The nine symptoms, as the textbook lists them:

• Depressed or irritable mood (required, or the next one)
• Loss of interests and pleasure — anhedonia (required, or the previous one)
• Significant (>5%) weight gain or loss in a month — or change in appetite
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive guilt
• Poor concentration or indecisiveness
• Recent thoughts of death or suicide

What it looks like clinically. Sadness and despair that do not let up. Alongside that painful, dysphoric mood come sleeplessness, appetite and weight falling away, and a withdrawal of interest from both pleasures and people. The sleep problem takes two forms: trouble getting to sleep, or waking in the middle of the night and lying there for hours, unable to get back. Movement slows and fatigue is marked in some; others are restless and agitated. Ordinary situations get read as heading for a bad outcome. Working and concentrating both become much harder.

Depressive episodes may begin suddenly or gradually and continue for a few weeks to months. About 20% exhibit a chronic form. The deck adds irritability, social withdrawal and physical symptoms to the picture.

Genetic and familial:

• Twin concordance for unipolar depression: 62% monozygotic, 28% dizygotic
• Adoptees with a biological family history of mood disorders have a higher incidence of major depression or manic-depressive illness than control adoptees — which separates inheritance from upbringing
• The textbook adds a caution: the large variation in clinical symptoms suggests developmental and environmental factors are as important as genetic factors

Demographic:

• Lifetime prevalence in the United States: 16.2%
• A twofold greater risk in women than in men after adolescence
• 2% to 6% of children and adolescents

Stress and neuroendocrine:

• Chronic stress-induced activation of the HPA system with elevated glucocorticoid secretion is found in 30% to 70% of people with major depression
• Uncontrollable stress interacting with genetic factors is the textbook's framing of how risk accumulates
• An individual's inability to cope with stressors, inexperience with flexible psychosocial and emotional skills, and lack of physical health all contribute

Inflammation:

• Inflammation is described as a risk factor that triggers the onset of depression
• In a study of 73,131 Danish individuals, elevated C-reactive protein was associated with increased risk of psychologic distress and depression

Social and course-related:

• Low social support and perceived loneliness predict poor response to treatment, early drop-out and heightened risk of relapse
• Prior episodes: at least 50% of people who recover from a first episode will experience another; the recurrence rate rises to approximately 80% in those with a history of two episodes

One negative finding worth keeping, because it prevents an error: although thyroid dysfunction can produce depressive features, people diagnosed with primary depression generally have normal thyroid function. A normal TSH does not rule depression in or out.

One-sentence version: in depression the stress axis is stuck on — the HPA system is chronically activated, cortisol is elevated, and the negative feedback that should switch it off is impaired.

The HPA axis:

• The hypothalamic-pituitary-adrenal system is what lets a person cope with stress
• Chronic stress-induced activation with elevated glucocorticoid secretion is found in 30% to 70% of people with major depression
• The direction of the association is informative: antidepressant drugs that are effective in normalising the HPA system are associated with a good clinical response, whereas persistent HPA dysregulation is related to continued depression or relapse

The immune link that runs alongside it:

• Psychosocial stress activates the immune system and increases secretion of proinflammatory cytokines — IL-1α, IL-1β, TNF-α and IL-6
• These modulate signalling throughout the periphery and brain and augment further secretion of HPA hormones and monoamine metabolism — so the stress axis and the inflammatory response drive each other

The hypothalamic-pituitary-thyroid axis:

• Hyperthyroidism often produces dysphoria, anxiety, irritability, emotional lability and cognitive impairment
• Severe hypothyroidism produces features of major depression, apathy, psychomotor slowing and dementia
• But people diagnosed with primary depression generally have normal thyroid function, and the causal mechanism underlying altered thyroid secretion and depression remains to be determined

How this shows up in the patient. The week 5 case works it forward: reduced serotonin, norepinephrine and dopamine → depressed mood and anhedonia; cortisol excess → fatigue and sleep disturbance; reduced hippocampal volume and prefrontal cortex hypoactivity → poor concentration and guilt.

The monoamine hypothesis sits underneath all of this: a deficit in the concentration of brain norepinephrine, dopamine and/or serotonin as the underlying cause of depression — in contrast to mania, which is proposed to result from elevated monoamine concentrations. The supporting evidence is pharmacologic: reduced monoamine metabolites in the CSF of depressed people, and dietary depletion of tryptophan (the precursor of serotonin) or inhibition of dopamine and norepinephrine synthesis producing a rapid return to depression in people successfully treated with antidepressants.

What the sources do establish:

• Approximately 80% of depressed persons will respond to antidepressant drugs, psychotherapy, or a combination of both
• SSRIs are the standard first-line treatment for major depression
• Selecting the initial antidepressant includes an assessment of: the person's symptoms, their age, the side effects, safety, cost and convenience of the medication

The worked example the textbook gives: medications that produce sedation may be helpful for the treatment of sleep disturbances. The symptom picture selects the drug, rather than the diagnosis selecting it.

When the first drug does not work:

• Approximately 50% may not show a favourable response during initial treatment
• 10% to 20% may continue to exhibit symptoms after 2 years
• If 2 months on one antidepressant produce no response, switching to a different one is the next step
• Adjunctive atypical antipsychotics — aripiprazole, brexpiprazole — are FDA approved for treatment-resistant depression
• ECT may be used when individuals fail to respond, or when they are severely depressed, pregnant, suicidal or psychotic; it relieves depressive symptoms in about 50% to 80%

In bipolar depression, antidepressants may cause cycle acceleration or induce mania. SSRIs and bupropion are less likely to do this than MAOIs or TCAs — which is a prescribing principle, not a side effect.

Set expectations about relapse. Best-available treatment — medication plus psychotherapy — still leaves at least half of those who recover from a first episode facing another one, and that figure climbs to 80% once someone has had two. Two things push it up: dropping out of therapy or stopping the drug, and thin social support with perceived loneliness.

Common SSRI side effects:

• Sleep disturbances — insomnia
• Nausea

Also reported:

• Agitation
• Allergic skin reactions
• Dry mouth
• Anxiety
• Altered appetite
• Sexual dysfunction

What SSRIs do not do is the distinguishing feature. Where MAOIs and TCAs act noticeably on the heart and on cholinergic transmission, SSRIs largely leave both alone. That absence is why they became first-line, and it is the most likely thing an exam item turns on.

The MAOI food and drug interactions, since they are the reason MAOIs are used less often:

• Tyramine-rich foods send the blood pressure sharply up — a hypertensive crisis. The foods named in the chapter: aged cheese; sour cream; broad bean pods; pickled herring; liver; canned figs; raisins; avocado.
• Four drug groups must be kept away from an MAOI — TCAs, SSRIs, stimulants, and over-the-counter flu remedies

A geriatric point on TCAs: the anticholinergic load is the problem in older adults. Where a TCA is still wanted, desipramine and nortriptyline are the usual choices, being lighter on all three fronts — anticholinergic, cardiac and sedating.

And on the atypicals: expect sedation, dry mouth, weight gain, constipation. Liver toxicity has been reported with nefazodone and trazodone. Venlafaxine and reboxetine escape most of what makes TCAs dangerous, though they can still cause sweating, a dry mouth and some drowsiness.

Pharmacologic:

• Lithium — individuals with bipolar I are treated with lithium, and in some cases with SSRIs
• Anticonvulsants — carbamazepine, valproate, gabapentin, lamotrigine, topiramate
• Second-generation antipsychotics — clozapine, risperidone, ziprasidone, quetiapine; many individuals are prescribed these in an outpatient setting. The deck names quetiapine and olanzapine.
• ECT — reserved for three situations: medication has not worked, the patient is pregnant, or there is cardiovascular disease

An honest gap the textbook states: the comparative effectiveness of mood stabilizers and antidepressants versus second-generation antipsychotics in individuals with bipolar disorder remains unknown. The drugs are established; the ranking between them is not.

Nonpharmacologic:

• Cognitive behavioural therapy
• Psychoeducation
• Family-focused therapy
• Mindfulness-based cognitive therapy
• Integrated collaborative care
• Monitor for suicidality and medication adherence

Format affects adherence, and the textbook is specific: individuals with bipolar disorder are more likely to continue combined treatment when it is delivered in family or group formats, or with brief psychoeducation — as opposed to formalised individual psychoeducation in an outpatient setting.

A pediatric caution. Bipolar II and ADHD share elevated behavioural activity, excessive talking, restlessness and distractibility. Misdiagnosing bipolar II as ADHD has real consequences: the stimulants used for ADHD can exacerbate the symptoms of a child with bipolar II. DSM-5 added disruptive mood dysregulation disorder for children aged 6 to 10 with frequent temper outbursts, irritability and bad moods, to keep them out of a bipolar diagnosis and off strong medications.

Up to 80% of individuals affected by panic disorder respond to CBT and antidepressant drugs — separately or in combination. That number is the headline: this is a treatable condition.

Cognitive behavioural therapy, and what it actually does:

• The work is to learn that the bodily symptoms will not kill you, and from there to take some control of the anxiety and the panic
• Breathing exercises to control hyperventilation lessen the intense physiologic symptoms — elevated heart and respiration rates
• A further benefit is awareness of adherence with drug medications
• For individuals with mild agoraphobia, CBT alone may be effective

Pharmacotherapy:

• SSRIs are considered first-line. Paroxetine and sertraline have received FDA approval specifically for panic disorder.
• Venlafaxine, a serotonin-norepinephrine reuptake blocker, is also effective
• Benzodiazepines — alprazolam, clonazepam — are other medications for treating panic disorder, and serve as adjunct or augmentation therapy for individuals who do not fully respond to SSRIs

Lifestyle measures from the deck: stress management and sleep hygiene, alongside the drug and the therapy.

Complications of panic disorder:

• Agoraphobia
• Depression
• Substance abuse
• Impaired social and occupational functioning
• Increased risk of suicide
• Chronic anxiety

Agoraphobia is the one the textbook develops. It calls it a notable complication of panic disorder, and defines it by what the person steers clear of: anywhere that getting out, or getting help, would be hard. In practice that means staying home rather than going out, avoiding queues and crowds, and not travelling by train, plane or car. At the severe end the person stops leaving the house at all.

Where the avoidance comes from. Panic attacks involve intense autonomic arousal — lightheadedness, tachycardia, difficulty breathing, chest discomfort, generalised sweating, general weakness, trembling, abdominal distress, chills or hot flashes. Symptoms originally occur spontaneously and last from several minutes to an hour. Between attacks, the individual worries about future panic attacks and fears losing control and dying. That anticipatory fear is the engine: the person begins avoiding wherever an attack happened, and the avoidance spreads.

This is also why CBT works the way it does — teaching that the physical symptoms are not fatal attacks the anticipatory fear rather than the attack itself. And it is why mild agoraphobia may respond to CBT alone.

The sources emphasise different halves of the same circuit. The textbook stresses norepinephrine, serotonin and benzodiazepine binding; the slides stress the amygdala, GABA and the HPA axis. These are complementary descriptions, not a disagreement — but both may be tested, so both are here.

Neurochemistry — the textbook's account:

• Reduction in α2-adrenergic receptor binding
• Decreased serotonin levels in CSF
• Reduced platelet binding of paroxetine, an SSRI
• Reduction of benzodiazepine binding in the left temporal hemisphere

Circuitry — the deck's account:

• Hyperactivity of the amygdala and dysregulation of the prefrontal cortex — a heightened fear response
• GABA deficiency — reduced inhibitory control over anxiety circuits
• Increased norepinephrine activity
• HPA axis overactivation — a chronic stress response

Imaging findings, which tie the two accounts together:

• In adults with GAD, increased anticipatory anxiety was associated with elevated cingulate cortex activity; both the anxiety and the cingulate activation were reduced after 8 weeks of venlafaxine. This suggests a decrease in cingulate activity predicts treatment efficacy.
• Among children and adolescents with the disorder, a brief flash of a masked angry face drove up activity in the right amygdala, and the more anxious the child, the bigger that response — which is abnormal amygdala activity showing up as threat vigilance.

Genetics: twin studies in women put concordance around 30% — real heritability — yet no chromosome-specific disease gene has been pinned down.

Epidemiology and course: lifetime prevalence 4.1% to 6.6%, somewhat higher in women. It usually appears in the early twenties, though it can start in childhood. Severity rises and falls, often with whatever the current stressors are; the disorder tends to be chronic, but symptoms may ease with age. Substance abuse is a frequent complication — people reach for alcohol or drugs to quiet the anxiety themselves.

As a group, anxiety disorders are the commonest psychiatric illness there is — somewhere between 10% and 30% of the population. Many of those people also carry symptoms of major depression, and the overlap is heavy enough that a shared neural basis has been proposed.

First-line therapeutics:

• SNRIs — venlafaxine
• SSRIs — paroxetine and escitalopram
• Symptoms can start easing inside a week, and the same drugs also treat the depression that so often comes with it

Second option:

• Buspirone, which has an affinity for serotonin 5-HT1A receptors
• Onset of clinical efficacy may take 2 weeks — slower than the SSRIs and SNRIs above
• Primary side effects, which lessen over time: dizziness, headaches, nausea, mild nervousness

For non-responders:

• Benzodiazepines, for individuals who do not respond to SNRIs or buspirone
• But because GAD tends to be chronic and comorbid with depression or other anxiety disorders, benzodiazepines are usually limited to short-term use and uncomplicated cases

Nonpharmacologic:

• Behavioural therapy to acquire relaxation techniques that control anxiety
• CBT for worry control and relaxation
• Mindfulness and stress-reduction techniques; exercise

The chronicity is the reason for the sequencing. A condition that lasts years should not be managed with a drug class that produces dependence, so the durable options come first and the benzodiazepine is a limited-term fallback.

One-sentence version: schizophrenia is a neurodevelopmental disorder in which dopamine transmission is too HIGH in one pathway and too LOW in another — which is why one drug cannot fix both halves of the illness.

Epidemiology: it affects 1% of people worldwide, men and women equally. Onset falls in young adulthood — the late teens into the early twenties — arriving a little sooner in men.

Genetic predisposition:

• Monozygotic twin concordance 30% to 50%
• Dizygotic twins and siblings 12% — still far above the 1% general-population figure
• Not a simple genetic disorder. Several genes on different chromosomes are involved, and the genes show reduced penetrance — individuals carry the disease genes without manifesting the illness
• Candidate genes: dysbindin, neuregulin 1, DISC1 — though the traits are complex and candidate genes have not always been directly implicated

Prenatal and perinatal vulnerability factors:

• Exposure to prenatal infection
• Prenatal nutritional deficiencies
• Perinatal complications — birth defects, neonatal hypoxia
• Upbringing in an urban environment

The leading hypothesis is that early environmental factors interfere with genetically programmed neural development, compromising brain structure and function. An early brain defect may remain silent and not affect the individual dramatically until later development requires adaptive use of those structures — which is why a developmental disorder presents in early adulthood.

Neuroanatomic alterations:

• Enlargement of the lateral and third ventricles; widening of frontocortical fissures and sulci
• Individuals with ventricular enlargement exhibit cognitive impairment, negative symptoms, and respond poorly to treatment
• Reduction in the thalamus — which may disrupt neurotransmission between frontal cortex and primary sensory and motor areas — and in temporal lobe areas including amygdala, hippocampus and parahippocampal gyrus
• Hippocampal volume loss in the first years of the illness, accelerating after age 50, strongly associated with global cognitive and socio-occupational impairment
• Accelerated grey matter loss in early-onset adolescents: 2% to 5% annually, against 0% to 1% in age-matched healthy adolescents
• The dorsolateral prefrontal cortex is hypoactive — blood flow and metabolism normally rise during working memory processing, and do not in schizophrenia

A clinically sobering detail: cortical tissue has already been lost before the person ever presents for help, and the loss goes on through the whole course of the illness even while they take antipsychotics.

The evidence for it:

• A strong positive correlation between the clinical potency of first-generation antipsychotics (chlorpromazine, fluphenazine, haloperidol) and their affinity for the dopamine D2 receptor
• High doses of drugs that dramatically increase dopaminergic transmission — levodopa, cocaine, amphetamine — produce a schizophrenic-like psychosis, reversed by dopamine blockers

The glutamate hypothesis, which sits alongside it:

• Underactivation of glutamate NMDA receptors contributes to schizophrenia
• CSF glutamate concentrations are reduced, with decreased cortical glutamate synthesis
• In unaffected individuals, blocking NMDA receptors with phencyclidine or ketamine facilitates BOTH positive and negative symptoms — which the dopamine hypothesis alone does not do

HALLUCINATIONS — a perception experienced without external stimulation of the sense organs:

• Auditory — hearing voices; voices commenting and voices conversing are listed separately
• Visual — images of animate and inanimate objects
• Somatic-tactile — experiencing touch or electrical sensations
• Olfactory and gustatory — unpleasant odours or tastes
• They may occur alone or together

DELUSIONS — a persistent belief contrary to the educational and cultural background of the individual:

• Persecutory and paranoid — spying, conspiracy, persecution, ridicule
• Grandiosity; guilt; religious; somatic
• Delusions of being controlled, of mind reading, of reference
• Thought broadcasting, thought insertion, thought withdrawal
• Referential delusions personalise ordinary stimuli — the textbook's example is believing a television talk show host is directing information specifically at them

POSITIVE FORMAL THOUGHT DISORDER / DISORGANIZED SPEECH — fluent speech that is difficult to comprehend:

• Derailment and loose associations — moving from one topic to another unexpectedly and illogically
• Tangentiality, circumstantiality, illogicality, incoherence
• Pressure of speech; distractible speech — becoming easily distracted while talking
• Poverty of content — a fair amount of spoken words conveying little information, the same phrases repeated throughout a conversation

BIZARRE BEHAVIOR — the conceptual equivalent of disorganized speech:

• Aggressive, agitated
• Clothing and appearance; poor personal hygiene
• Repetitive, stereotyped — the textbook's example is stereotyped rocking; also aimless behaviour
• Social and sexual behaviour
• Incongruity of affect — inappropriate situational affect, such as hostility without provocation or child-like silliness in sober situations
• Difficulty engaging in goal-directed activities

For contrast, the negative dimensions — deficits in normal functioning: affective flattening (near absence of emotional or facial expression), anhedonia (unable to experience pleasure or pain, with a sense of detachment), alogia (absence of spontaneous speech), and avolition (a deficit in spontaneous or goal-directed behaviour, such as completing simple daily tasks).

The symptoms, as the textbook lists them:

• Elevated mood
• Irritable mood
• Inflated self-esteem
• Decreased need for sleep
• Excessive talking
• Racing / crowded thoughts
• Distractibility
• Increase in goal-directed activity
• Excessive risky activities

What it looks like:

• Elevated euphoria and self-esteem, and feelings of grandiosity
• Energy greatly enhanced after only a few hours of sleep each night — but the increased energy does not lead to organised plans and thoughts
• Poor judgement in spending money, becoming hypersexual, making poor business commitments
• Excessive, rapid, loud and pressured speech; skipping from one topic of conversation to another
• Easily distracted both when speaking and when performing tasks
• The deck adds hyperactivity and agitation

Approximately 50% of manic individuals develop psychotic symptoms — delusions or hallucinations — which require hospitalisation. Mania symptoms may significantly impair the individual and trigger psychosis.

Course: mania tends to switch on and switch off abruptly, running anywhere from days to months, and a depressive phase typically follows it. Recurrence risk is high, and higher still when treatment is delayed.

Prevalence of bipolar disorder runs 3% to 5% of the general population, with twin concordance reaching 62% in monozygotic and 42% in dizygotic pairs. Leave either mood disorder untreated and physical illness follows for a proportion of patients — cardiovascular disease, obesity, diabetes, thyroid disease.