Chapter 22: Mental Disorders

Fear

An adaptive response to threatening situations. Many fears are innate, others learned.

Schizophrenia

"The splitting of psychological functions" -Most common form of chronic psychosis. (1-2% prevalence rate; more common in men. -Age of onset: adolescence (men) or early adulthood (women). -Acute schizophrenia: sudden onset, high likehood of recovery. Can be caused by drug use. -Chronic: gradual onset, long term.

Stressor

(Stimulus) can be a physical or psychological challenge/threat. Example: Someone chasing you or you having to give a presentation in front of people.

MRI AND PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and PTSD. (2003)

- 3 groups were compared, 1. women with ptsd and childhood sex abuse hx, 2. women with childhood sex abuse hx but no ptsd. 3. women with neither (control group). The size of their hippocampus was compared. - The first group which were women with both hx and ptsd had a lower hippocampal volume. -They also found that when they did a verbal memory task that would rely on hippocampal function, that the subjects with abuse but no PTSD showed nice activation of the hippocampus on both sides of the brain.. But those with both hx and PTSD showed less activity due to smaller volume.

Diathesis-Stress Hypothesis of Depression

- Also strong evidence for role gene-enviroment interactions. -Diathesis: genetic predispostion for a certain disease. Inherting a particular type of gene variant, is going to put people at increased risk for developing a disease or condition. Stress: Early childhood abuse, neglect, or other stressful life events. -For depression, the gene that has been implicated is the gene that codes for the serotonin transporter. The gene is called SLC6A4 on chromosome 17. -We can inherit to 3 different genotypes of this gene, we can have two long alleles (I/I) from each parent, 1 long and 1 short (I/s), or 2 short (s/s). -Inheritance of the 2 short alleles (s/s) may predispose an individual to MDD following a stressful experience. -Brain imaging has shown that people with the s/s genotype have more hyperactive amygdala, in a response to negative emotional stimuli. -Those with (I/I) genotype have low risk of developing depression even with mutiple stressful life events. The (s/I) group has a low risk of developing MDD with no or one stressful life event. The risk does increase as you get to 3 or 4 stressful life events. The s/s group start out as a low risk, but as multiple stressful life events keep increasing the risk increases. It's been replicated a bunch of times.

Problems with ECT

- Causes memory loss because the temporal lobes are being targeted which is important for memory. -Retrograde amnesia for events occuring up to 6 months before ECT. -Temporary anterograde amnesia also possible. -Mechanism of why it works is still unknown. The theory is that passing electrical currents through these electrodes and targeting the temporal lobe, it jump starts hippocampal activity. Which may restore the hippocampus's ability to regulate the HPA axis that was lost in depression.

Cortisol and Negative Feedback

- Cortisol also when released goes back up to the brain and stops the release of CRH/CRF and ACTH from the Hypothalamus and Anterior pituitary. Cortisol causes a negative feedback loop.

What Causes Schizophrenia?

- Current theories: Genetics, Enviromental factors, Neurotransmitter abnormalities. -Neurodevelopmental hypothesis: sxs arise due to abnormalities in prenatal or early postnatal development.

Amygdala Regulation of the HPA Axis

- Emotionally relevant stimuli activate the amygdala which then stimulates the HPA axis. There are direct connections between the amygdala and the PVN of the Hypothalamus, so if the amygdala is activated thats is going to cause the PVN to release CRH

Benzodiazepines

- Examples: Valium, Xanax, Klonopin. -Most commonly prescribed anxiolytic drug (5% in US). -Also rx as hypnotics, muscle relaxers, at high doses can be used as anticonvulsants. -Agonists at the GABA receptor (help enhancing GABA activity in the brain). They do this by binding to and enhancing activity at GABA (A) receptors which has a site for the benzo to bind. When that happens the receptor changes it's shape making it more easier for GABA to bind.

Electroconvulsive Therapy (ECT) for Depression

- One of the most effective treaments for depression and mania. -80% success rate, sometimes after first session. -Reseting the electrical activity in the brain. Electrical currents passed between two electrodes placed on the scalp (temporal lobes). It triggers seizure activity in the temporal lobes. -Patients are given muscle relaxants and anesthesia to prevent violent movements during the seziures.

Novel Treatment: Ketamine

- Orignially used as an anesthetic in people but now only used as an anesthetic in veterinary settings. -It is also a party/recreational drug called Special K. -It is a NMDA glutamate receptor antagonist. -It is called a dissociative anesthetic because when people take the drug recreationally, they really out of it and don't remeber anything done. -Research in giving people ketamine infusions was leading to rapid antidepressant effects within hours. People were getting relief of their sxs. -This can be helpful for people with treament resistant depression that don't respond to therapy or medication. -Design drug that mimics the effects of ketamine but not actually ketamine. So they developed Esketamine nasal spray (Spravato). It does have the rapid antidepressant effect. Effects last up to a week. It was offically approved by the FDA in Feb 2019.

Neural Correlates of Anxiety: HPA Axis Dysregulation.

- Patients with anxiety disorders that have increased activity in the amygdala will ultimately have increased HPA Axis activity because the amygdala activates the HPA axis. -Increased HPA Axis results in.. 1. Increased CRF, ACTH, cortisol release 2. Reduced negative feedback 3. Reduced hippocampal function.

Study on structure and the volume of gray matter in genotype patients.

- People with a short allele (s/s) or (s/I) had reduced gray matter in the amygdala and cingulate cortex.

Neurobiology of Exposure Therapy

- Study done in 2012, looked at whether traditional psychotherapy can have effects on the neurobiology that underlie anxiety. -The study did intense exposure therapy for people with spider phobia. Exposure therapy works for phobias and PTSD. -Those partcipants underwent exposure therapy that took over a few hours vs a few weeks. So at the end they look at changes in the brain that may have resulted due to the therapy. They found that the participant's fear was reduced on standard questionaires of phobias for spiders. -The lower scores on the questionaire, went with changes in activity in the brain which they found with a FMRI. As result, there was decreased activity in the amygdala, cingulate cortex, insula and the vmPFC. As well as increased activity in the dorsallateral PFC. So the logical part of ther brain (dlPFC) is more active while the emotional parts of the brain are less active.

Major Depressive Disorder (MDD)

- common psychiatric condition. - Affects 5% of the US population - sxs include: Lowered mood, Decreased interest or pleasure in all activites (anhedonia).

Evidence for the Monoamine Hypothesis as a cause of depression.

-3 findings in the 1960's 1. Blood pressure drug "reserpine" caused psychotic depression in 20% of patients. This is because in order to reduce blood pressure "reserpine" depletes Norepinephrine and Serotonin by stopping both from loading into synaptic vesicles thus preventing release. Which is good for blood pressure but not good in the brain (mood and functioning). 2. Monoamine oxidase (MAO) inhibitors: used to treat tuberculosis caused elevation of mood. This because MAO inhibitors block the MAO enzyme that destroys NE, DA, and 5-HT. So by doing that these neurotransmitters are more avaliable at the synapse, MAO increases the level of them in the brain. 3. Discovery that impramine, already used as antidepressant, inhibits reuptake of NE and 5-HT. Leaving it at the synpase.

Enviromental Factors Implicated in Schizophrenia

-Birth complications (premature, low birth weight, hypoxia). -Infections and autoimmune reactions (season of birth effect,(born during cold and flu season), Rh incompability). -Exposure to toxins (toxoplasma gondii found in cat feces). -Prenatal/early life extreme stress (e.g famine). -Early childhood head injury. -Drug use (marijuana, psychostimulants).

SSRIs (selective serotonin reuptake inhibitors) for Anxiety Disorders

-Blocks serotonin reuptake transporters so serotonin can not come back into the brain. Increasing the amount of serotonin avaliable in the synaptic cleft. -Especially effective fro OCD. Meaning there are low levels of serotonin with people with OCD. -They take a few weeks to start working. There are theories to why that happens, the strongest theory is that the true effect of these drugs is not the increase serotonin itself, but the effects on other neural circuits as a result of more serotonin available. So those effects on the neural circuts take a few weeks before relief of sxs.

Sxs of Schizophrenia

-Can be broken into two categories: Positive and Negative. -Positive is when there is presence of abnormal behvaior/cognition. Such as delusions, hallucinations, Inappropriate affect, incoherent/disorganized speech, bizzare behaviors (lack of hygiene/diff with everyday tasks. -Negative is where there is an absence of normal bhevaior/cognition. Such as flat affect, alogia (reduced or absent speech), avolition (no motivation), Anhedonia (inability to feel pleasure), Catatonia (remaining motionless for long periods).

The Monoamine Hypothesis of Depression

-Depression is a result of dysfunction within one or more of the monoamine neurotransmitter systems. Monoamine neurotransmitters are Dopamine, Epinephrine, Norepinephrine, and Serotonin. -The ones that are dysfunctional in particular for depression are serotonin and norepinephrine.

Evidence for the Dopamine Theory

-Drugs that increase dopamine levels (e.g cocaine, amphetamine) can trigger psychosis or exacerbated sxs. Drugs that deplete dopamine levels (resperine) reduce schizophrenia sxs (i.e, they have antipsychotic effects.

Gene Enviroment Interaction

-Enviroment factors effect the genes and then cause the sxs.

Atypical (second generation) antipsychotics

-Examples include Risperdal, Abilify, Latuda, Caplyta (New). -They still block DA receptors but not as much at typical antipsychotics do. They have lower affinity. (Fewer motor side effects). -Antagonists at serotonin, NE, ACh (muscarnic), histamine receptors. - Other side effects: -Weight gain -Neuroleptic, malignant syndrome. -Stroke, blood clots, cardiac death.

Transcranial Magnetic Stimulation (TMS)

-FDA approved. -Non-invasive treatment. -Magnetic coil is applied to the scalp and it provides electrical stimulation to neurons below in the brain. -Target site: dorsolateral prefrontal cortex. -Sessions last 25-50 min, several times per week.

Neurotransmitter Abnormalities in Anxiety Disorders

-GABA: 1. Not enough GABA in the brain. There is a loss of balance between excitation (Glutamate) and inhibiton (GABA). Too much Glutamate not enough GABA. -Serotonin: Low levels of serotonin may be a predisposing factor.

Hormonal Disruptions in Depression

-HPA axis hyperactivity. -one of the most consistent findings in depression. -Elevated levels of cortisol in blood. Lack of negative feedback and hippocampal regulation -Animal models: showed lower GR in the hippocampus due to increased cortisol causing dysfunction in HPA axis regulation. Can be triggered by chronic stress and low levels of maternal care in rodents. -May explain link between chronic stress, anxiety and depression. -estrogen, women can develop depression due to change in estrogen levels.

Problems with Benzodiazepines

-High abuse/addiction potential -Rebound anxiety upon withdrawal -Interactions with other drugs that bind to GABA (A) receptors.

Genetic Evidence for Schizophrenia

-High concordance rate ( if one twin has the disorder what is the likelyhood percentage that the other twin has it as well). For identical or monozygotic twins (45%) and for faternal or dizygotic twins its (10%). Shared genetics increases the likelyhood. - Tends to "run in families" -Many candidate genes identified, but the most famous one is (DISC 1) which stands for (disrupted in schizophrenia) - The DISC 1 mutations can be inherited from parents or pop up (spontaneous aka de novo mutations). -Most of these genes dealing with schizophrenia are involced in neurodevelopmental processes. -Gene interactions likely.

Treatments for Depression

-In addition to psychotherapy, several biological-based treatments. Combination of both medicine and psychotherapy is the best tx for depression. -Pharmacological: 1. Antidepressant drugs 2. Ketamine -Non-pharamcological 1. Electroconvulsive therapy 2. Transcranial magnetic stimulation (TMS).

Anxiety Disorders

-Inappropriate expression of fear/stress that interferes with daily functioning. -Up to 30% of American affected at some point.

Neural Correlates of Anxiety: Amygdala Reactivity

-Increased activity in the amygdala is seen with people with anxiety. The amygdala is overactive and is more strongly connected with other brain regions. -Neuro transmitter system abnormalities also documented.

Biological Bases of Depression

-Monoamine Hypothesis: Depression is caused by alterations in the monoamine neurotransmitter system in the brain. -Gene-enviroment interactions (diathesis stress hypothesis) -Hormonal disruptions (HPA axis)

Impairment to the Hippocampus negative feedback loop function can result in

-Neuron destruction -Decreased short-term memory -Decreased contextual memory -Poor regulation of endocrine response to stress.

Types of Anxiety Disorders

-Panic disorder -Agoraphobia -GAD -Social phobia -Specfic phobias -PTSD -OCD

Tx for Anxiety Disorders

-Psychotherapy: Exposure therapy -Pharmacotherapy: Benzodiazepines, SSRIs

Evidence for the Glutamate Theory

-Receptor abnormalities in hippocampus, PFC, and other area in postmortem tissue from people with scizophrenia. - Phencyclidine; (angel dust") and NMDA receptor antagonist, can exacerbate and even induce sxs.

Effectiveness of Typical Antipsychotics

-Relieve positive symptoms of schizophrenia by blocking DA receptors in the mesocorticolimbic pathway. -Not good at relieving Negative sxs. -Also block DA receptors in the Nigrostriatal pathway. -Typical Antipsychotics end up causing Tardive Dyskinesia. Results in 1. Purposeless, repetitive involuntary movments. (muscles of the head and face). 2. Difficult to treat, can't be cured. Due to long-term used of Typical Antipsychotics which block DA receptors in the Nigrostriatal pathway.

Classes of Antidepressants continued

-Selective serotonin reuptake inhibitors (SSRIs) (e.g Prozac, Zoloft, Paxil, and Lexapro). Specfically block reuptake of serotonin. They only work at the serotonin transporter. Selective Norephinephrine reuptake inhibitors (SNRIs) (e.g Edromax in Europe). They specifically block reuptake of NE. They have mixed evidence for effectiveness.

Brain Abnormalities in Schizophrenia

-Some abnormalities are structural while others are functional. Not only seen in people with the condition, but also seen in 1st degree relatives which puts them at an increase risk of developing the disorder. As well as people who have only had 1 psychotic episode. -Abnormalities such as: Decreased gray matter volume in cortical areas like the hippocampus, amygdala, insula, cingulate cortex, prefrontal cortex, and over 50 brain areas. Also widespread loss of neurons (postmortem studies) -Enlarged lateral ventricles. (right and left side of the forebrain). - Disorganized of neurons in the hippocampus. - (Hypofrontality) Reduced activity of the frontal lobe when during cogntive tasks. (Wisconsin card sort) -Theory: Reason why schizophrenia doesn't present itself until adolescence is because these abnormalites aren't fully present until brain develop is just about finished. So until these strucutres and connectivity is fully devoped you wont' see those abnormalities and the sxs will not express themselves.

FRMI study in genotype patients looking at amygdala activity.

-The found that people with any short allele, whether (s/s) or (s/I) did show increase in activity in the amygdala than (I/I) people.

Problems with Antidepressants

-They take several weeks to work. There are theories to why that is, the strongest one is that antidepressants exert their effects by triggering long-term molecular adaptations. -Effective in up to 60- 70% of patients treated for MDD, but often requires much trial and error. Trying different types antidepressants to see if anything works but it doesn't it is called treatment resistant depression.

Schizophrenia Treatments

-Typical Antipsychotic Drugs: First drugs developed to treat schizophrenia. -Dopamine D2 receptor antagonists. Haloperidol, Spiroperidol, Chlorpromazine. -Positive correlation: between affnity for D2 receptors and their clinical effectiveness. So, the more potently one of these drugs blocks D2 receptors the effective it is at relieving sxs of schizophrenia. Spiroperidol has the highest affinty making it the most effective.

Cortisol

-binds to glucocorticoid receptors (GR), these receptors are found in almost every tissue in the body. That is why stress reeks such havoc. -Effects of cortisol on the body include 1. increased plasma glucose levels 2. Decreased immune function 3. Inhibiton of insulin (normally takes up excess glucose).

The Glutamate Theory

-sxs are due to decreased actvitiy at glutamatergic synapses.

The Dopamine Theory

-sxs of schizophrenia are a result of too much dopamine signaling in the brain. - 2 major DA pathway: 1. Mesocorticolimbic pathway function: Emotional expression/experience. -Response to rewards, including abused drugs. 2. Nigrostriatal pathway function: Voluntary/goal-directed movements.

Types of Affective Disorders

1. Major depressive disorder (MDD) 2. Bipolar disorder 3. Seasonal affective disorder (SAD)

HPA axis

1. Stressor triggers release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus (PVN). 2. The Anterior pituitary has receptors for CRH, so when CRH binds to those receptors the Anterior pituitary will release another hormone called adrenocorticotropic hormone (ACTH). 3. The ACTH then goes to the kidney via the bloodstream and acts on the kidney in the adrenal gland. The ardenal gland has a lot of receptors for ACTH, so once it binds the receptors the adrenal gland releases cortisol.

Classes of Antidepressants

1. Tricyclics (e.g imipramine) blocks reuptake of serotonin and norepinephrine. Less commonly used today due to side effect/risk profiles. 2. Monamine oxidase inhibitors (MAOI) reduce enzymatic degradation of serotonin and NE. These are problematic because they interact with other drugs and food.

Regulation of the HPA Axis

CRH/CRF released from the PVN can be either activated or inhibited by the Amygdala or Hippocampus.

Anxiety

Feelings of fear, worry, uneasiness, dread in the absence of a threat. Thinking about the threat where there is no threat is anxiety, where fear is a response to immediate danger.

Stress

Physiological response that you body and brain have to an actual or potential stressor.

Hippocampal Regualtion of the HPA Axis

The hippocampus has a high concentration of glucocorticoid receptors, which are the receptors that bind cortisol. So when cortisol gets released and goes up to the brain, it binds the GR in the hippocampus and then shuts down the PVN which then inhibits the release of CRF/CRH. So in additon to cortisol being able to directly inhibit the Hypothalamus and Anterior Pituitary from releasing hormones, it can also do that by binding to GR in the hippocampus. Another negative feedback. -Hippocampal negative feedback loop function can be impaired by chronic stress (high release of cortisol to the GR overwhelming) causing it to not be able to regualte the HPA axis.

The Stress Response

When we encounter a stressor and our brain responds to it, that can trigger a couple different things like activating the -Two-system view: 1. Sympathetic nervous system, which releases epinephrine/norepinephrine. Which in turn acts on your heart, lungs and blood vessels. 2. Hypothalamo-pituitary adrenal (HPA) axis. Which will release cortisol a horomone. When both systems are activated the result is increased vigliance/arousal and avoidance behavior.

Affective disorders (Depression)

emotional disturbances that interfere with daily functioning. Meaning you don't want to go to work or school or socialize with other people. You don't want to do the activities that you used to enjoy.

Affect (Depression)

emotional state or mood.