<PAGE>

As filed with the Securities and Exchange Commission on April 18, 2001
Registration No. 333-
================================================================================

                       SECURITIES AND EXCHANGE COMMISSION
                             Washington, D.C. 20549

                          ----------------------------

                                    FORM S-8
                             REGISTRATION STATEMENT
                                     UNDER
                           THE SECURITIES ACT OF 1933

                         -----------------------------

                            CYPRESS BIOSCIENCE, INC.
             (Exact name of registrant as specified in its charter)

       Delaware                                          22-2389839
(State of Incorporation)                    (I.R.S. Employer Identification No.

                          ----------------------------

                        4350 Executive Drive, Suite 325
                              San Diego, CA 92121
                    (Address of principal executive offices)

                         -----------------------------
                     2000 Equity Incentive Plan, As Amended
                           (Full title of the plans)

                          Jay D. Kranzler, Ph.D., M.D.
                            Chief Executive Officer
                            Cypress Bioscience, Inc.
                        4350 Executive Drive, Suite 325
                              San Diego, CA 92121
                                 (858) 452-2323
 (Name, address, including zip code, and telephone number, including area code,
                             of agent for service)

                          ----------------------------

                                   Copies to:
                            Frederick T. Muto, Esq.
                            Denise L. Woolard, Esq.
                               Cooley Godward LLP
                        4365 Executive Drive, Suite 1100
                              San Diego, CA 92121
                                 (858) 550-6000

                          ----------------------------

<TABLE>
<CAPTION>
                        CALCULATION OF REGISTRATION FEE
==============================================================================================================================
                                                                    Proposed Maximum     Proposed Maximum
      Title of Securities                                               Offering            Aggregate          Amount of
       to be Registered              Amount to be Registered (1)    Price per Share (2)  Offering Price (1)  Registration Fee
-----------------------------------------------------------------------------------------------------------------------------
<S>                                 <C>                              <C>               <C>                <C>
Stock Options and Common Stock
 (par value $.02)                         562,500 shares                 $0.785             $441,562.50          $110.39
=============================================================================================================================
</TABLE>

(1)  Includes 562,500 shares issuable pursuant to Registrant's 2000 Equity
     Incentive Plan, as amended.

(2)  Estimated solely for the purpose of calculating the amount of the
     registration fee pursuant to Rule 457(c) and Rule 457 (h)(1) of the
     Securities Act of 1933, as amended (the "Securities Act").  The price per
     share and aggregate offering price are calculated on the basis of the
     average of the high and low sales prices of Registrant's Common Stock on
     April 11, 2001, as reported on The Nasdaq SmallCap Market.
<PAGE>

                INCORPORATION OF CERTAIN DOCUMENTS BY REFERENCE

     The following documents filed by Cypress Bioscience, Inc. (the "Company")
with the Securities and Exchange Commission (the "SEC") are incorporated by
reference into this Registration Statement except as modified or superseded or
modified herein:

     (a)  The Company's 10-K for the year ended December 31, 2000.

     (b)  Form 8-A containing a description of the Company's securities.

     All reports and other documents subsequently filed by the Company pursuant
to Sections 13(a), 13(c), 14 and 15(d) of the Securities Exchange Act of 1934,
as amended, prior to the filing of a post-effective amendment which indicates
that all securities offered have been sold or which deregisters all securities
then remaining unsold, shall be deemed to be incorporated by reference herein
and to be a part of this registration statement from the date of the filing of
such reports and documents.



                           DESCRIPTION OF SECURITIES

     Not applicable.



                     INTERESTS OF NAMED EXPERTS AND COUNSEL

     Not applicable.
<PAGE>

                   INDEMNIFICATION OF DIRECTORS AND OFFICERS



     Section 145 of the General Corporation Law of the State of Delaware (the
"Delaware Law") empowers a Delaware corporation to indemnify any persons who
are, or are threatened to be made, parties to any threatened, pending or
completed legal action, suit or proceeding, whether civil, criminal,
administrative or investigative (other than an action by or in the right of such
corporation), by reason of the fact that such person was an officer or director
of such corporation, or is or was serving at the request of such corporation as
a director, officer, employee or agent of another corporation or enterprise.
The indemnity may include expenses (including attorneys' fees), judgments, fines
and amounts paid in settlement of such action, suit or proceeding, provided that
such officer or director acted in good faith and in a manner he or she
reasonably believed to be in or not opposed to the corporation's best interest,
and, for criminal proceedings, had no reasonable cause to believe his or her
conduct was illegal.  A Delaware corporation may indemnify officers and
directors against expenses (including attorney's fees) in connection with the
defense or settlement of an action by or in the right of the corporation under
the same conditions, except that no indemnification is permitted without
judicial approval if the officer or director is adjudged to be liable to the
corporation.  Where an officer or director is successful on the merits or
otherwise in the defense of any action referred to above, the corporation must
indemnify him or her against the expenses which such officer or director
actually and reasonably incurred.

     The Company's Bylaws provide that the Company will indemnify its directors
and executive officers and may indemnify its other officers, employees and other
agents to the fullest extent permitted by Delaware Law. The Company is also
empowered under its bylaws to enter into indemnification contracts with its
directors and officers and to purchase insurance on behalf of any person who it
is required or permitted to indemnify. Pursuant to this provision, the Company
has entered into indemnity agreements with each of its directors and officers
and currently maintains directors and officers insurance coverage.

                      EXEMPTION FROM REGISTRATION CLAIMED

      Not applicable.
<PAGE>

                                    EXHIBITS


<TABLE>
<CAPTION>


Exhibit
Number     Description
------     -----------
<C>        <S>
   5.1     Opinion of Cooley Godward LLP.
  23.1     Consent of Ernst & Young LLP, Independent Auditors.
  23.2     Consent of Cooley Godward LLP is contained in Exhibit 5.1 to this Registration Statement.
  24.1     Power of Attorney is contained on the signature page.
  99.1     2000 Equity Incentive Plan, as amended.(1)
  99.2     Form of Stock Option Agreement(1)
</TABLE>
(1) Incorporated by reference to the Form 10-K filed on April 2, 2001 for the
    year ended December 31, 2000.

                                  UNDERTAKINGS


Item 9.  Undertakings.

  The undersigned Registrant hereby undertakes:

     (1)  To file, during any period in which offers or sales are being made, a
post-effective amendment to this Registration Statement to include any material
information with respect to the plan of distribution not previously disclosed in
this Registration Statement or any material change to such information in the
Registration Statement;

     (2)  That, for the purpose of determining any liability under the
Securities Act, each such post-effective amendment shall be deemed to be a new
registration statement relating to the securities offered therein, and the
offering of such securities at that time shall be deemed to be the initial bona
fide offering thereof;

     (3)  To remove from registration by means of a post-effective amendment any
of the securities being registered which remain unsold at the termination of the
offering; and

     (4)  That, for purposes of determining any liability under the Securities
Act, each filing of the Registrant's annual report pursuant to Section 13(a) or
Section 15(d) of the Exchange Act (and, where applicable, each filing of an
employee benefit plan's annual report pursuant to Section 15(d) of the Exchange
Act) that is incorporated by reference in the Registration Statement shall be
deemed to be a new registration statement relating to the securities offered
therein, and the offering of such securities at that time shall be deemed to be
the initial bona fide offering thereof.

     Insofar as indemnification for liabilities arising under the Securities Act
may be permitted to directors, officers and controlling persons of the
Registrant pursuant to the foregoing provisions or otherwise, the Registrant has
been advised that in the opinion of the Commission such indemnification is
against public policy as expressed in the Securities Act, and is, therefore,
unenforceable.  In the event that a claim for indemnification against such
liabilities (other than the payment by the Registrant of expenses incurred or
paid by a director, officer or controlling person of the Registrant in the
successful defense of any action, suit or proceeding) is asserted by such
director,
<PAGE>

officer or controlling person in connection with the securities being
registered, the Registrant will, unless in the opinion of its counsel the matter
has been settled by controlling precedent, submit to a court of appropriate
jurisdiction the question whether such indemnification by it is against public
policy as expressed in the Securities Act and will be governed by the final
adjudication of such issue.
<PAGE>

                                   SIGNATURES

     Pursuant to the requirements of the Securities Act of 1933, as amended, the
Registrant certifies that it has reasonable grounds to believe that it meets all
of the requirements for filing on Form S-8 and has duly caused this Registration
Statement to be signed on its behalf by the undersigned, thereunto duly
authorized, in the City of San Diego, State of California, on April 18, 2001.

                                    Cypress Bioscience, Inc.

                                    By:            /s/ Jay D. Kranzler
                                       -------------------------------

                                    Title:  Chief Executive Officer
                                          -------------------------------------


                               POWER OF ATTORNEY

     Know to All Persons By These Presents, that each person whose signature
appears below constitutes and appoints Jay D. Kranzler, M.D., Ph.D., as his true
and lawful attorney-in-fact and agent, with full power of substitution and
resubstitution, for him and in his name, place and stead, in any and all
capacities, to sign any and all amendments (including post-effective amendments)
to this Registration Statement, and to file the same, with all exhibits thereto,
and other documents in connection therewith, with the Securities and Exchange
Commission, granting unto said attorney-in-fact and agent, full power and
authority to do and perform each and every act and thing requisite and necessary
to be done in connection therewith, as fully to all intents and purposes as he
might or could do in person, hereby ratifying and confirming all that said
attorney-in-fact and agent, or his substitutes or substitute, may lawfully do or
cause to be done by virtue thereof.

     Pursuant to the requirements of the Securities Act of 1933, as amended,
this Registration Statement has been signed by the following persons in the
capacities and on the dates indicated.

<TABLE>
<CAPTION>
                 Signature                              Title                              Date
<S>                                          <C>                                      <C>
        /s/  Jay D. Kranzler                 Chief Executive Officer, Chief           April 18, 2001
-------------------------------------------  Financial Officer, Chairman of the
      (Jay D. Kranzler, M.D., Ph.D.)         Board (Principal Executive and
                                             Accounting Officer)


        /s/  Samuel D. Anderson              Director                                 April 18, 2001
-------------------------------------------
           (Samuel D. Anderson)


          /s/  Larry J. Kessel               Director                                 April 18, 2001
-------------------------------------------
           (Larry J. Kessel, M.D.)
</TABLE>
<PAGE>

<TABLE>

<S>                                         <C>                                       <C>
                                             Director                                 April   , 2001
-------------------------------------------
           (Charles Nemeroff)


        /s/  Jack H. Vaughn                  Director                                 April 18, 2001
-------------------------------------------
(Jack H. Vaughn)
</TABLE>
<PAGE>

                                 EXHIBIT INDEX

<TABLE>
<CAPTION>

Exhibit
Number                                       Description
---------                                    -----------
<C>        <S>
   5.1     Opinion of Cooley Godward LLP.
  23.1     Consent of Ernst & Young LLP.
  23.2     Consent of Cooley Godward LLP is contained in Exhibit 5.1 to this Registration Statement.
  24.1     Power of Attorney is contained on the signature page.
  99.1     2000 Equity Incentive Plan, as amended.(1)
  99.2     Form of Stock Option Agreement.(1)
</TABLE>

(1) incorporated by reference to the Form 10-K filed on April 2, 2001 for the
    year ended December 31, 2000.
[{"type": "S-8", "sequence": "1", "filename": "ds8.txt", "description": "FORM S-8", "secsgml_size_bytes": 14720}]
{"company-data": {"conformed-name": "CYPRESS BIOSCIENCE INC", "cik": "0000716054", "assigned-sic": "2836", "irs-number": "222389839", "state-of-incorporation": "DE", "fiscal-year-end": "1231"}, "filing-values": {"form-type": "S-8", "act": "33", "file-number": "333-59164", "film-number": "1605791"}, "business-address": {"street1": "4350 EXECUTIVE DRIVE,SUITE 325", "city": "SAN DIEGO", "state": "CA", "zip": "92121", "phone": "2062989400"}, "mail-address": {"street1": "401 QUEEN ANNE AVE NORTH", "city": "SEATTLE", "state": "WA", "zip": "98109"}, "former-company": {"former-conformed-name": "IMRE CORP", "date-changed": "19920703"}}
As filed with the Securities and Exchange Commission on April 18, 2001
Registration No. 333-
================================================================================

                       SECURITIES AND EXCHANGE COMMISSION
                             Washington, D.C. 20549

                          ----------------------------

                                    FORM S-8
                             REGISTRATION STATEMENT
                                     UNDER
                           THE SECURITIES ACT OF 1933

                         -----------------------------

                            CYPRESS BIOSCIENCE, INC.
             (Exact name of registrant as specified in its charter)

       Delaware                                          22-2389839
(State of Incorporation)                    (I.R.S. Employer Identification No.

                          ----------------------------

                        4350 Executive Drive, Suite 325
                              San Diego, CA 92121
                    (Address of principal executive offices)

                         -----------------------------
                     2000 Equity Incentive Plan, As Amended
                           (Full title of the plans)

                          Jay D. Kranzler, Ph.D., M.D.
                            Chief Executive Officer
                            Cypress Bioscience, Inc.
                        4350 Executive Drive, Suite 325
                              San Diego, CA 92121
                                 (858) 452-2323
 (Name, address, including zip code, and telephone number, including area code,
                             of agent for service)

                          ----------------------------

                                   Copies to:
                            Frederick T. Muto, Esq.
                            Denise L. Woolard, Esq.
                               Cooley Godward LLP
                        4365 Executive Drive, Suite 1100
                              San Diego, CA 92121
                                 (858) 550-6000

                          ----------------------------
CALCULATION OF REGISTRATION FEE
==============================================================================================================================
                                                                    Proposed Maximum     Proposed Maximum
      Title of Securities                                               Offering            Aggregate          Amount of
       to be Registered              Amount to be Registered (1)    Price per Share (2)  Offering Price (1)  Registration Fee
-----------------------------------------------------------------------------------------------------------------------------
Stock Options and Common Stock
 (par value $.02)                         562,500 shares                 $0.785             $441,562.50          $110.39
=============================================================================================================================
(1)  Includes 562,500 shares issuable pursuant to Registrant's 2000 Equity
     Incentive Plan, as amended.

(2)  Estimated solely for the purpose of calculating the amount of the
     registration fee pursuant to Rule 457(c) and Rule 457 (h)(1) of the
     Securities Act of 1933, as amended (the "Securities Act").  The price per
     share and aggregate offering price are calculated on the basis of the
     average of the high and low sales prices of Registrant's Common Stock on
     April 11, 2001, as reported on The Nasdaq SmallCap Market.
INCORPORATION OF CERTAIN DOCUMENTS BY REFERENCE

     The following documents filed by Cypress Bioscience, Inc. (the "Company")
with the Securities and Exchange Commission (the "SEC") are incorporated by
reference into this Registration Statement except as modified or superseded or
modified herein:

     (a)  The Company's 10-K for the year ended December 31, 2000.

     (b)  Form 8-A containing a description of the Company's securities.

     All reports and other documents subsequently filed by the Company pursuant
to Sections 13(a), 13(c), 14 and 15(d) of the Securities Exchange Act of 1934,
as amended, prior to the filing of a post-effective amendment which indicates
that all securities offered have been sold or which deregisters all securities
then remaining unsold, shall be deemed to be incorporated by reference herein
and to be a part of this registration statement from the date of the filing of
such reports and documents.

                           DESCRIPTION OF SECURITIES

     Not applicable.

                     INTERESTS OF NAMED EXPERTS AND COUNSEL

     Not applicable.
INDEMNIFICATION OF DIRECTORS AND OFFICERS

     Section 145 of the General Corporation Law of the State of Delaware (the
"Delaware Law") empowers a Delaware corporation to indemnify any persons who
are, or are threatened to be made, parties to any threatened, pending or
completed legal action, suit or proceeding, whether civil, criminal,
administrative or investigative (other than an action by or in the right of such
corporation), by reason of the fact that such person was an officer or director
of such corporation, or is or was serving at the request of such corporation as
a director, officer, employee or agent of another corporation or enterprise.
The indemnity may include expenses (including attorneys' fees), judgments, fines
and amounts paid in settlement of such action, suit or proceeding, provided that
such officer or director acted in good faith and in a manner he or she
reasonably believed to be in or not opposed to the corporation's best interest,
and, for criminal proceedings, had no reasonable cause to believe his or her
conduct was illegal.  A Delaware corporation may indemnify officers and
directors against expenses (including attorney's fees) in connection with the
defense or settlement of an action by or in the right of the corporation under
the same conditions, except that no indemnification is permitted without
judicial approval if the officer or director is adjudged to be liable to the
corporation.  Where an officer or director is successful on the merits or
otherwise in the defense of any action referred to above, the corporation must
indemnify him or her against the expenses which such officer or director
actually and reasonably incurred.

     The Company's Bylaws provide that the Company will indemnify its directors
and executive officers and may indemnify its other officers, employees and other
agents to the fullest extent permitted by Delaware Law. The Company is also
empowered under its bylaws to enter into indemnification contracts with its
directors and officers and to purchase insurance on behalf of any person who it
is required or permitted to indemnify. Pursuant to this provision, the Company
has entered into indemnity agreements with each of its directors and officers
and currently maintains directors and officers insurance coverage.

                      EXEMPTION FROM REGISTRATION CLAIMED

      Not applicable.
EXHIBITS
Exhibit
Number     Description
------     -----------
5.1     Opinion of Cooley Godward LLP.
  23.1     Consent of Ernst & Young LLP, Independent Auditors.
  23.2     Consent of Cooley Godward LLP is contained in Exhibit 5.1 to this Registration Statement.
  24.1     Power of Attorney is contained on the signature page.
  99.1     2000 Equity Incentive Plan, as amended.(1)
  99.2     Form of Stock Option Agreement(1)
(1) Incorporated by reference to the Form 10-K filed on April 2, 2001 for the
    year ended December 31, 2000.

                                  UNDERTAKINGS

Item 9.  Undertakings.

  The undersigned Registrant hereby undertakes:

     (1)  To file, during any period in which offers or sales are being made, a
post-effective amendment to this Registration Statement to include any material
information with respect to the plan of distribution not previously disclosed in
this Registration Statement or any material change to such information in the
Registration Statement;

     (2)  That, for the purpose of determining any liability under the
Securities Act, each such post-effective amendment shall be deemed to be a new
registration statement relating to the securities offered therein, and the
offering of such securities at that time shall be deemed to be the initial bona
fide offering thereof;

     (3)  To remove from registration by means of a post-effective amendment any
of the securities being registered which remain unsold at the termination of the
offering; and

     (4)  That, for purposes of determining any liability under the Securities
Act, each filing of the Registrant's annual report pursuant to Section 13(a) or
Section 15(d) of the Exchange Act (and, where applicable, each filing of an
employee benefit plan's annual report pursuant to Section 15(d) of the Exchange
Act) that is incorporated by reference in the Registration Statement shall be
deemed to be a new registration statement relating to the securities offered
therein, and the offering of such securities at that time shall be deemed to be
the initial bona fide offering thereof.

     Insofar as indemnification for liabilities arising under the Securities Act
may be permitted to directors, officers and controlling persons of the
Registrant pursuant to the foregoing provisions or otherwise, the Registrant has
been advised that in the opinion of the Commission such indemnification is
against public policy as expressed in the Securities Act, and is, therefore,
unenforceable.  In the event that a claim for indemnification against such
liabilities (other than the payment by the Registrant of expenses incurred or
paid by a director, officer or controlling person of the Registrant in the
successful defense of any action, suit or proceeding) is asserted by such
director,
officer or controlling person in connection with the securities being
registered, the Registrant will, unless in the opinion of its counsel the matter
has been settled by controlling precedent, submit to a court of appropriate
jurisdiction the question whether such indemnification by it is against public
policy as expressed in the Securities Act and will be governed by the final
adjudication of such issue.
SIGNATURES

     Pursuant to the requirements of the Securities Act of 1933, as amended, the
Registrant certifies that it has reasonable grounds to believe that it meets all
of the requirements for filing on Form S-8 and has duly caused this Registration
Statement to be signed on its behalf by the undersigned, thereunto duly
authorized, in the City of San Diego, State of California, on April 18, 2001.

                                    Cypress Bioscience, Inc.

                                    By:            /s/ Jay D. Kranzler
                                       -------------------------------

                                    Title:  Chief Executive Officer
                                          -------------------------------------

                               POWER OF ATTORNEY

     Know to All Persons By These Presents, that each person whose signature
appears below constitutes and appoints Jay D. Kranzler, M.D., Ph.D., as his true
and lawful attorney-in-fact and agent, with full power of substitution and
resubstitution, for him and in his name, place and stead, in any and all
capacities, to sign any and all amendments (including post-effective amendments)
to this Registration Statement, and to file the same, with all exhibits thereto,
and other documents in connection therewith, with the Securities and Exchange
Commission, granting unto said attorney-in-fact and agent, full power and
authority to do and perform each and every act and thing requisite and necessary
to be done in connection therewith, as fully to all intents and purposes as he
might or could do in person, hereby ratifying and confirming all that said
attorney-in-fact and agent, or his substitutes or substitute, may lawfully do or
cause to be done by virtue thereof.

     Pursuant to the requirements of the Securities Act of 1933, as amended,
this Registration Statement has been signed by the following persons in the
capacities and on the dates indicated.
Signature                              Title                              Date
/s/  Jay D. Kranzler                 Chief Executive Officer, Chief           April 18, 2001
-------------------------------------------  Financial Officer, Chairman of the
      (Jay D. Kranzler, M.D., Ph.D.)         Board (Principal Executive and
                                             Accounting Officer)

        /s/  Samuel D. Anderson              Director                                 April 18, 2001
-------------------------------------------
           (Samuel D. Anderson)

          /s/  Larry J. Kessel               Director                                 April 18, 2001
-------------------------------------------
           (Larry J. Kessel, M.D.)
Director                                 April   , 2001
-------------------------------------------
           (Charles Nemeroff)

        /s/  Jack H. Vaughn                  Director                                 April 18, 2001
-------------------------------------------
(Jack H. Vaughn)
EXHIBIT INDEX
Exhibit
Number                                       Description
---------                                    -----------
5.1     Opinion of Cooley Godward LLP.
  23.1     Consent of Ernst & Young LLP.
  23.2     Consent of Cooley Godward LLP is contained in Exhibit 5.1 to this Registration Statement.
  24.1     Power of Attorney is contained on the signature page.
  99.1     2000 Equity Incentive Plan, as amended.(1)
  99.2     Form of Stock Option Agreement.(1)
(1) incorporated by reference to the Form 10-K filed on April 2, 2001 for the
    year ended December 31, 2000.