Articles to Read by End of Second Year
One of the first papers to introduce the possibility of a neuroleptic-induced supersensitivity psychosis. Assumes tardive dyskinesia (TD) results from neostriatal supersensitivity. Schizophrenia (as opposed to other forms of psychosis) is, at its core, a disease of dopamine deficiency in one area of the brain leading to hypersensitivty in another area. Mania with psychotic features, therefore, would not be subjected to NIS. On withdrawal, patients develop psychosis with POSITIVE symptoms only. In fact, negative symptoms seemed to improve. On withdrawal, one would see TD as well. TD, therefore, is not a result of dopamine blockade, but hypersensitivity and would occur in tandem with positive psychotic symptoms during withdrawal.
There are 7 characteristics: 1) Appears immediately after AP are discontinued. Deterioration is often seen at end of injection interval or in QD dosing (TD follows this pattern as well). Recommend split doses. 2) History is consistent with exposure to AP 3) TD occurs in tandem with NIS, therefore TD can help identify deterioration due to natural history of schizophrenia or NIS- if patient also uses anticholinergics that may mask TD but not NIS 4) NIS patients also have high prolactin 5) patients will develop tolerance to AP and need higher doses 6) most effective treatment is increasing the AP and using an AP with strong DA activity 7) it exists on a continuum
Kane J, Hongfeld G, Singer J, Meltzer H and the Clozaril Collaborative Study Group. Clozapine for the treatment resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789-796
Classic study demonstrating clozapine’s superiority to chlorpromazine in treatment-resistant schizophrenia that led to re-discovery of clozapine in clinical practice
Five-year follow up of the IPSS which found prognosis of schizophrenia was better in developing countries than in the developed world. A favorite among "anti-psychiatry" scientology nut jobs as evidence against use of psychotropic medications, although the study has nothing to do with medication and does not opine on it all. Hypothesizes that in some developing countries studied there is better family support and better social acceptance of the illness (such as in Cali) which affects outcomes. Also speculates that in developing countries there is higher incidence of rapid, acute psychosis that resolves quickly therefore has better prognosis. Overall, authors of the study do not definitely make a conclusion as to why the difference in outcomes exist.
This study shows that if antipsychotics don’t have an effect in the first week, they probably never will, and the most pronounced effects are in the first two weeks of treatment. It was once believed that a phenomenon called “depolarization block” is the reason for delayed response. This is due to inactivation of dopaminergic firing after prolonged exposure to AP. It’s been consistently observed in rat models that this takes 3 weeks. Authors call out these prior studies as having poor methods. Paper stresses difference between delayed onset and delayed realization of full improvement. Does opine that some early improvement may actually be due to reduction in nonspecific symptoms (anxiety, agitation) as opposed to core psychotic symptoms. However, their study showed improvement even when controlling for these factors. Significant because if drug efficacy can be predicted in 1 week, we can make changes more confidently.
A modern classic, this paper describes how the dopamine hypothesis can explain the positive symptoms of schizophrenia. Diagnostic level = mind/behavioral level (phenomenology); Treatment level = neurobiology and pharmacologic. Dopamine is a neurochemical "wind" that stokes the psychotic fire. Key concept: Dopamine mediates the conversion of neural representation of external stimuli from neutral information into either an attractive or aversive entity. The "attribution of salience" is a process whereby thoughts and events grab attention and drive goal-directed behavior because of their association with reward and punishment. In normal brains, dopamine does not create this process, it simply mediates it. However, in the abnormal, schizophrenic brain, dopamine actually creates salience, albeit aberrant ones. Before psychosis actually develops in a schizophrenic, patients experience a perplexing and anxiety-laden state marked by exaggerated importance of certain ideas. This is not usually observed by the clinician because patients present after psychosis has developed. Ask the patient about this, and they will tell you about how they developed a greater "awareness" of the world around them.
On delusions: A patient struggles to make sense of a particular experience when aberrant salience is imposed upon it, leading to "psychotic insight" which serves as a guide for future thoughts and actions. On hallucinations: similar concept but is a more direct process in which aberrant salience affects memories and perceptions.
Despite dampening of aberrant salience (excessive neurochemical activity), the delusion still persists but bothers the patient less so. Studies of the 1950's suggest that anti-psychotics simply induce the subject to "forget" their motive. It modulates the behavior by modulating the significance of it although the core belief is still present. Psychological and cognitive interventions are necessary for resolving the delusion (if possible). The paper states that specific psychotherapeutic techniques, used in tandem with pharmacology, would be feasible in eliminating delusions. Problem: anti-psychotics are not pleasant medications and have a natural tendency to induce dysphoria. They may dampen salience, but they have a side effect of also dampening normal human drive's and reduce pleasure. Research should be taken to find an anti-psychotic that exclusvely dampens one pathway but not the other.
CATIE study showed olanzapine was more effective than other atypical antipsychotics, with no difference between typical and atypical antipsychotics. When developed, atypicals promised better safety profile and at the time of this paper made up 90% of market share of anti-psychotics. Medications studied: Olanzapine, Quetiapine, Risperidone, Perphenazine, and Ziprasidone. Because non-compliance with anti-psychotics is very high, the authors used time until discontinuation as the primary outcome measure. Results: time to discontinuation (due to efficacy) was longer with Olanzapine (so based on this metric it is more effective). In addition, fewer patients in the Olanzapine group were hospitalized during the study. Quetiapine and Ziprasidone may be less effective due to sub-therapeutic doses- most doses were decided based on trying to avoid side effects.
Most anticholinergic: Quetiapine. Most sedating: Olanzapine and Quetiapine. Most weight-gain/syndrome x: Olanzapine. Improvement in syndrome x: Ziprasidone. Increased Prolactin: Risperidone. QTc: no significant difference of any drugs studied. EPS: No differences.
In summary, due to high rate of discontinuation overall (74%) there is substantial limitations in effectiveness of any of these drugs. Olanzapine appears to be the best based on efficacy and reduced hospitalization. Effectiveness of other drugs probably all about the same but difficult to tell due to possibility of inadequate dosing.
CARE study showed adding risperidone to clozapine no more effective than clozapine alone
Jones PB, Barnes TR, Davies L et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1) Arch Gen Psychiatry 2006; 63:1079-87
CUtLASS study was British equivalent of the CATIE using more of the typical antipsychotics and confirming the new drugs cost more and have no additional benefit on quality of life
Kahn RS, Fleischhacker WW, Boter H et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371:1085-97
EUFEST study found that first-episode psychosis like chronic schizophrenia responds just as well to the older drugs as the newer drugs
An extremely clever model uniting Schneider’s first rank symptoms as theory of mind deficits in context of other biological and neuropsychological findings in schizophrenia.
A common mechanism, involving minimization of prediction error (new learning), may underlie perception and inference. Disruption of this mechanism may cause both delusions and hallucinations. Delusions are not the result of disordered reasoning- the symptoms suggest that patients with schizophrenia are particularly related to a sense of passivity- that is, being the subject of an external force. This relates to deficit theory.
Deficit theory: patient persistently attends to stimuli that should be ignored and generates complex accounts of why these stimuli are important; therefore the abnormality lies in the patient’s attention to stimuli as opposed to their attempt to explain why they are important. This may be due to failure to tag these stimuli as self-generated. In other words, this theory states that certain positive symptoms are caused by a deficit in self-monitoring, ie there is misattribution of self-generated actions to others. If there is attenuation of sensory consequences than an active movement would feel like a passive movement and therefore appear as if one’s actions were controlled by an external force.
Predictability of one’s own actions allows one to easily understand the action, and its sensory consequences become dampened. Predictable results are easy to ignore. Unpredictable events (which appear external) are hard to ignore. Indeed, it is essential to experience these stimuli and incorporate them into an updated understanding of the environment. This has been objectively studied.
Logical reasoning is not actually impaired in patients with schizophrenia; rather it is a defect in probabilistic reasoning. A belief is simply a probability that something about the world is true. Deficit in integration of new knowledge into beliefs is central to delusions. Deluded patients jump to conclusions and are more inflexible in changing their beliefs when faced with dis-confirmatory evidence.
Blocking is a phenomenon that states new learning results 2 co-occurring stimuli generates surprise (aka prediction error). Partial loss of this effect is seen in schizophrenia (and with use of amphetamines) resulting in abnormalities in prediction error. Prediction error is regulated by dopamine- increased dopamine causes learning from gains but no learning from losses- speculates this explains why gambling addiction is sometimes associated with patients treated with dopamine agonist. To apply this to schizophrenia, increased dopamine causes delusions to become resistant to being disproved because evidence in favor of the delusion (gain) is reinforced but evidence against the delusion (loss) is ignored.
There is a hierarachy of beliefs: lower levels (perception) and higher levels (beliefs). Positive symptoms of schizophrenia result from an abnormality of the brain inference mechanism such that new evidence (stimuli) is not properly integrated leading to false prediction errors (or false learning).
Tl;dr: Delusions are result of impairment in integrating new information due to abnormal learning processes and a deficit in probabilistic reasoning. This is physiologically related to dopamine which affects the salience of experiences and causes resistance to disproving fixed, false beliefs.
This study found clozapine was associated with reduced morality in comparison to other antipsychotics or no treatment in schizophrenia
This paper shows that dopamine dysregulation is not found in those with treatment resistant schizophrenia and thus dopamine antagonists are worthless in these patients.
25-35% of patients with schizophrenia show limited response to anti-psychotic agents. At least 50% dopamine receptor occupancy is necessary to generate a response in most patients. Earlier studies found that some patients achieved this occupancy but did not respond. Therefore, D2 occupancy may be necessary but not sufficient in many cases. It is proposed that either these patients have lower uptake or an exceptionally hyperactive dopaminergic system causing resistance. PET imaging was used to assess dopamine uptake in this study. The conclusion is that treatment-resistant patients have significantly lower dopamine synthesis capacity. They note that plasma homovanillic acid (dopamine metabolite) is higher in patients that respond to treatment. Higher synaptic dopamine levels also correlated with improved treatment outcomes. One question raised was, is treatment resistant schizophrenia related to the stage of the disease or does it represent a specific sub-type? A prior study demonstrated that treatment resistance was present throughout the course of the subjects' illnesses, implying that treatment response was dependent on the sub-type.
This suggests either that patients with treatment-resistant illness start with a different underlying pathophysiology or that antipsychotics have an effect on their dopamine synthesis capacity, albeit one that does not reduce symptoms. Future studies are necessary to replicate these findings and determine which other neurotransmitters are involved. Given the success of clozapine, which has relatively low D2 activity, it is proposed that the glutamate system and its interaction with other neurotransmitters may be an important factor in this sub-group.
Important study finding that both antipsychotics and duration of relapses cause brain shrinkage- also suggest using the lowest doses possible. Schizophrenics have loss of brain volume, but why? First, definition of relapse needs to be established. Relapse was historically defined as 1) number of hospotalizations OR 2) increase of 25% of symptom severity. Modern definition includes 6 components: hospitalization, rating scale change, self injury, violence, SI, or clinicians judgement of worsening symptoms.
Next, is brain volume loss due to schizophrenia or the high doses of antipsychotics that accompany relapse management? Prior evidence suggest that there are 4 predictors of brain tissue loss in order of most significant (each controlled for the other 3): intensity of treatment = illness duration > illness severity >>> substance abuse (almost no effect). This study looks at two new predictors: time spent in relapse and number of relapses.
For this study a relapse was defined as a rating of moderately severe symptoms for 1 week for any 1 positive symptom or at least 2 negative symptoms. Also used the above criteria (csernansky) for comparison.
Results: relapses early in disease were frequent but brief, later relapses were longer but less often. Greater relapse duration was associated with global tissue loss more pronounced in frontal lobe and white matter. Number of relapses was not associated with tissue loss. After controlling for other factors, treatment intensity was also studied and found global tissue loss. 0.56 cc / 4 mg haldol year (.56 cc of brain is loss each year in a patient who is on 4 mg haloperidal equivalent dosing/day) which is much smaller than animal studies which suggest 10% brain loss each year. Limitations: confounders- patients with a more severe variant of schizophrenia may have both longer relapses and more tissue loss. Also treatment is naturalistic, random assignment protocol would be preferred but is unrealistic.
Summary: Probably, duration of relapse and intensity of treatment contribute most to tissue loss although there are some confounders and the mechanism for either is not yet known. Number of relapses does not contribute. A mechanism has been postulated: glutamate excitotoxicity mediated by dopaminergic systems.
Extremely useful review of the field of prodromal or at-risk mental state.
The high risk state (HRS) is a relatively new construct used to define the potentially prodromal symptoms of schizophrenia. Its utility is in developing treatment for the prevention of psychotic disorders. Symptoms of HRS is non-specific and suggests that schizophrenia is only one possible outcome. It is analogous to chest pain in that there are many possible underlying etiologies. Schizotypal PD is, clinically, most similar to the high risk state and shares the most characteristics.
Prodromal symptoms on average lasted 5 years and was observed in 73% of cases of first time psychosis. There are two broad sets of criteria used to diagnose the HRS: UHR and BS criteria. UHR requires one or more: attenuated psychotic symptoms (APS), brief limited intermittent psychotic episode (BLIP), genetic risk and marked deterioration syndrome (GRD). There are multiple interview methods developed to make an assessment. BS is more subjective and assesses disturbances in perception, thought process, language and attention. BS suspected to detect very early prodromal state and UHR later. However, less than 40% of patients who have prodromal symptoms actually develop psychosis. Some people develop prodrome that resolves only to re-emerge later as full blown psychosis (outpost syndrome). Negative symptoms are also very prominent and social impairment, in particular, is a predictor of long-term outcome. Lots of different imaging studies have been done with variable results. Most promising is PET dopamine striatal uptake studies which have shown elevated dopamine synthesis.
Predicting transition to psychosis. Negative predictive value (NPV) of BS in HR individuals is 96%. Psychosis transition predicted mostly by executive and verbal impairment in addition to anhedonia and asociality. There are no reliable recommendations for prevention of transition- CBT, omega 3, and antipsychotics were 3 treatments the study suggested may be beneficial.
DSM-5 update: HRS has been excluded from the DSM-5. Although authors agree that it is a valid syndrome, it has unreliable diagnostic criteria and uncertainty of what to do with such a diagnosis (no agreed upon treatment strategy). The concern is that such a diagnosis may result in inappropriate treatment with anti-psychotics, etc.
This meta-analysis shows substantial differences in efficacy and side-effect profiles of different antipsychotic agents with clozapine, amisulpride and olanzapine coming out as most effective, and asenapine, lurasidone, and iloperidone coming out as least effective
Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013; 70:913-920
Controversial study that confirms older data that continued antipsychotic use leads to poorer functional outcomes with better symptom control than discontinuation/early dose reduction
Kuhn R. The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J Psychiatry 1958; 115:459-464
First paper to describe the use of TCA imipramine and suggest it is particular beneficial in melancholic depression
West ED, Dally PJ. Effects of iproniazid in depressive syndromes. Br Med J 1959; 1:1491-1494
One of the first papers to report MAOIs are effective especially in atypical depressions
Fava GA. Can long-term treatment with antidepressant drugs worsen the course of depression? J Clin Psychiatry 2003; 64:123-133
Nearly every branch of medicine has treatments that can potentially aggravate a condition it is trying to treat. First time this applied to psych was 1994 when it was suggested that long-term antidepressant use may cause a biochemical vulnerability to depression and worsen the illness in addition to decreasing liklihood of future reponse.
States that duration of treatment has no effect on prognosis. In fact, statistical trends show higher liklihood of relapse with longer treatments. Many studies have showed similar results: relatively short treament (less than 24 weeks) shows benefit compared to placebo but longer treatment (after 62 weeks) showed no benefit. These studies suggest antidepressants do not have a protective effect after 6 months. Course of recovery after discontinuation was identical. This has an interesting implication: anti-depressants may not actually change the pattern of recovery, but simply speeds up the natural course. This also applies to antidepressants causing rapid cycling in bipolar.
Several older studies with MAOIs and TCAs showed higher relapse in patients who were treated and had very mild depression. Also been seen that treating panic disorder with SSRI has increased liklihood of unmasking a depressive disorder.
Oppositional model of tolerance: continued drug treatment may recruit processes that oppose the initial acute effects of drug alteration.
Long been hypothesized that antidpressants restore a disturbed balance between 5HT1a, b and 5-HT12. Possible that, under certain conditions, they may actually cause an imbalance. Speculated that 5-HT1 and 2 are part of a common pathway of the HPA axis. 5-HT2 receptor antagonist (ketanserin) used in Cushing's Disease yields temporary decrease in ACTH. Studies have shown that in patients with normalized HPA axis, antidepressants may recruit ACTH activation resulting in loss of clinical effect.
"We strongly suspect that many patients who are simply unhappy or dysphoric receive these drugs, with predictable consequences in terms of morbidity from side ffects, mortality from overdose, economic waste, and irrational, unproductive clinical management"
Conclusion: there is insufficient data to suggest antidpressants cause depression; however what is good for the average patient may be detrimental to a minority. When antidepressant tratment is prolonged more than 6-9 months, we may inadvertently recruit different phenomena such as tolerance, episode acceleration, and paradoxical effects. Commonly shared clinical assumptions (longer treatment is better) are challenged by research evidence.
Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, Sertraline, or Venlafaxine-XR after failure of SSRIs for Depression. N Engl J Med 2005; 354:1231-1242
STAR*D trial finds only 20% remit after one failed antidepressant, and bupropion, sertraline and venlafaxine are just as bad as each other
Trivedi MH, Fava M, Wisniewski SR et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243-1252
STAR*D trials finds augmentation strategies all as bad as each other and no better than switching to another agent
Fava M, Rush AJ. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psychosom 2006; 75:139-153
This paper from the STAR*D team outlines how to maximize initial response and engagement in treatment and proposes using combined or augmentation strategies much earlier than is the case
McGrath PJ, Steward JW, Fava M et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry 2006; 163:1531-1541
STAR*D report finds response rate after three failed antidepressants is about 14% and that combo of venlafaxine and mirtazapine is easier to use and better tolerated than tranylcypromine
Trivedi MH, Rush AJ, Wisniewski SR et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 28-40
STAR*D study finds remission rates only 30% for first trial of citalopram and that it takes about 6-8 weeks to note remission, longer than previously claimed
Beck AT. The evolution of the cognitive model of depression and its neurobiological correlates. Am J Psychiatry 2008; 165:969-977
It is now possible to sketch out possible genetic and neurochemical pathways that interact with or are paallel to cognitive variables. A hypersensitive amygdala, for example, is connected with patterns of negative beliefs. This, in combination with hypoactive prefrontal cortex is associated with diminished cognitive appraisal.
Beck gives background into why he developed CBT. He was interested in the paradox between depression and the natural instincts of self-preservation, sex, and pleasure. Leading hypothesis of his time was that depression was inward hostility.
Cross-sectional Model: Initially, he studied dreams of his patients believing he'd find hostile dream content in depressed patients but he found the opposite. Dream content appeared to contain the same themes as patients concious cognitions- negative self-evaluation but in a far more exaggerated form. He saw that in dreams there was extreme distortions in the interpretation of the experience. When Beck corrected these misinterprations, depression seemed to lift after about 10-12 sessions.
He identified two core factors: 1) negativity about one-self and 2) systematic cognitive bias in information processing leading to selective attention to negative experiences. Dysfunctional attitudes are embedded within cognitive structures (or schemas) and therefore have structural qualities such as stability, density, thresholds, and levels of activation. The salience of the schema is dependent on the intensity of the negative experience and the threshold for activation (successive stressful experiences). When schmas are activated, they skew information processing which directs the patients attention to negative stimuli which translates an experience into a distorted negative event. These negative schemas are hypersalient and therefore lead to global negative perceptions about reality.
Developmental Model: parental loss correlated to adult depression because negative schemas develop at time of the loss and are re-activated later.
Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009; 373:747-758
Mirtazapine and venlafaxine are the most efficacious, duloxetine and reboxetine don’t work, and sertraline or citalopram are probably the best first-line agents for depression
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Adminstration. PLOS Med 2008; 5:e45 doi:10.1371/journal.pmed.0050045
The best known study to report from unpublished data that antidepressants are no better than placebo except in the most severe depressive episodes
Harmer CJ, Goodwin GM, Cowen PJ. Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Br J Psychiatry 2009; 195:102-108
An attempt at explaining antidepressant action in cognitive neuropsychological terms
Classic paper that first used lithium to treat mania, absolute must read. Lithium first used in gout. As it became more widely used, an antidepressant effect was noticeable. Over time toxic effects became noticeable- in particular cardiac depression and upset stomach.
In 1927 Lithium Bromide was seen as the most potent bromide this was believed to be due to the small atomic weight of Lithium, therefore the bromide ion was believed to be the active ingredient. At the time, Lithium was widely used in epilepsy but after it's toxicity was discovered (due to Lithium not the bromide) it fell out of favor. LiBr was eventually phased out for Li Urate and finally Li Carbonate which is the least toxic of the 3. In 1944 the British discovered that some wells in the UK contained high concentrations of Lithium and populations who ingested this water had low incidence of mental illness.
Paper goes on to discuss 10 cases. Patients generally suffered from a "chronic manic excitement" averaging about 5 years although some cases were "recurrent". Most were older, 40-60. They were all inpatient. Dramatic results with a range of 10-20 'grains' of Lithium BID - TID. (1 grain = 65 mg) Many discharged. Many relapsed after poor compliance, readmitted, successfully treated and discharged again. There were also 6 cases of patients with schizophrenia taking Li. Patients became sedated and less agitated but otherwise no fundamental improvement.
Paper states that in theory Lithium should cause a depressive state as it is anti-manic. Li Citrate tolerated up to 20 grains TID (this is 1300 mg TID or 3900 per day). Li Carbonate = 1/2 of Li Citrate dose. Start with highest dose and reduce dose by about half based on patient response. Give after meals.
Concludes stating that maybe Lithium is a better alternative to lobotomy.
Janowsky DS, Epstein RS. Playing the manic game –interpersonal maneuvers of the acutely manic patient. Arch Gen Psychiatry 1970; 22:252-26
Describes the frustrating and destructive maneuvers ‘manic’ patients catch clinicians in. Possibly more relevant to borderline patients, I find this slightly outmoded and offensive, but seems well-loved by more seasoned psychiatrists of all stripes
Yonkers KA. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004; 161:608-620
Nice review of management of bipolar disorder in women
Nierenberg AA, Ostacher MJ, Calabrese JR et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry 2006; 163:210-216
Bipolar depression is hard to treatment and augmenting antidepressants with lamictal, inositol or risperidone are just as bad as each other
Miklowitz DJ, Otto MW, Frank E et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhanced Program. Arch Gen Psychiatry 2007; 64:419-426
Shows family focused therapy, IPSRT and CBT as useful therapies in treatment of bipolar depression
Sachs GS, Nierenberg AA, Calabrese JR et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007; 356:1711-1722
STEP-BD study found antidepressants don’t work in bipolar disorder
Geddes, JR, Goodwin GM, Rendell K et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomized open-label trial. Lancet 2010; 375:385-395
Lithium is better than valproate, and there benefit of combining the two isn’t clear
Cipriani A, Barbui C, Salanti G et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011; 378:1306-1315
This meta-analysis finds that antipsychotics are the best treatment for acute mania rather than lithium or mood stabilizers.
McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012; 379:721-728
Toxicity of lithium has been overblown with ESRD being a rare complication. Li also causes hyperparathyroidism and checking Ca periodically is recommended
Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 2013; 346:f3646
Updated meta-analysis finds lithium still appears to have anti-suicidal properties
Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet 2013; 381:1672-1682
Reviews the evidence for pharmacological and psychological treatments in bipolar disorder
Rosen DH. Suicide survivors. A follow-up study of persons who survived jumping from the Golden Gate and San Francisco-Oakland Bay Bridges. West J Med 1975; 122:289-294
Classic study interviewing survivors of the Golden Gate Bridge attempted suicides argues for suicide barriers. Must read.
Harris EC, Barraclough B. Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry 1997; 170:205-228
Meta-analysis finds mental disorders except for mental retardation and dementia increase risk of suicide
Suicide is a global problem. Mood disorders account for 60% of suicides. 66% of suicide victims have contact with a PCP within 1 month of the suicide.
Suicide experts from 15 countries met and identified 5 areas of prevention: 1) education and awareness 2) screening for high risks people 3) treatment 4) restricting access to lethal means 5) media reporting suicide.
1) - PUBLIC - modest effects on public attitudes regarding treatment of depression BUT no effect on primary outcomes such as people seeking treatment or suicide attempts; PCPs - Many studies (mostly european) showed that educating PCPs had favorable outcomes 2) - SCREENING - asking about suicide does not increase behavior, screening increases diagnosis and treatment but no evidence it reduces suicidal behavior 3) - TREATMENT - RCTs of medication has not reduced suicide perhaps due to low incidence of suicide however areas with higher Rx rates in US and Europe show correlation to low suicide rates. Regarding psychotherapy- CBT halved the reattempt rate in suicide 4) - MEANS PREVENTION - multiple means prevention (barriers on bridges, less toxic medicines, gun control) have all resulted in lower suicide rates 5) - MEDIA - responsible reporting can reduce
Conclusion: Best prevention strategy is PCP education and means restriction. While SSRI efficacy is established at treating MDD and theoretically reduces suicide attempts, this association needs to be studied directly.
A comprehensive but biased review of suicide prevention strategies that places too much emphasis on clinical approaches and not enough on means prevention but still worth reading
Stone M, Laughren T, Jones ML et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009; 339:b2880
Extensive meta-analysis of clinical trials showing that risk of suicidality is age-related, and antidepressants may reduce suicides in the elderly
Gitlin MJ. A psychiatrist’s reaction to a patient’s suicide. Am J Psychiatry; 156:1630-1634
Discusses the experience of losing a patient to suicide
Ehlers A, Clark DM. A cognitive model of posttraumatic stress disorder. Behav Res Therapy 2000; 38:319-345
An insightful and extremely useful model for understanding chronic PTSD from the cognitive perspective
Summerfield D. The invention of posttraumatic stress disorder and the social usefulness of a psychiatric category. Br Med J 2001; 322:95-98
Provocative discussion of PTSD as a sociopolitical construct
Roy-Byrne PP, Craske MG, Stein MB. Panic disorder. Lancet 2006; 368:1023-1032
Concise overview of panic and its treatment
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. soldiers returning from Iraq. N Engl J Med 2008; 31:453-463
mTBI is common in OIF Veterans and often highly comorbid with PTSD symptoms
Abramowitz JS, Taylor S, McKay D. Obsessive-compulsive disorder. Lancet 2009; 374:491-499
Summarizes cognitive-behavioral and biological aspects of OCD and its treatment
Groves JE. Taking care of the hateful patient. N Engl J Med 1978; 299:883-887
Classic paper describes 4 ‘hateful’ patients in the medical setting
Vaillant GE. The beginning of wisdom is never calling a patient a borderline; or, the clinical management of immature defenses in the treatment of individuals with personality disorders. J Psychother Pract Res 1992; 1:117-134
Classic, extremely well written and useful discussion of managing different defenses in difficult patients
Kernberg O. Borderline personality organization. J Am Psychoanal Assoc. 15:641-685
Classic psychoanalytic paper popularizes the borderline personality organization construct which is described from different psychodynamic perspectives
Leichsenring F, Leibing E, Kruse J, New AS, Leweke F. Borderline personality disorder. Lancet 2011; 377:74-84
Comprehensive review of borderline personality disorder and its treatment. The drugs don’t really work.
Yager J, Andersen AE. Anorexia nervosa. N Engl J Med 2005; 353:1481-1488
Concise summary of management of anorexia nervosa
Treasure J, Claudino AM, Zucker N. Eating disorders. Lancet 2010; 375:583-93
Nice overview on biology of eating disorders and review of evidence for different therapies
Khantzian EH. The self-medication hypothesis of addiction. Am J Psychiatry 1985; 142:1259-1264
This psychodynamic view of addiction as self-medication has proved enduring and influential in clinical practice and popular culture despite no supporting evidence
Project MATCH Research Group. Matching alcoholism treatments to client heterogeneity: project MATCH three-year drinking outcomes. Alcohol Clin Exp Res 1998 22:1300-1311
12-step facilitation, CBT, and motivational interviewing are all beneficial in alcoholism, with patient characteristics helping to match best treatment. Angry alcoholics do better with MI.
Johns A. Psychiatric effects of cannabis. Br J Psychiatry 2001; 178:116-122
Reviews the psychiatric complications of cannabis use
Arsenault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ 2002; 325:1212-1213
First prospective longitudinal study to establish adolescent cannabis use as a risk factor for psychosis
Koston TR, O’Connor PG. Management of drug and alcohol withdrawal. N Engl J Med 2003; 348:1786-1795
Comprehensive overview of withdrawal syndromes and their management
Anton RF, O’Malley SS, Ciraulo DA et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA 2006; 295:2003-2017
Naltrexone is better than acamprosate for alcohol dependence when combined with CBT
Laaksonen E, Koski-Jannes A, Salspuro M, Ahtinen H, Alho H. A randomized, multicenter, open-label, comparative trial of disulfiram, naltrexone and acamprosate in the treatment of alcohol dependence. Alcohol Alcohol 2008; 43:53-61
Disulfiram may actually be better than naltrexone or acamprosate when combined with behavior therapy in alcohol dependence
Van Winkel R, Kahn Rs, Linszen DH et al. Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. Arch Gen Psychiatry 2011; 68:148-57
Shows gene-environment interaction between SNPS in AKT1 and cannabis use in increasing risk of psychosis which has been replicated, unlikely previous studies involving SNPs of COMT
McKetin R, Lubman DI, Baker AL, Dawe S, Ali RL. Dose-related psychotic symptoms in chronic methamphetamine users: evidence from a prospective longitudinal study. JAMA Psychiatry 2013; 70:319-324
First prospective longitudinal study to establish causal relationship and dose-dependence between methamphetamine use and psychosis
Volkow ND, Swanson JM. Clinical practice: adult attention deficit-hyperactivity disorder. N Engl J Med 2013
Up-to-date review of adult ADD
Bowlby J. The making and breaking of affectional bonds. I. Aetiology and psychopathology in the light of attachment theory. An expanded version of the Fiftieth Maudsley Lecture, delivered before the Royal College of Psychiatrist, 19 November 1976. Br J Psychiatry 1977; 130:201-210
Very readable paper summarizes key findings of attachment theory and its relevance to psychopathology throughout the lifespan
Rutter M, Sroufe LA. Developmental psychopathology: concepts and challenges. Dev Psychopathol 2000; 12:265-296
The father of child psychiatry outlines the developmental approach to psychopathology
Baron-Cohen S. The extreme-male brain theory of autism. Trends Cogn Sci 2002; 6:248-254
This paper gives a compelling account of autism as the extreme variant of the ‘male brain’
March J, Silva S, Petrycki S et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescences with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 2004; 292:807-820
TADS study showed combination of CBT and fluoxetine was best treatment for adolescent depression
Jensen PS, Arnold LD, Swanson JM et al. 3-year follow-up of the NIMH MTA Study. J Am Acad Child Adolesc Psychiatry 2007; 56:989-1002
Important ADHD study showed benefits of stimulant treatment did not persist after initial phase of treatment compared with behavior therapy
Sikich L, Frazier JA, McClellan J et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizoaffective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165:1420-31
TEOSS study finds molindone (now defunct) is just as good as the newer drugs in early onset psychotic disorders
Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer’s disease. IV: Disorders of behavior. Br J Psychiatry 1990; 157:86-94
Outlines the most common behavioral disturbances in Alzheimer’s from a sample of 178 patients, and finds features of Kluver-Bucy syndrome occur more commonly than is realized
Howard RJ, Juszszak E, Ballard CG t al. Donepezil for the treatment of agitation in Alzheimer’s Disease. N Engl J Med 2007; 357: 1382-1392
Donepezil doesn’t help agitation in context of Alzheimer’s disease
Howard RJ, McShane R, Lindesay J et al. Donepezil and memantine for moderate-to-severe Alzheimer’s Disease. N Engl J Med 2012; 366:893-903
There is a small functional benefit to donepezil or memantine in moderate-to-severe Alzheimer’s with no difference between the two and no additional benefit of the combination
Inouye SK. Delirium in older persons. N Engl J Med 2006; 354:1157-1165
Nice overview of diagnosis, causes and management of delirium in the elderly
McKeith IG, Dickson DW, Lowe J et al. Diagnosis and management of dementia with Lewy bodies. Neurology 2005; 12:1863-1872
Most recent guidelines for diagnosis and management of LBD
Saczynski JS, Marcanonio ER, Quach L, Fong TG, Gross A, Inouye SK, Jones RN. Cognitive trajectories after postoperative delirium. N Engl J Med 2012; 367:30-39
Reminder that most patients post-delirium do not return to baseline and experience significant decline in cognitive functioning
Schneider LS, Tariot PN, Dagerman KS et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006; 355:1528-1538
CATIE-AD study compares antipsychotics for Alzheimer’s – they are all as bad as each other and do more harm than good
Definitive review of decisional capacity assessment for clinicians
Barsky AJ, Saintford R, Rogers MP, Borus JF. Nonspecific medication side-effects and the nocebo phenomenon. JAMA 2002; 287:622-627
Describes the nocebo effect as a common occurrence in anxious patients, and a cognitive model for understanding its development
Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, Torsades de pointes, and psychotropic medications. Psychosomatics 2013; 54:1-13
Comprehensive up-to-date review on QTc prolongation and psychotropic drugs. Turns out we vastly overestimate the significance of cardiac risk of drugs.
Block SD. Psychological issues in end-of-life care. J Palliat Med 2006; 9:751-772
Comprehensive review of psychological problems and psychiatric disorders at the end-of-life
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005; 352:1112-1120
Comprehensive review of serotonin syndrome comparing it to other differentials
Eastwood S, Bisson JI. Management of factitious disorders: a systematic review. Psychother Psychosom 2008; 77:209-218
Systematic review of case reports and series of factitious disorder highlighting bleak prognosis and difficulties keeping these patients engaged in care.
Groves JE. Management of the borderline patient on a medical or surgical ward: the psychiatric consultant’s role. Int J Psychiatry Med 1975; 6:337-48
Practical suggestions on how to manage difficult patients in the medical setting
Kayser MS, Kohler CG, Dalmau J. Psychiatric manifestations of paraneoplastic disorders. Am J Psychiatry 2010; 167:1039-1050
Discusses the emerging field of autoimmune-mediated neuropsychiatric disorders
McDermott BE, Feldman MD. Malingering in the medical setting. Psychiatr Clin N Am 2007; 30:645-662
Detailed review of malingering and its detection
Stone J, Carson A, Sharpe M. Functional symptoms and signs in neurology: assessment and diagnosis. J Neurol Neurosurg Psychiatry 2005; 76(Suppl I): i2-i12
Stone J, Carson A, Sharpe M. Functional symptoms and signs in neurology: management. J Neurol Neurosurg Psychiatry 2005; 76(Suppl I): i13-21
These two papers discuss the assessment and management of conversion disorder including examination maneuvers for eliciting functional neurology
1/3 of new neuro outpatients are regarded as "not at all" or "somewhat" explained by disease. Paper stresses that neurologist should not be irritated by functional symptoms but should be interested in them.
Ask questions about physical symptoms first and mood last. The more physical symptoms that present the less likely the complaint will be explained by disease. When asking about mood, frame the question in context of symptoms: "do your symptoms make you feel down or frustrated?" Don't forget to ask about feelings of dissociation which is relatively common. Do not ask about abuse or neglect until future visits.
3 nuggets: 1) inconsistently tells you its functional but not concious or unconciously produced. 2) functional signs do not exclude possibility of also having the disease 3) all exam manuevers are limited in sensitivity, specificity, etc.
Hoover sign: raise unaffected leg straight up, if weakness is functional, the affected leg will press down. May be positive in case of cortical neglect.
Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry 2007; 164:870-876
Up to date review of neuroleptic malignant syndrome
Anjala AV, Smetana GW. Medical evaluation of patients undergoing electroconvulsive therapy. N Engl J Med 2009; 360:1437-1444
Discusses the medical workup and preparation of patients for ECT
Rose D, Fleischmann P, Wykes T, Leese M, Bindman J. Patients’ perspectives on electroconvulsive therapy: systematic review. BMJ 2003; 326:1363
This user-led study reveals that autobiographical memory problems persist more commonly than is believed
UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet 2003; 361:799-808
The most comprehensive meta-analysis of ECT for depression showing its efficacy in depressive states
Kendell RE, Cooper JE, Gourlay AJ, Copeland JRM, Sharpe L, Gurland BJ. Diagnostic criteria of American and British psychiatrists. Arch Gen Psychiatry 1971; 25: 123-130
The UK-US diagnostic study showed American Psychiatrists diagnosed more schizophrenia than their British counterparts in every case, including cases of depression, manic-depressive illness and even personality disorder, establishing importance of reliability in psychiatric diagnosis
Murphy JM. Psychiatric labeling in cross-cultural perspective. Science 1976; 191:1019-1028
This paper describes the concept of madness or mental illness existing across cultures dispelling mental illness as the result of simply labeling deviance or a convenient myth
Rosenhan DL. On being sane in insane places. Science 1973: 179:250-258
This classic study questioned the validity of psychiatric diagnosis by having pseudopatients get admitted to psychiatric hospital who then remained there despite no further reports of symptoms of mental illness!
Old paper (1977), possibly a bit outdated in some areas but otherwise a sensible position on biopsychosocial model. Engel argues that the problem with psychiatry (namely, a desire to medicalize diagnoses) is the same problem with medicine as a whole. He states that Medicine is in a crisis because physicians are not concerned with psychosocial issues and believe that they lie outside of their responsibility. He identifies 2 positions: 1) abandonment of the medical model and eventual dissolution of psychiatry as a profession or 2) strict adherence to the medical model. However, he states that neither of these positions is correct because the medical model of medicine itself is flawed and therefore this is not a crisis of psychiatry but a much larger crisis of the entire medical profession.
Also makes the argument that the scientific biomedical model of disease is just western culture's form of a 'folk' model and is a specific perspective about disease that may not be scientific at all. This creates a dogma that requires discrepant data to be either forced into the model or excluded; as opposed to science where a model is either revised or abandonded when it fails to account for all data. Interestingly, the biomedical model creates a condition in which mental illness can only be classified into 2 groups: reductionist- all behavioral symptoms are reduced to biological phenomenon OR exclusionist- whatever is not capable of being explained is excuded from the category of disease.
Historically, disease has been defined not by biology but changes in behavior. States that reductionism in medicine started about 500 years ago when Christians were premitted the practice of dissection. More importantly, the church forbade the scientific study of the mind and behavior as it saw it as competition with the concept of the soul. All diseases go through a process as following: symptoms (1st) -> syndromes (2nd) -> pathology (3rd). Reductionist argue that psychiatry is stuck at the second stage and simply has not movd on to the third. States that "problems with living" (szasz) or "sick" are defined by the patient and whether or not the patient accepts entry into the health care system. Does give some credit to the profession by stating that psychiatrists are so busy warring among each other they fail to appreciate that it is the only specialty concerned primarily with the study of the human condition.
In summary, medicine is concerned with the "how" but not the "why" or "what for". New theories and knowledge will not shift the paradigm of the biomedical model. Rather, economic forces will need to force the profession to change.
First part regards history of psychiatry and growing interest in psychoanalysis in the 1950's and the divergence psychiatry had from biology and science. Argues that by combining descriptive psychiatry with analysis, the profession was greatly empowered with clinical insight. However, it did so by weakening its ties with experimental medicine. Kandel states that psych as a profession is only partially to blame for this. Neuroscience was an immature science in the 1940's and given that most behavior is correlated to the cerebral cortex and is equipotential is was then (and still now) impossible to localize specific lesions. Prior failures to merge psychiatry with neuroscience is due to this. Later on in the later half of the century the desire to merge the two simply became regarded as unncessary.
Today (or 1998) enough advances in neuroscience have been made to allow for rapprochement with psychiatry. Kandel identifies 5 principles. 1) every mental process is derived from the brain even in situations where a mental disturbance is caused by the environment. 2) genetics is one component of determining mental illness. 3) genetics do not account for all mental illness- he appears to describe epigenetics here and states "nurture is ultimately expressed as nature". 4) Learning causes alterations in gene expression (again, epigenetics?). 5) Psychotherapy works because it does so through learning which therefore induces changes in gene expression that alters the structure and strength of synaptic connections- states that future brain imaging should be able to quantitate the outcome of psychotherapy.
To point 1) he goes on in some detail about the paranoia social scientists have in accepting biology as part of the mind and identifying their misconceptions regarding how genes work (that biological processes are strictly determined by genes and the sole function of a gene is transmission of hereditary information). Corrects these notions by clarifying that genes are simply templates but their transcriptional function is responsive to environmental factors. Point 2) he has a very long discussion on genetics of schizophrenia and basic genetic principles. States that schizophrenia has probably 10-15 loci in the population worldwide and a combo of 3-5 loci is needed to cause the disease in an individual. Points 3 and 4) he emphasizes need for neuropathology of mental illness and better imaging techniques. Also discusses brodmann's areas and how learning can change synapses there. Point 5) there is evidence that parts of the brain change following psychotherapy.
Future psychiatrist will need expert knowledge of the brain- a knowledge that is different but fully comparable to that of a well-trained neurologist. States that there is a paradox where scientifically we are reaching a new high in research and interest in understaning neuroscience and behavior but interest among medical students is low. He attributes lack of medical student interest due to the non-medical nature of psychiatry. States that if we use a biological model we can successfully explain biological as well as psychosocial determinants.
Kendler KS. Explanatory models for psychiatric illness. Am J Psychiatry 2008; 165:695-702
Kendler proposes psychiatric disorders are understood best pluralistically with multiple levels of explanation and biological understanding will not supplant more macro level understanding of disorders but enhance it
Szasz T. The myth of mental illness. Am Psychol 1960; 15:113-118
This classic article of the book with the same title claims because the mind is a metaphor, it cannot be diseased, and thus mental illness is a myth. Szasz prefers to conceive of psychiatric disorders as problems in living. Given the cachet of these views in popular culture, this is essential reading.