind is a memoir by Dr Kay Redfield Jamison who lives with bipolar disease.

She is a well respected psychiatrist with a prestigious career.

Had personal struggles with wanting to take medications.

History of Bipolar Disorder

400 BC - Hippocrates links the black bile of melancholia with the yellow bile of mania.

1899 - Emil Kraepelin introduces the term "manic-depressive” into psychiatric textbooks.

1949 - Australian doctor John Cade discovers the efficacy of lithium as a treatment.

1968 - The DSM changes to the term manic-depressive illness and biological perspectives come to dominate.

2010 - New draft of DSM proposed.

Rates and Epidemiology

For most the onset for Bipolar occurs in late teens and early 20’s.

Rates in general population for adults is between 1% and 4% depending on criteria.

In elders in community rates are between 1% and .5%

Rates in nursing homes are as high 10%.

Psychosocial factors increase severity of symptoms and predicts health, behavioral problems, and rate of relapse.

Family relationships, Poverty, Racism, Lack of Social Relationships, Life Stress are Key Factors in Prognosis.

Mood DisorderDiagnosis

1. Identify episode of mania, hypomania, depression or mixed episode.

2. From the episode the diagnosis is given.

3. In bipolar the rate of change and severity of symptoms are key diagnostic questions.

Diagnosis Bipolar Spectrum

Bipolar I disorder: One or more manic episodes. Subcategories specify whether there has been more than one episode, and the type of the most recent episode.

Bipolar II disorder: No manic episodes, but one or more hypomanic episodes and one or more major depressive episode.

Hypomanic episodes do not go to the full extremes of mania.

Cyclothymia: A history of hypomanic episodes with periods of depression that do not meet criteria for major depressive episodes.

Bipolar Disorder NOS (Not Otherwise Specified): This is a catchall category, diagnosed when the disorder does not fall within a specific subtype.

Rapid cycling: Most people who meet criteria for bipolar disorder experience a number of episodes, on average 0.4 to 0.7 per year, lasting three to six months. Rapid cycling is defined as having four or more episodes per year.

Bipolar Disorder: Sami Khalife, Vivek Singh, David J. Muzina http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/psychiatry-psychology/bipolar-

disorder/#f0015

Neurobiological Changes

MRI studies in bipolar disorder: Increase in the volume of the lateral ventricles, globus pallidus, abnormalities in hypothalamic-pituitary-adrenal axis (HPA axis).

The "kindling" theory: A genetic predisposition is catalyzed by stressors that lowers threshold for mood episodes and disrupts emotional regulation. After this occurs often enough mood symptoms self-perpetuate.

Disruptions in mitochondria and neuron pump also have been identified.

Individuals with bipolar disorder have alterations in:Circadian rhythms, sleep, diurnal cortisol and melatonin.

Psychosocial Factors and Symptoms

Individuals with bipolar disorder can lead very productive lives if there is the right social and emotional support.

More then individuals with psychosis individuals with bipolar tend to be in higher paying work.

However there is often a lower reported quality of life for individuals with bipolar disorder despite successes.

If there are significant life stressors, poor social support, chaos, etc. there is another life course for the illness.

Biology of Bipolar Disorder

Disruptions in iterative loops (feed back loops):

Striatal–Thalamic–Prefrontal – Modulates behavioral regulation and motor planning. Sub-cortical regions are different from controls.

Amygdala, Midline Cerebellum – Limbic modulating regions are disrupted in bipolar disorder and effected by bipolar medication.

Anterior Cingulate Cortex, Dorsolateral Prefrontal Cortex – Abnormal activation may disrupt frontal lobe functioning leading to bipolar symptoms.

https://www.youtube.com/watch?v=W1TMZASCR-I

Biology of Bipolar Disorder

Disrupted Iterative Loops (feed back loops):

SGPFC (a region of anterior cingulate) and amygda project to hypothalmus and may lead to neurovegitative symptoms.

Damage to the Caudate head (part of basal ganglia) can lead to frontal lobe dysfunctions that change the feed back loops (iterative loops) between these symptoms and may cause bipolar disorder.

Biology of Bipolar Disorder

Disrupted metabolism, neurochemicals: Change in D2 (dopamine 2) binding sites in individuals

with psychotic features and bipolar.

Differences in choline production in the striatum (not mood dependent), cingulate (dependent on mood), and frontal lobes. (may be reflective of depression states)

Changes are found in metabolism as measured by changes in functioning in metabolites. May indicate a hypermetabolism leads to changes in how the brain fires. Some studies indicate lithium reverses this but not Depakote. (decreased marker in DLPC = emotional regulation)

Biology of Bipolar Disorder

“…patients not treated with antipsychotics or mood stabilizers exhibited significantly higher activation throughout the motor cortex, basal ganglia and thalamus compared with patients who were receiving these medications, suggesting that mood stabilizers and antipsychotics may normalize cortical and subcoritcal hyperactivity associated with bipolar disorder.”

Implications

These findings may imply that the brain of individuals with bipolar might have two challenges:

Hyperactive subcortical regions.

Hypoactive frontal lobe regulation of emotional processes.

Bio-Psychosocial Treatments Medications: Lithium, Anticonvulsants

(depakote & tegretol), Atypical Antipsychotics.

CNS Depressents (e.g. Benzodiazipines)

Anti-depressants have limited data and most data show that they are not effective.

Psychotherapy regard to relapse prevention: Cognitive behavioral therapy. Family-focused therapy. Psychoeducation

Psychotherapy regard to residual depr. symptoms: Social rhythm therapy. Cognitive-behavioral therapy.

Discussion:

Managing Treatment Adherence…

http://psychopharmacologyinstitute.com/antipsychotics-videos/first-second-generation-antipsychotics-treatment-bipolar-disorder/

Side Effect Profiles: Lithium

Nausea, vomiting, and diarrhea.

Trembling.

Increased thirst and increased need to urinate.

Weight gain in the first few months of use.

Drowsiness.

A metallic taste in the mouth.

Abnormalities in kidney function.

Abnormalities in thyroid function

Side effects include: Black outs, slurred speech, Arrhythmia or a heart block, and an increased white blood cell count.

Side Effect Profiles Anti-psychotics

Blurred vision

Dry mouth

Drowsiness

Muscle spasms or tremor

Involuntary facial tics

Weight gain

Constipation

Health problems…

Rapid Weight Gain

Risk of Diabetes

Increased risk of heart disease (rare) and stroke.

Increases in levels of the hormone prolactin that may result in development of breasts and milk production.

Orthostatic hypotension.

NOTE: Antipsychotics, particularly atypicals, appear to cause changes in insulin levels by blocking the muscarinic M3 receptor

Withdrawal Antipsychotics

Common Withdrawal Symptoms:

Nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia, anxiety, agitation, restlessness, and insomnia.

“Super Sensitive Psychosis” Some cases a withdrawl psychosis caused by medication not a resergence of symptoms.

Tardivedysconisia as a withdrawl symptom.

Withdrawal can occur even switching between medications. Not all providers use this information.

Cholinergic Rebound Rare:

Symptoms and Signs Diarrhea (and Diaphoresis) and abdominal cramping Urination, Miosis (pinpoint pupils), Bradycardia (muscarinic) or Tachycardia (nicotinic), Emesis (Nausea and Vomiting), Lethargy, Salivation Anxiety or Agitation, Seizures, Coma

Side Effect Profiles Anti-Convulsants

All anticonvulsants can cause side effects. Between 44 and 95 percent of the people taking them experience at least one.

The most common are dizziness, sleepiness, and nausea.

Some of the newer anticonvulsants cause swelling of hands and feet, weight gain, blurry vision, trouble concentrating, and memory lapses.

Topamax – Weight loss, kidney stones, skin crawling parasthisias.

Side Effect Profiles Anti-Convulsants

Depakote and Tegratol – Monitor drug levels, hepatic functioning and for depicted impact on pancreas. (Periodic liver testing for depicted)

Life-threatening rashes, including Stevens-Johnson Syndrome (Tegratol, Oxcarbazepine & Lamotrigine).

Oxcarbazepine & Pregabalin (Lyrica): Rare first dose anaphylactic shock.

Carbamazepine, divalproex/ valproic acid, lamotrigine, oxcarbazepine: Although rare, serious and life-threatening multi-organ hypersensitivity might occur during the first two weeks of treatment. Symptoms are diverse but include multiple organ systems.

All anticonvulsants can increase suicidality.

Side Effects for Immediate Consult with Doctor

Overheating or dehydration: If you feel hot, dizzy, or faint, head to a cooler area or take a cool shower or bath and drink plenty of fluids. Call your doctor to report your symptoms.

Chest pain, shortness of breath, or persistent elevated or irregular heart beats: These symptoms could be related to a number or possible side effects or blood level problems and are medical emergencies.

Skin reactions: Allergies and skin reactions can happen with any medication and should be reported immediately. Some medications can cause severe and dangerous skin conditions.

Seizures or loss of consciousness: Seizures and loss of consciousness may be related to various medication side effects and should be considered a medical emergency.

Involuntary muscle movements: Some medications can cause muscle reactions that need to be addressed before they become long-term problems.

Suicidal thoughts, severe agitation or worsening of your symptoms: Although these are not necessarily side effects of any medication, some medications may aggravate your bipolar symptoms or simply fail to treat them, leading to thoughts of suicide or other negative emotional and behavioral symptoms. http://blogs.psychcentral.com/bipolar/2008/12/managing-bipolar-medication-side-effects/

Psychological Treatments

Cognitive Behavioral Therapy: Targets the relationship between thoughts, feelings and behaviors.

Family Focused Therapy: Helps recognize signs of impending episodes or relapses, increase communication and conflict resolution, teaches problem-solving skills, and helps individual create concrete steps to get support in a crisis.

Psychoeducation: Teaches individuals about the disorder and helps develop tools to manage symptoms.

Interpersonal and Social Rhythm Therapy

Is a treatment combining psychological and medical interventions.

Finds “dysregulation in circadian rhythms” as a cause for episodes.

PET found effects of sleep deprivation in the medial prefrontal cortex (mood and emotion regulation centers).

Sleep deprivation leads to increase in positive mood for people who are depressed.

Three Pathways to Bipolar Episode

1) Stressful life events.

2) Disruptions in social rhythms.

3) Medication non-adherence.

Interpersonal and Social Rhythm Therapy

1) The link between mood and life events.

2) The importance of maintaining regular daily rhythms.

3) The identification and management of potential precipitants of rhythm dysregulation with special attention to interpersonal triggers.

4) The facilitation of mourning the lost healthy self.

5) The identification and management of affective symptoms.

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CasCase Consultation

Closing Questions

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