OCD treatments - typical and atypical antipsychotics, capsulotomy, deep brain stimulation are discussed

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Part 1.
Brain Anatomy

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DNA, the Brain, and Human Behavior

Human Brain Development

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Broca's Limbic Lobe, Papez's Circuit, and MacLean's Limbic System

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Subcortical Brain Structures, Stress, Emotions, and Mental Illness

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Part 2:
Neurotransmitters
and Emotional Systems

Brain Neurotransmitters—an Introduction

Brain Neurotransmitters and Illness

Emotions are Hard-Wired in the Brain: Introduction to Ancestral Brain Systems

The SEEKING-VIGILANCE Construct

The Brain's SEEKING System

Attention, Learning, and Memory: The VIGILANCE System

Rage: an Innate Brain System

Fear: an Innate Brain system

PANIC/LOSS: an Innate Brain System

PLAY: an Innate Brain System

The MATING System, the Brain, and Gender Determination

CARE: an Innate Brain System Important to Motherhood

Part 3:
Innate Behavior, Grooming, OCD, and Tourette Syndrome

Depression, Obsessions, and Compulsions: Concepts in Ethology and Attachment Theory

Body Dysmorphic Disorder, Trichotillomania, and Skin Picking

OCD and Tourette Syndrome: Causes and Symptoms

OCD, Dopamine, and the Nucleus Accumbens

   OCD Treatments Including Antipsychotic Medications

Dopamine neurons in the brain.


OCD Treatments Including Antipsychotic Medications

In reading this webpage, it is important to remember that increased dopamine is associated with increased stress and anxiety. I learned this first from Robert M. Sapolsky's Why Zebras Don't Get Ulcers: The Acclaimed Guide to Stress, Stress-Related Diseases, and Coping (2004). Sapolsky writes: When it comes to psychiatric disorders, it seems that increases in the catecholoamines have something to do with still trying to cope and the effort that involves… ." He also defines anxiety as "a disorganized attempt to cope … dominated by catecholamines." Catecholamines include dopamine, norepinephrine, and epinephrine. See Brain Neurotransmitters—an Introduction.

Nic J. van der Wee et al. have conducted a study of serotonin and dopamine levels in patients whose anxiety symptoms were not being treated with medications. "Our study provides direct evidence for the involvement of the brain's dopaminergic system in social anxiety disorder in patients who had no prior exposure to medication," says van der Wee in a Science 2.0 blog entry detailing the study. Also, you may access the full-text article from Journal of Nuclear Medicine.

Regarding OCD, the first-line treatment for obsessions and compulsions is selective serotonin reuptake inhibitors (SSRIs). Unfortunately, SSRIs sometimes do not provide adequate relief from symptoms. In "A Review of Antipsychotics in the Treatment of Obsessive Compulsive Disorder" (2006), Fineberg, Gale, and Sivakumaran write: "Although many individuals with obsessive compulsive disorder (OCD) show significant improvement after treatment with serotonin reuptake inhibitors (SRIs), the treatment effect is usually partial and residual symptoms remain in most cases despite continued treatment." Fineberg, Gale and Sivakumaran conclude that results from placebo-controlled studies using antipsychotics to augment SRI treatment "argue persuasively for further exploration of the efficacy of this approach in resistant cases of OCD."

Before considering an antipsychotic, however, it is important to fully evaluate whether symptoms are a result of obsessions, compulsions, or perseveration. We discuss these symptoms in Displacement, stereotypies, frustration, and perseveration—understanding ADHD, OCD, PTSD, and Tourette Syndrome and then in a second subsection titled Perseveration (ADHD) or compulsion (OCD)?

Insufficient norepinephrine. When one is unable to focus attention and meet expectations, anxiety will result. So resulting symptoms might be a mix of unfocused attention and anxiety. It might be difficult to figure out whether symptoms are related more to inattention and insufficient norepinephrine OR compulsions brought on by accompanying anxiety and increased dopamine. So trying medications such as imipramine and desipramine seems reasonable before trying an antipsychotic.

Insufficient dopamine. As we discuss in The role of norepinephrine and dopamine in ADHD and OCD, lower levels of dopamine release in the nucleus accumbens may be one cause of perseveration. So if perseveration is identified, an antipsychotic could possibly exacerbate symptoms in that it further decreases neurotransmission in dopamine pathways. On the other hand, since it releases "a cascading release of catecholamines," according to Wikipedia, and since dopamine is a catecholamine, psychostimulants such as dextroamphetamine might help.

Excessive dopamine. If excessive dopamine is driving compulsions, then adding a low-dose antipsychotic should help.

So in finding the right medicine(s) to treat what seems like compulsive behavior, the following scenarios are possible:

    Insufficient norepinephrine / Adequate dopamine
    Insufficient norepinephrine / Insufficient dopamine
    Insufficient norepinephrine / Excessive dopamine
    Adequate norepinephrine / Insufficient dopamine
    Adequate norepinephrine / Excessive dopamine
    Adequate norepinephrine / Adequate dopamine / Other cause

In addition to efficacy, there are several other factors to consider when evaluating medicines. First, assessing any dangerous drug interactions is imperative. Secondly, it is important to consider the side effects and risks associated with a particular drug. Finally, it is important to evaluate the relative dosage of a particular drug required to remit symptoms; a lower dose will produce less problematic side effects.

Dopamine and uncertainty:

Denys, Zohar, and Westenberg, in "The Role of Dopamine in Obsessive-Compulsive Disorder: Preclinical and Clinical Evidence" (2004) write: "One way to understand OCD is that the normal cortical inhibition of the amygdala is malfunctioning and that the anxiety responses induced by the amygdala therefore become more intrusive and chronic in patients with OCD. … When dopamine is increased, the ability of the prefrontal cortex to suppress the affective responses generated in the amygdala is attenuated." As we discuss in OCD, Dopamine, and the Nucleus Accumbens, the amygdala inputs directly to the nucleus accumbens, which receives dopamine signaling from the ventral tegmental area (VTA).

As we discuss in OCD and Tourette Syndrome: Causes and Symptoms, the OCD sufferer may have difficulty in knowing that an action is complete. One way to describe the OCD patient is that he/she is overly motivated to complete a task and will keep working at something over and over again trying to get a sense of completion. In The Brain's SEEKING System, we discuss how dopamine is a key neurotransmitter involved in motivated behavior. Denys, Zohar, and Westenberg write: "Recently, Fiorillo et al. demonstrated that dopamine neurons show increased firing during prolonged periods of uncertainty. Subjective uncertainty is a main feature of pathologic gambling and plays a major role in OCD." The abstract for the Denys, Zohar, and Westenberg article follows:

Obsessive-compulsive disorder (OCD) is a frequent and chronic psychiatric disorder that has been linked closely to the serotonin system mainly because of the antiobsessional efficacy of selective serotonin reuptake inhibitors (SSRIs). A limitation of the serotonin hypothesis of OCD is that a substantial number of the patients with OCD show no significant improvement after an adequate trial with SSRIs. There is substantial evidence that these patients may benefit from addition of antipsychotics to their ongoing SSRI treatment, suggesting that dopamine also might play a role in the pathophysiology of OCD. …

Provided here is a link to the Fiorillo et al. article, "Discrete Coding of Reward Probability and Uncertainty by Dopamine Neurons." The authors write: "The coding of uncertainty suggests a possible role for dopamine signals in attention-based learning and risk-taking behavior" (emphasis added). The full-text article is available at no cost with registration.

Does increased serotonin help reduce dopamine levels?

It is my opinion that dopamine antagonists like haloperidol can be helpful in curbing obsessions and compulsions because 1) they reduce stereotyped innate behaviors such as grooming, which we discuss in Grooming, patterns, antipsychotics, and mice. Judith L. Rapoport, in The Boy Who Couldn't Stop Washing: The Experience & Treatment of Obsessive-Compulsive Disorder (1989), notes that at some point, "almost 85 percent of our patients have some grooming or washing ritual." 2) Dopamine antagonists reduce dopamine signaling in the nucleus accumbens, the structure that I contend serves as an actuator to turn on steady-state obsessions and compulsions.

Even so, I do not think we should rule out serotonin as a player in producing obsessions and compulsions. The idea here is that perhaps increased serotonin somehow works to decrease dopamine. Lorrain et al. have found evidence that serotonin release in the lateral hypothalamic area of rats can inhibit dopamine release in the nucleus accumbens. In this case, researchers are studying the release of dopamine in the nucleus accumbens of the male rat before, during, and after copulation. Even so, results may have wider implications. The authors emphasize, in "Lateral Hypothalamic Serotonin Inhibits Nucleus Accumbens Dopamine: Implications for Sexual Satiety" (1999), that their "findings may also provide insights concerning the inhibitory control of other motivated behaviors activated by the NAcc [nucleus accumbens] … ." For a discussion regarding the role of gamma-aminobutyric acid (GABA) in inhibiting dopamine-induced motivation, see Is the nucleus accumbens an actuator?

Why have so few studies addressed the use of typical antipsychotics in treating obsessions and compulsions?

Generally speaking, typical antipsychotics were developed in the 1950s, primarily to treat schizophrenia and other forms of psychosis. Their patents have long expired and, relative to newer medicines, they can be inexpensively obtained.

The Wikipedia entry for antipsychotics explains that "the drugs in the second generation, known as atypical antipsychotics, have been developed more recently, although the first atypical anti-psychotic, clozapine, was discovered in the 1950s and introduced clinically in the 1970s." Many of the newer atypical antipsychotics enjoyed patent protection in the 1990s and the first part of the 21st century so they generated more profit during this time when compared to typical antipsychotics available in generic form.

We will discuss other differences between typical and atypical antipsychotics below.

The question is this: Considering only the treatment of obsessions and compulsions, why have so few research studies been conducted using typical antipsychotics when compared to the number of research studies that have been conducted using atypical antipsychotics?

The importance of understanding whether a drug is an agonist or an antagonist for a given neurotransmitter:

Neurotransmitters such as dopamine, norepinephrine, and serotonin, when released from the axon terminals of neurons, cross the synapse and bind to receptors on nearby neurons. Neurotransmission, in sort of a chain reaction from one neuron to the next, is the result.

Often, for a single neurotransmitter, there are multiple distinct receptors. Psychoactive drugs often bind to at least some of these receptors. Sometimes, a single drug may bind to receptors of more than one neurotransmitter. This binding can have an antagonistic effect on neurotransmitter action from one cell to the next, inhibiting neurotransmission. Thus, the drug is called, for example, a dopamine antagonist or perhaps a serotonin antagonist.

The Wikipedia entry for agonist, as used in pharmacology states: "An agonist is a chemical that binds to a receptor of a cell and triggers a response by the cell. An agonist often mimics the action of a naturally occurring substance." In our discussions, the naturally occurring substances would be neurotransmitters. So generally, an agonist promotes neurotransmission.

There is, however, some complications regarding the use of the terms agonist and antagonist. There are often a variety of receptors for each neurotransmitter, and different receptors have different functions. For example, Levant reported in "The D3 Dopamine Receptor: Neurobiology and Potential Clinical Relevance" (1997) that "Although the D3 receptor has been implicated in numerous behaviors, the receptor is most widely cited in the modulation of locomotor activity… . In contrast to the D2 receptor, in which stimulation is believed to increase locomotion, stimulation of the D3 site appears to inhibit locomotor activity." So it is not enough to know whether or not a drug is an "agonist" or "antagonist" for a particular neurotransmitter. We also need to know exactly what specific receptors a medication targets. This seems to be more of a problem with newer drugs that have actions not yet well understood.

Antipsychotics—risks increase with dosage:

We know that typical antipsychotic drugs such as thioridazine and haloperidol decrease signaling in dopamine pathways. The primary caution regarding these drugs is that higher doses increase the risk of tardive dyskinesia. As it turns out, the newer atypical antipsychotics can also produce tardive dyskinesia. Risk seems to be associated with the dopamine-blocking properties of each drug. So there is good reason to try safer drugs first, such as serotonin reuptake inhibitors or other antidepressants such as imipramine and desipramine as appropriate, and as a fallback plan consider taking the smallest dose possible of an antipsychotic medication that also remits symptoms. A medical doctor specializing in psychopharmacology or a medical doctor familiar with both your symptoms and the neurological causes of OCD can help you make decisions.

It is important to note that the dosage of a typical antipsychotic such as haloperidol or thioridazine, for successful treatment of obsessions and compulsions, might prove to be much lower than that required to treat schizophrenia. From personal experience with OCD, what a psychiatrist would call "chronic, treatment-resistant OCD," I can say that 0.5 mg of haloperidol once daily is very effective in deactivating symptoms without psychotherapy of any sort. Below, you will see recommendations for researchers in the field regarding antipsychotic dose. My view is that one should never take more of an antipsychotic than is absolutely necessary to remit problematic symptoms. You do not want to unnecessarily suppress your natural motivation.

In the previously cited "A Review of Antipsychotics in the Treatment of Obsessive Compulsive Disorder" (2006), Fineberg, Gale, and Sivakumaran write: "Treatment should therefore begin with very low doses, increased cautiously subject to tolerability (e.g., 0.25 – 0.5 mg haloperidol, titrated slowly to 2 – 4 mg: McDougle and Walsh, 2001)." The McDougle and Walsh article referenced here is from Fineberg, Marazitti, and Stein (eds), Obsessive Compulsive Disorder: A Practical Guide.

In Part 2 of MyBrainNotes.com, we discuss Tardive Dyskinesia, a serious disorder that can result from taking antipsychotic medications, especially at higher doses and for extended periods of time. If you take the jump link provided here, remember to use the BACK button on your browser to return to his section.

In Part 2 of MyBrainNotes.com, we also discuss another side effect of antipsychotics, hyperprolactinaemia, in a paragraph about the tuberoinfundibular dopamine pathway. If you take the jump link provided here, remember to use the BACK button on your browser to return to this section. I am not sure whether atypical antipsychotics carry the same risk for hyperprolactinaemia. In any event, remember that lower doses of any drug will produce less noticeable side effects. From personal experience taking 0.5 mg of haloperidol once daily, hyperprolactinaemia has not been a problem for me.

Medication caution—thioridazine:

Thioridazine and Prozac (fluoxetine hydrochloride) should not be administered together. The U.S. Federal Drug Administration's approved labeling enclosure for Prozac states: "Thioridazine should not be administered with Prozac or within a minimum of 5 weeks after Prozac has been discontinued (see WARNINGS)." Very technical language in the "WARNINGS" section includes the following: "Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism."

Medication caution—atypical antipsychotics:

Some people suffering from schizophrenia who have been treated with atypical antipsychotics have suffered from either newly emerged or exacerbation of obsessions and/or compulsions during treatment. We will discuss atypical antipsychotics below. Fineberg, Gale, and Sivakumaran write: "Some authors have reported emergent obsessions during treatment of schizophrenia with atypical antipsychotics, which may be related to their [the medications] mixed receptor antagonist properties (Sareen et al., 2004). Obsessive-compulsive symptoms have, however, long been recognized to be common among patients with schizophrenia (Poyurovsky and Koran, 2005) and may well be linked to the schizophrenic disorder as opposed to the antipsychotic treatment."

I found two other studies that discuss emergence or exacerbation of obsessions and/or compulsions in schizophrenic patients taking atypical anti-psychotics. For reference, those articles are:


Why typical may be better than atypical antipsychotics:

Newer drugs are not always better. First of all, Jones et al., in "Randomized Controlled Trial of the Effect on Quality of Life of Second- vs First-Generation Antipsychotic Drugs in Schizophrenia," report that patients in the study taking the older, first-generation typical antipsychotics, "showed a trend toward greater improvements in Quality of Life Scale and symptom scores," when compared to patients taking atypical antipsychotics. This finding is especially important when you consider that these patients, suffering from schizophrenia, may be taking higher doses of the typical antipsychotics than would be necessary to treat obsessions and compulsions. In a Washington Post article, the Consumers Union of the United States reports: "If you're thinking about taking a drug that's been around for only a few years, ask your doctor whether there's an older, equally effective one. (It will probably be less expensive too.)"

Bloch, et al., in "A Systematic Review: Antipsychotic Augmentation With Treatment Refractory Obsessive-Compulsive Disorder" (2006), searched electronic databases including PubMed, PsychINFO, Embase, and CENTRAL for "relevant double-blind trials using keywords 'antipsychotic agents' or 'neuroleptics' and 'obsessive-compulsive disorder'. Search results and analysis were limited to double-blind, randomized control trials involving the adult population." The authors concluded:

Antipsychotic augmentation in SRI-refractory OCD is indicated in patients who have been treated for at least 3 months of maximal-tolerated therapy of an SRI. Unfortunately, only one-third of treatment-refractory OCD patients show a meaningful treatment response to antipsychotic augmentation. There is sufficient evidence in the published literature, demonstrating the efficacy of haloperidol and risperidone, and evidence regarding the efficacy of quetiapine and olanzapine is inconclusive.

I would like to note here that as of January 1, 2010, I have found only one study (described below) of haloperidol used to treat OCD and one study of haloperidol used to treat trichotillomania. Consequently, I question the Block et al. assumption that "only one-third of treatment-refractory OCD patients show a meaningful treatment response to antipsychotic augmentation." The use of haloperidol has not been adequately studied and the study that was performed has some problems with presentation that I will discuss later in this section. Also, as you will see in the discussion that follows, I contend that meaningful results in a placebo-treated group subsequently treated with haloperidol have been overlooked.

Typical antipsychotics considered:

Haloperidol 0.5 mg tablets, a medication option for the treatment of ocd. I contend that given the evidence of dopamine involvement in driving obsessions and compulsions, the medical research and practitioner communities have nonetheless hesitated to adequately explore the use of typical antipsychotics in the treatment of obsessions and compulsions. This may be due to several factors: 1) the early misassumption that OCD was a psychological disorder while Tourette Syndrome was a neurological disorder, 2) the categorization of these drugs as antipsychotics combined with the fact that many OCD patients do not display psychotic or schizophrenic-like symptoms, 3) an early and possibly faulty assumption that the newer atypical antipsychotics would produce less side effects than typical antipsychotics, 4) the failure to adequately examine use of low-dose antipsychotics to treat obsessions and compulsions, and 5) a general lack of understanding of the neurocircuitry and neurochemistry behind motivation.

While treating patients with OCD, Judith Rapoport explains in The Boy Who Couldn't Stop Washing that "sooner or later I thought that, as Freud had with the Rat Man, I would come to know the guilty wish or fear behind the patient's washing, checking, or counting." Finally, however, she concluded that they patients "never 'needed' these symptoms to maintain balance or control over some internal psychological conflict."

The following reports regarding drug treatment for obsessions and compulsions are presented in reverse chronological order, with the most recent material presented first. Regarding the Van Ameringen article mentioned below, wherein OCD and Tourette Syndrome are dichotomized in a very subtle manner, I should note that we discuss the close relationship between OCD and Tourette Syndrome in OCD and the corpus striata complex (basal ganglia).

1999: Van Ameringen et al., in "The Potential Role of Haloperidol in the Treatment of Trichotillomania," write:

We review the clinical phenomenology and pharmacological response of trichotillomania, and suggest that it may be more related to Tourette Syndrome than to OCD. Serotonin reuptake inhibitors (SRIs) are typically employed in the treatment of OCD, while neuroleptic medications such as haloperidol are typically used in the treatment of Tourette syndrome. … Eight of nine patients responded to haloperidol treatment, with seven experiencing complete or near complete cessation of hair pulling. … Results suggest that the addition of haloperidol to SSRIs or haloperidol alone may be effective in the treatment of trichotillomania. Results also encourage speculation about the relation of OCD, Tourette Syndrome, and trichotillomania.

1994: For most articles listed in PubMed.gov, there appears the title, publication information, an introductory paragraph or two that can be referred to as an "abstract," a "summary," or "background." This introductory information is usually the only narrative information that appears in PubMed.gov and is the most read portion of any article, especially after initial publication. Regarding the McDougle et al. article cited below, you may access the Archives of General Psychiatry website from PubMed.gov for the full text but one-time payment or a subscription is required. The PubMed "Background" section for "Haloperidol Addition in Fluvoxamine-Refractory Obsessive-Compulsive Disorder. A Double-Blind, Placebo-Controlled Study in Patients With and Without Tics" follows as a block quotation. I have used bold typeface and a font color to highlight somewhat contradictory information. I will discuss other problems with the study's presentation below.

BACKGROUND: To determine the efficacy of adding haloperidol to the treatment of patients with obsessive-compulsive disorder (OCD), with or without a comorbid chronic tic disorder, who were refractory to adequate treatment with the serotonin-uptake inhibitor fluvoxamine alone. It was hypothesized that OCD patients with a concurrent chronic tic disorder would preferentially respond to this treatment. METHODS: Sixty-two patients with a primary DSM-III-R diagnosis of OCD received placebo fluvoxamine for 1 week, followed by 8 weeks of active fluvoxamine. Thirty-four of these patients were refractory to fluvoxamine and were randomized in a double-blind fashion to 4 weeks of treatment with either haloperidol (n = 17) or placebo (n = 17) added to ongoing fluvoxamine treatment. The placebo-treated group included five women and 12 men, six inpatients and 11 outpatients, and eight patients with a comorbid chronic tic disorder. The haloperidol-treated group consisted of two women and 15 men, three inpatients and 14 outpatients, and seven patients with a comorbid chronic tic disorder. All 34 patients completed the entire study. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Clinical Global Impression scale were the principal measures of treatment outcome. RESULTS: Haloperidol addition was significantly better than placebo in reducing the severity of obsessive-compulsive symptoms as measured by the Y-BOCS. Eleven of 17 patients responded to the haloperidol, compared with none of 17 patients given placebo. Eight of eight patients with comorbid chronic tic disorders, such as Tourette's disorder, responded to double-blind haloperidol addition to ongoing fluvoxamine treatment. Haloperidol addition was of little benefit in treating OCD patients without tics. Fluvoxamine blood levels were not related to treatment response. CONCLUSIONS: The results of this study suggest that OCD patients with a comorbid chronic tic disorder constitute a clinically meaningful subtype of OCD that might require conjoint serotonin-uptake inhibitor/neuroleptic therapy for effective symptom reduction.

It is especially important to note that regarding this 1994 study, in which at the time the authors conclude "Haloperidol addition was of little benefit in treating OCD patients without tics," McDougle et al. later write in A Double-Blind, Placebo-Controlled Study of Risperidone Addition in Serotonin Reuptake Inhibitor-Refractory Obsessive-Compulsive Disorder" (2000): "To date, only 1 controlled study has found a drug (haloperidol) to be efficacious in augmenting response in patients with obsessive-compulsive disorder (OCD) refractory to serotonin reuptake inhibitor (SRI) monotherapy; patients with comorbid chronic tic disorders showed a preferential response." I am fairly certain this is a reference to the previously cited McDougle et al. 1994 article. Furthermore, I contend that the authors, in the 2000 article, should have written: "Only one controlled study has been done …" but I am a stickler for language, especially when it matters.

McDougle et al. write: "It was hypothesized that OCD patients with a concurrent chronic tic disorder would preferentially respond to this treatment." They go on to conclude that haloperidol was of help to those OCD patients who also had chronic tic disorder. Within the body of the article, however, in the Patients and Methods section, the authors write: "Obsessive-compulsive disorder patients with comorbid tic disorders were specifically sought from the community." All this seems to indicate a focus on proving a hypothesis about tic disorder rather than studying the effects of haloperidol in decreasing obsessions and compulsions.

The actual results of this study are, I think, extremely valuable. The primary problems relate to communication and presentation. When one reads just the title of the study combined with the "Background" that is displayed in PubMed.gov, one could get the impression that haloperidol is useful ONLY in treating patients who have BOTH obsessive-compulsive symptoms and tic disorder. I contend that this limited information, widely distributed through PubMed.gov, has inappropriately discouraged researchers and practitioners from employing haloperidol to treat obsessions and compulsions in patients that do not present with tic disorder and do not respond to fluvoxamine alone.

Another problem relates to numbers. The authors of the study write: "Eleven of 17 patients responded to the haloperidol, compared with none of 17 patients given placebo. Eight of eight patients with comorbid chronic tic disorders, such as Tourette's disorder, responded to double-blind haloperidol addition to ongoing fluvoxamine treatment." The problem with this last sentence is that just previously, the authors indicate that only seven patients in the haloperidol treated group had comorbid chronic tic disorder. In the complete article, a table used to organize data indicates that eight of the 17 patients treated with both fluvoxamine and haloperidol had comorbid chronic tic disorder or Tourette Syndrome.

Regardless of the contradiction outlined above, if 11 of 17 patients responded to the haloperidol, then how do the authors justify their next strongly worded statement? "Haloperidol addition was of little benefit in treating OCD patients without tics." If 8 patients in the haloperidol group had tic disorder and responded to haloperidol, then that still leaves 3 patients without tics who also responded to the haloperidol (33% of haloperidol-treated patients supposedly without tics). Also, I think it is possible that at least some people diagnosed with obsessive-compulsive disorder also have tic disorder but that they are perhaps unaware of the tics, which may be subtle.

Although explanation does not appear in the Background portion of the article, the authors explain in the body of the article that the patients who were given haloperidol also received benztropine mesylate. Some of these patients also received "propranolol hydrochloride." And some of these patients also received "low-dose benzodiazepines." This means any one of these patients could have been taking five drugs simultaneously: fluvoxamine, haloperidol, benstropine mesylate, propranolol hydrochloride, and low-dose benzodiazepines. I am not a chemist but it seems to me that all these drugs could easily have skewed results.

The 1994 McDougle et al. study reports: "Patients were given haloperidol 2 mg/d for 3 days, with the dosage then increased by 2 mg every 3 days, to a maximum of 10 mg/d." I contend this is too much haloperidol and could affect patient attitude, compliance, and symptom reporting. As noted above, in Fineberg, Marazitti, and Stein (eds), Obsessive Compulsive Disorder: A Practical Guide (2001), McDougle and Walsh recommend only 0.25–0.5 mg haloperidol, titrated slowly to 2–4 mg. There is a big difference between the 10 mg of haloperidol used in the 1994 study and the 2001 recommendations.

It is important to consider how the subjective state of a person taking 0.5 mg of haloperidol per day would be dramatically different from the subjective state of a person taking 10 mg per day (10 mg is 20 times more medication that 0.5 mg). I contend that some of the patients in the 1994 McDougle et al. study who took haloperidol may not have responded well to 1) either the larger dose of haloperidol or 2) the combination of up to five drugs administered simultaneously. Also, I think it is important to clarify that antipsychotics should not be increased subject only to tolerability. They should be increased only if lower doses do not provide adequate relief from symptoms, subject to tolerability.

Most importantly, in the body of the 1994 McDougle et al. article, the authors write: "After completing the 4-week double-blind phase of the study, 14 of 17 placebo-treated patients received open haloperidol addition to fluvoxamine for 4 weeks. In this group, haloperidol addition caused a significant improvement in scores on the Y-BOCS … but not on the HAM-D …, Hamilton Rating Scale for Anxiety …, or Patient-Rated Anxiety Scale … . Eight (57%) of 14 patients who were given 4 weeks of open haloperidol addition showed a response (five marked, three partial)."

The 57% response rate referred to above was not discussed in the Background section that appears in PubMed.gov. Of the patients in the placebo group who were later treated with haloperidol "four (80%) of five patients with tics (TS, n=2; chronic motor tic disorder, n=2) were responders, whereas four (44%) of nine without tics responded … . I contend that the 44% response rate among patients supposedly without tics is significant enough to include in the more widely distributed and read Background section of the study.

My take on all this is that if I had obsessions and/or compulsions that did not respond to selective serotonin reuptake inhibitors, and that contributed to severe depression, or that interfered substantially in my happiness, interpersonal life, or career, I would want the opportunity to consider adding low-dose haloperidol. I choose not to get dramatic here. I wish to point out, however, that in the United States, only licensed health-care providers can provide such access and I do not think they have been getting the information they need to help patients make good decisions.

There is of course another angle here. If a psychotherapist proscribes medicine that deactivates symptoms, patients might not come to psychotherapy. And sometimes, perhaps a practitioner decides that psychotherapy is more important. This idea makes me livid so I will not explore it further. I will quote Judith L. Rapoport again here. In The Boy Who Couldn't Stop Washing: The Experience & Treatment of Obsessive-Compulsive Disorder (1989), she writes: "After I got to know a patient well and had gained his trust, sooner or later I [mistakenly] thought that, as Freud had with the Rat Man, I would come to know the guilty wish or fear behind the patient's washing, checking, or counting… . But it was the process of treating my patients with drugs or behavior therapy that finally convinced me that they never 'needed' these symptoms to maintain balance or control over some internal psychological conflict."

Atypical antipsychotics considered:

I contend that the positive results shown in the use of atypical antipsychotics to treat obsessions and compulsions are due to dopamine antagonist properties. We will take a look at such studies below. It should be remembered, however, that the atypical antipsychotics are multi-dimensional. Risperidone, for example, also appears to have an antagonistic effect on at least some serotonin receptors. Haloperidol has no such effect. The logic of combining a serotonin-reuptake inhibitor with a drug that is antagonistic to serotonin is not clear to me but I am not a chemist and I understand that serotonin has a number of different receptors.

For each atypical antipsychotic listed below, I have included links to additional resources. The Family Practice Notebook website cites a lot of good technical information. I am hoping to track down primary sources and clarify the functional properties for atypical drugs and—for the nonscientist—expand general understanding of how the drugs work. Meanwhile, please consider this section a work in progress. More work certainly needs to be done to determine which drugs work best to curb obsessions and compulsions at the lowest relative dose with fewest side effects. As mentioned previously, as dosages increase so do side effects.

For reference, I have listed the atypical antipsychotics below in alphabetical order, described with information that I have culled from a variety of sources. Atypical antipsychotics are not well understood and sometimes I found what seems to be contradictory information. Where possible, I have provided a link to the manufacturer's product information.

    Aripiprazole (trade name Abilify, Abilify Discmelt), according to the Wikipedia entry, is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression. The well-referenced Wikipedia entry for aripiprazole states: "Aripiprazole's mechanism of action is different from those of the other FDA-approved atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, ziprasidone, and risperidone). Rather than antagonizing the D2 receptor, aripiprazole acts as a D2 partial agonist. Aripiprazole is also a partial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor. It also antagonizes the 5-HT77 receptor and acts as a partial agonist at the 5-HT2C receptor, both with high affinity." Bristol-Myers Squibb's patent on Abilify expires on October 20, 2014 (source).



    Clozapine (trade name Clozaril) was clinically introduced in the 1970s. According to Novartis product information, clozapine "does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor … ." A few sentenances later, the product information reads: "CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors." So Novartis product information seems to imply that clozapine is a dopamine antagonist. However, in "Is Clozapine an (partial) Agonist at Both Dopamine D1 and D2 Receptors?" (1998) David M. Jackson, Hakån Wikström, and Yi Liao write: "Evidence also supports the hypothesis that clozapine is not only a dopamine D1 agonist but also can be considered a dopamine D2 agonist." Clozapine has five adverse side-effects that the drug industry calls "black box warnings." The patent for clozapine has long expired.



    Olanzapine (trade names Zyprexa, Zyprexa Zydis, Zalasta, Zolafren, Olzapin, Rexapin or in combination with fluoxetine Symbyax). The Family Practice notebook site (link provided below) cites "PDQ" with the following information (note that serotonin is a monoamine): "As a selective monoaminergic antagonist, olanzapine binds with high affinity binding to the following receptors: serotonin, dopamine, muscarinic M1-5, histamine H1, and alpha1-adrenergic receptors; it binds weakly to gamma-aminobutyric acid type A, benzodiazepine, and beta-adrenergic receptors. Although its exact mechanism of action in schizophrenia is unknown, it has been proposed that olanzapine's antipsychotic activity is mediated through a combination of dopamine and serotonin type 2 antagonism." Eli Lilly's patent for Zyprexa expires on April 23, 2011 (source).



    Quetiapine (trade name Seroquel). The Family Practice Notebook site below cites the NCI with the following information: "A dibenzothiazepine derivative with antipsychotic property. Quetiapine fumarate antagonizes serotonin activity mediated by 5-HT 1A and 5-HT2 receptors. With a lower affinity, this agent also reversibly binds to dopamine D1 and D2 receptors in the mesolimbic and mesocortical areas of the brain leading to decreased psychotic effects, such as hallucinations and delusions. In addition, quetiapine also binds to other alpha-1, alpha-2 adrenergic and histamine H1 receptors." AstraZeneca's patent on Seroquel expires on September 26, 2011 (source).



    Risperidone (trade name Risperdal). Although a primary source is preferred and will be sought, the Family Practice Notebook site (link provided below) cites the "NCI" as the source of the following information: "Risperidone selectively antagonizes serotonin (5-HT) effects via cortical 5-HT2 receptor, and, to a lesser extent, competes with dopamine at the limbic dopamine D2 receptor. The antagonism leads to decreased psychotic effects, such as hallucinations and delusions." The patent for Risperdal expired in March 2007, and sales have since declined substantially (source).



    Ziprasidone (trade names Geodon, Zeldox). According to the well-referenced Wikipedia entry for ziprasidone, "it has been theorized that its antipsychotic activity is mediated primarily by antagonism at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of ziprasidone, but the significance of 5-HT2A antagonism is debated among researchers. Ziprasidone has perhaps the most selective affinity for 5-HT2A receptors relative to D2 and 5-HT2C receptors of any neuroleptic. Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and orthostasis." As a sidenote, according to the Wikipedia entry, "Orthostatic hypotension (also known as postural hypotension, orthostasis, and … a dizzy spell …) is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up." Pfizer's patents on Geodon expire on March 2, 2012 (source).


NOTE: The following reports are presented in reverse chronological order, with the most recent material presented first. Excerpts from introductory material are used here. To access complete introductory material, click on the linked title of each study.

2009 (paliperidone, a metabolite of risperidone): In “The Recognition and Treatment of Pathological Skin Picking: A Potential Neurobiological Underpinning of the Efficacy of Pharmacotherapy in Impulse Control Disorders,” Spiegel and Finklea detail their findings regarding treatment of skin picking. They found that fluoxetine (generic for Prozac) alone did not provide relief from compulsive symptoms. However, when they added paliperidone, a metabolite of one of the newer antipsychotics, risperidone, the patients' symptoms remitted. "After four months on a combination of [paliperidone] and [fluoxetine], our patient showed nearly complete resolution of symptoms. The authors explain that paliperidone is antagonistic to "centrally located dopamine (D2) and serotonin (5HT2A) receptors."

2005 (risperidone): Erzegovesi et al., in "Low-Dose Risperidone Augmentation of Fluvoxamine Treatment in Obsessive-Compulsive Disorder: A Double-Blind, Placebo-Controlled Study," write:

All patients received 12 weeks of a standardized open-label fluvoxamine monotherapy and then continued for 6 weeks with placebo or risperidone in a double-blind design. Results showed a significant effect of risperidone addition, at the end of the double-blind phase (18th week), only for fluvoxamine-refractory patients. Five patients on risperidone (50%) and two (20%) on placebo became responders, with a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decrease > or =35%. Risperidone was generally well tolerated, except for a mild transient sedation and a mild increase in appetite. This preliminary study suggests that even very low (0.5 mg) risperidone doses are effective in OC patients who were nonresponders to a standardized treatment with fluvoxamine.

2005 (quetiapine): Fineberg et al., in "Adding Quetiapine to SRI in Treatment-Resistant Obsessive-Compulsive Disorder: A Randomized Controlled Treatment Study," write:

Twenty-one adult treatment-resistant OCD patients were randomized to 16 weeks of augmentation with either quetiapine (n = 11) or placebo (n = 10). Patients with significant comorbidities, including tic-spectrum disorders, were not included. The treatment was well tolerated, with only one premature dropout in each treatment-group. The primary analysis showed that individuals in the quetiapine-treated group showed a 14% mean improvement in baseline Yale-Brown Obsessive-Compulsive Scale scores at study endpoint compared with a 6% improvement in those treated with placebo, but this difference did not reach statistical significance (F<1). Three patients treated with quetiapine met criteria for clinical response, compared to one patient who was treated with placebo.

2005 (quetiapine): Carey et al., in "Quetiapine Augmentation of SRIs in Treatment Refractory Obsessive-Compulsive Disorder: A Double-Blind, Randomised, Placebo-Controlled Study," conclude: "Quetiapine did not demonstrate a significant benefit over placebo at the end of the six-week treatment period (p = .636)." The link provided above provides access to the complete article. I find this article difficult to interpret. It appears that medications were administered in larger doses. For example, the authors write: "Two subjects withdrew from the study prematurely (Week 1 and Week 4) due to severe levels of sedation."

2004 (quetiapine): Denys et al. conducted a study titled "A Double-Blind, Randomized, Placebo-Controlled Trial of Quetiapine Addition in Patients with Obsessive-Compulsive Disorder Refractory to Serotonin Reuptake Inhibitors." I also question the dosage of quetiapine used in this study since the authors report side effects that I consider serious. The authors write:

Eight (40%) of 20 patients in the quetiapine group and 2 (10%) of 20 patients in the placebo group were responders … . The most common side effects in the quetiapine group were somnolence, dry mouth, weight gain, and dizziness. CONCLUSION: The results of this study show that quetiapine in addition to an SRI is beneficial for patients with OCD who do not respond to SRI treatment alone.

2004 (olanzapine): Shapira et al., in "A Double-Blind, Placebo-Controlled Trial of Olanzapine Addition in Fluoxetine-Refractory Obsessive-Compulsive Disorder," conclude that their findings "indicate no additional advantage of adding olanzapine for 6 weeks in OCD patients who have not had a satisfactory response to fluoxetine for 8 weeks, compared with extending the monotherapy trial."

2004 (olanzapine): Bystritsky et al, in "Augmentation of Serotonin Reuptake Inhibitors in Refractory Obsessive-Compulsive Disorder Using Adjunctive Olanzapine: A Placebo-Controlled Trial," write:

Six (46%) of 13 subjects in the olanzapine group showed a 25% or greater improvement in Y-BOCS score compared with none in the placebo group. The final mean dose of olanzapine was 11.2 (SD = 6.5) mg/day. Medication was well tolerated. Only 2 (15%) of 13 subjects who received olanzapine discontinued because of side effects: sedation (N = 1) or weight gain (N = 1). CONCLUSION: These results provide preliminary evidence that adding olanzapine to SRIs is potentially efficacious and well tolerated in the short-term treatment of patients with refractory OCD.

2003 (risperidone): Hollander et al., in "Risperidone Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: A Double-Blind, Placebo-Controlled Study," Hollander et al. write:

Four patients on risperidone (40%) and none (0%) on placebo were responders with both a Clinical Global Impression - Improvement (CGI-I) score of 1 or 2 and a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decrease >/=25%. Risperidone was generally well tolerated: there were 3 dropouts, 1 on risperidone and 2 on placebo. Better Y-BOCS insight score at baseline significantly correlated with a greater CGI-I score at endpoint on risperidone augmentation. Risperidone may be an effective and well-tolerated augmentation strategy in treatment-resistant OCD subjects, but larger sample size studies are required to demonstrate this.

2001 (risperidone): In "Risperidone Augmentation of Specific Serotonin Reuptake Inhibitors in the Treatment of Refractory Obsessive-Compulsive Disorder: Report of Two Cases," Sun, Lin, and Wu write:

Herein we report our experience with two OCD patients, one with a poor response to fluoxetine 80 mg per day for 3 months, and the other with poor response to fluoxetine 60 mg per day for 3 months. Both OCD patients also proved to have a poor response to paroxetine 60 mg per day for 6 weeks. Neither patient had received any psychotherapy or behavioral therapy. Both patients showed significant improvement in their obsessive-compulsive symptoms as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), after risperidone 1 mg per day was added to their on-going use of paroxetine 60 mg per day. Within 4 weeks of adding risperidone, the two patients' Y-BOCS scores had decreased by 57% and 53%. This result suggests that risperidone augmentation of SSRI may be a good choice and an effective treatment strategy for refractory OCD.

2000 (risperidone): McDougle et al. conducted a study titled "A Double-Blind, Placebo-Controlled Study of Risperidone Addition in Serotonin Reuptake Inhibitor-Refractory Obsessive-Compulsive Disorder," which is now available free, in full, on the internet. In the following "Background" narrative from PubMed.gov, note that the first sentence refers to the 1994 McDougle et al. study of haloperidol, which we extensively discuss earlier on this page. Again, a more accurate version would read: Only one controlled study has been done ...

BACKGROUND: To date, only 1 controlled study has found a drug (haloperidol) to be efficacious in augmenting response in patients with obsessive-compulsive disorder (OCD) refractory to serotonin reuptake inhibitor (SRI) monotherapy; patients with comorbid chronic tic disorders showed a preferential response. This report describes the first controlled study of risperidone addition in patients with OCD refractory to treatment with SRI alone. METHODS: Seventy adult patients with a primary DSM-IV diagnosis of OCD received 12 weeks of treatment with an SRI. Thirty-six patients were refractory to the SRI and were randomized in a double-blind manner to 6 weeks of risperidone (n = 20) or placebo (n = 16) addition. Behavioral ratings, including the Yale-Brown Obsessive Compulsive Scale, were obtained at baseline and throughout the trial. Placebo-treated patients subsequently received an identical open-label trial of risperidone addition. RESULTS: For study completers, 9 (50%) of 18 risperidone-treated patients were responders (mean daily dose, 2.2 +/-0.7 mg/d) compared with 0 of 15 in the placebo addition group (P<. 005). Seven (50%) of 14 patients who received open-label risperidone addition responded. Risperidone addition was superior to placebo in reducing OCD (P<.001), depressive (P<.001), and anxiety (P =.003) symptoms. There was no difference in response between OCD patients with and without comorbid diagnoses of chronic tic disorder or schizotypal personality disorder. Other than mild, transient sedation, risperidone was well tolerated. CONCLUSION: These results suggest that OCD patients with and without comorbid chronic tic disorders or schizotypal personality disorder may respond to the addition of low-dose risperidone to ongoing SRI therapy.

Antipsychotics and eating disorders:

In Cassano et al., "Six-month Open Trial of Haloperidol as an Adjunctive Treatment for Anorexia Nervosa: A Preliminary Report" (2003), researchers evaluate the effectiveness of haloperidol "as an adjunctive treatment for resistant anorexia nervosa restricting subtype (AN-R)." They write: "Thirteen outpatients with treatment-resistant AN-R were treated for 6 months with haloperidol in addition to standard treatment." Preliminary data from the study suggest "that low doses of haloperidol might be effective as an adjunctive treatment for patients with severe AN-R."

Although the abstract is somewhat confusing, I would like to draw attention to a Verhagen et al. study titled "Dopamine Antagonism Inhibits Anorectic Behavior in an Animal Model for Anorexia Nervosa" (2009). The authors provide data to "support a role for dopamine in anorexia associated hyperactivity." In their research, dopamine antagonists (antipsychotic medications that decrease dopamine transmission) decreased activity levels and increased food intake in an animal model.

I found two articles related to the use of atypical-antipsychotics to treat eating disorders. They are: 1) Brambilla et al., "Olanzapine therapy in anorexia nervosa: psychobiological effects" (2007) and 2) Mehler-Wex et al, "Atypical Antipsychotics in Severe Anorexia Nervosa in Children and Adolescents—Review and Case Reports" (2008).

Capsulotomy as an OCD treatment:

The term capsulotomy, as will be used below, refers to lesioning of the internal capsule. It is important to note the proximity of the internal capsule to the nucleus accumbens. Used previously, the image below (links to source) is from the Temple University School of Medicine's Department of Anatomy and Cell Biology website. I have added the labeling here.

Brain anatomy model - specimen: Location of nucleus accumbens and internal capsule, part of the corpus striata - also called the basal ganglia.

The more limited lesioning described here using radiofrequency is an improvement on surgeries done in the 1960s, which could result in frontal-lobe dysfunction. Christensen et al., in "Anterior Capsulotomy for Treatment of Refractory Obsessive-Compulsive Disorder: Results in a Young and an Old Patient" (2002) write:

2002: The objective of this case report was to assess the effect of anterior capsulotomy for obsessive-compulsive disorder (OCD) in 2 patients beyond extremes of age ranges of published radiofrequency capsulotomy. The youngest patient developed OCD at age 10 with increasing symptoms of tension and worry. The symptoms were refractory to medications and behavioral therapy. He underwent anterior capsulotomy at age 18. The older patient was 64 at the time of surgery. His OCD began about age 17 with checking and counting rituals. His obsessions extended into other areas such as fear of injuring people while driving. His work performance was greatly compromised. Despite medication trials his rituals and obsessions intensified. After 47 years of severe symptoms he underwent surgery. The youngest patient returned to high school full-time and graduated. He was able to read and comprehend without obsessing about the meaning of words. His thinking and behavior became symptom free and he married 4.5 years after surgery. His score on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after surgery on no medication is zero. The older patient improved gradually without medication. He could play with and touch his grandchildren for the first time. He could drive a car again and his Y-BOCS dropped from 30 preoperatively to 8. Twenty-four months after surgery he is essentially free of obsessions, compulsions and anxiety. We conclude that treatment-refractory OCD may be alleviated by anterior radiofrequency capsulotomy in the young and the old patient. This study expands the documented age range of response from 18 to 64.

Deep-brain stimulation as an OCD treatment:

Post-operative T1-weighted brain MRI depicts exact electrode placement in the desired target area - an ocd treatment. Sturm et al., in "The Nucleus Accumbens: A Target for Deep Brain Stimulation in Obsessive-Compulsive- and Anxiety-Disorders" (2003), provide evidence that the nucleus accumbens, rather than the internal capsule, is more directly involved in producing obsessions and compulsions. In previous studies, lesioning of the internal capsule probably impacted the nucleus accumbens since, as Sturm et al. note, the nucleus accumbens "is located immediately underneath the anterior limb of the internal capsule… . Sturm et al. "chose the shell region of the right nucleus accumbens as the target for deep-brain stimulation in a pilot series of four patients with severe obsessive-compulsive and anxiety disorders." The researchers found that "significant reduction in severity of symptoms" was achieved in three of the four patients treated. In their published paper, the caption for the image to the right reads: "Post-operative T1-weighted MRI depicts exact electrode placement in the desired target area. Note the dark artefact surrounding the electrode, which is due to disturbance of the local magnetic field by the electrode and not caused by tissue damage." The abstract from their paper follows:

2003: As a central relay structure between the amygdala, basal ganglia, mesolimbic dopaminergic areas, mediodorsal thalamus, and prefrontal cortex, the nucleus accumbens seems to play a modulatory role in the flow of information from the amygdaloid complex to the latter areas. If disturbed, an imbalanced information flow from the amygdaloid complex can yield obsessive-compulsive and anxiety disorders. These can be counteracted by blocking the information flow within the shell region of the nucleus accumbens by means of deep-brain stimulation (DBS).

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